Pippa Corrie

Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.

<h2>Summary</h2><h3>Background</h3> We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. <h3>Methods</h3> TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m², 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m² orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2–4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. <h3>Findings</h3> The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4–12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1–8·8] <i>vs</i> 6·9 months [6·4–7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97–1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3–9·7], HR 1·05, 98·25% CI 0·85–1·29, p=0·64; overall log-rank of χ²_2df=4·3; p=0·11). The commonest grade 3–4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). <h3>Interpretation</h3> Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. <h3>Funding</h3> Cancer Research UK and KAEL-GemVax.

Cisplatin and gemcitabine is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer; expression of VEGF and its receptors is associated with adverse outcomes. We aimed to assess the effect of the addition of cediranib (an oral inhibitor of VEGF receptor 1, 2, and 3) to cisplatin and gemcitabine on progression-free survival.In this multicentre, placebo-controlled, randomised phase 2 study, we recruited patients aged 18 years or older with histologically confirmed or cytologically confirmed advanced biliary tract cancer from hepatobiliary oncology referral centres in the UK. Patients were eligible if they had an ECOG performance status of 0-1 and an estimated life expectancy of longer than 3 months. Patients were given first-line cisplatin and gemcitabine chemotherapy (25 mg/m(2) cisplatin and 1000 mg/m(2) gemcitabine [on days 1 and 8 every 21 days, for up to eight cycles]) with either 20 mg oral cediranib or placebo once a day until disease progression. We randomly assigned patients (1:1) with a minimisation algorithm, incorporating the stratification factors: extent of disease, primary disease site, previous treatment, ECOG performance status, and centre. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00939848, and was closed on Sept 30, 2014; results of the final analysis for the primary endpoint are presented.Between April 5, 2011, and Sept 28, 2012, we enrolled 124 patients (62 in each group). With a median follow-up of 12·2 months (IQR 7·3-18·5), median progression-free survival was 8·0 months (95% CI 6·5-9·3) in the cediranib group and 7·4 months (5·7-8·5) in the placebo group (HR 0·93, 80% CI 0·74-1·19, 95% CI 0·65-1·35; p=0·72). Patients who received cediranib had more grade 3-4 toxic effects than did patients who received placebo: hypertension (23 [37%] vs 13 [21%]; p=0·05), diarrhoea (eight [13%] vs two [3%]; p=0·05); platelet count decreased (ten [16%] vs four [6%]; p=0·09), white blood cell decreased (15 [24%] vs seven [11%]; p=0·06) and fatigue (16 [24%] vs seven [11%]; p=0·04).Cediranib did not improve the progression-free survival of patients with advanced biliary tract cancer in combination with cisplatin and gemcitabine, which remains the standard of care. Although patients in the cediranib group had more adverse events, we recorded no unexpected toxic effects. The role of VEGF inhibition in addition to chemotherapy for patients with advanced biliary tract cancer remains investigational.Cancer Research UK and AstraZeneca Pharmaceuticals.

Integration of variant reads across patient-specific mutation loci enables sensitive ctDNA quantification in plasma cell-free DNA sequencing data.

<h2>Abstract</h2> Cytotoxic chemotherapy drugs primarily damage proliferating cells and we now know the molecular target of most of the drugs in clinical use. Even so, non-specificity of cytotoxic agents is a major drawback and potential to damage normal tissues means that cure with chemotherapy is not often achieved. With advances in science, rational drug design is now becoming a reality, but these mechanism-driven, targeted agents are likely to be additions to, rather than substitutes for, conventional chemotherapy drugs. As cancer treatment becomes increasingly complex, the challenge for clinicians and scientists now is to manipulate our treatments to maximize benefit and minimize harm for the individual patient.

The outlook for patients with advanced pancreatic cancer remains poor, despite significant advances in our understanding of pancreatic tumor biology. One emerging theme highlights the distinct composition of the pancreatic tumor microenvironment. Hyaluronic acid is a hydrophilic glycosaminoglycan whose production within the tumor leads to increased interstitial tumor pressure, thereby limiting the access of potentially effective circulating anticancer drugs via reduced tumor perfusion. PEGylated rHuPH20 is a multiply PEGylated recombinant human hyaluronidase that has shown promising efficacy in preclinical models and early phase clinical trials in pancreatic cancer patients. Here, we discuss these findings, and the rationale for the ongoing randomized Phase III trial (HALO-109-301), which seeks to definitively define the efficacy of PEGylated rHuPH20 alongside gemcitabine and nab-paclitaxel in previously untreated, hyaluronic acid-high, stage IV pancreatic cancer.

IntroductionHepatotoxicity from T-cell checkpoint blockade is an increasingly common immune-related adverse event, but remains poorly characterised and can be challenging to manage. Such toxicity is generally considered to resemble autoimmune hepatitis, although this assumption is extrapolated from limited clinicopathological reports of anti-cytotoxic T-lymphocyte-associated protein 4-induced hepatotoxicity.MethodsHere we report, with full clinicopathological correlation, three cases of T-cell checkpoint inhibitor-induced hepatotoxicity associated with anti-programmed cell death protein 1 agents.ResultsWe find that a major feature of these cases is biliary injury, including a unique case of vanishing bile duct syndrome, and that such toxicity was poorly responsive to long-term immunosuppression (corticosteroids and mycophenolate mofetil). Any potential benefits of long-term immunosuppression in these cases were outweighed by therapy-related complications.DiscussionWe discuss potential aetiologies and risk factors for immune-mediated biliary toxicity in the context of the limited literature in this field, and provide guidance for the investigation and supportive management of affected patients.

To enable standardisation of care of pancreatic cancer patients and facilitate improvement in outcome, the United Kingdom's National Institute for Health and Care Excellence (NICE) developed a clinical guideline for the diagnosis and management of pancreatic cancer in adults. Systematic literature searches, systematic review and meta-analyses were undertaken. Recommendations were drafted on the basis of the group's interpretation of the best available evidence of clinical and cost effectiveness. There was patient involvement and public consultation. Recommendations were made on: diagnosis; staging; monitoring of inherited high risk; psychological support; pain; nutrition management; and the specific management of people with resectable-, borderline-resectable- and unresectable-pancreatic cancer. The guideline committee also made recommendations for future research into neoadjuvant therapy, cachexia interventions, minimally invasive pancreatectomy, pain management and psychological support needs. These NICE guidelines aim to promote best current practice and support and stimulate research and innovation in pancreatic cancer.

Melanomas can have multiple coexisting cell states, including proliferative (PRO) versus invasive (INV) subpopulations that represent a “go or grow” trade-off; however, how these populations interact is poorly understood. Using a combination of zebrafish modeling and analysis of patient samples, we show that INV and PRO cells form spatially structured heterotypic clusters and cooperate in the seeding of metastasis, maintaining cell state heterogeneity. INV cells adhere tightly to each other and form clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation in which INV cells facilitate dissemination of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of clustering and PRO/INV states. Isolation of clusters from patients with metastatic melanoma revealed a subset with heterotypic PRO-INV clusters. Our data suggest a framework for the co-existence of these two divergent cell populations, in which heterotypic clusters promote metastasis via cell-cell cooperation.

<h3>Importance</h3> Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. <h3>Objective</h3> To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. <h3>Design, Setting, and Participants</h3> The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. <h3>Exposures</h3> SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. <h3>Main Outcomes and Measures</h3> The primary end point was all-cause mortality within the primary hospitalization. <h3>Results</h3> Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19–related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). <h3>Conclusions and Relevance</h3> The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed.

In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42 % of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen.

Melanoma is a leading cause of lost productivity due to premature cancer mortality. Melanoma frequently spreads to the brain and is associated with rapid deterioration in quality and quantity of life. Until now, treatment options have been restricted to surgery and radiotherapy, although neither modality has been well studied in clinical trials. However, the new immune checkpoint inhibitors and molecularly targeted agents that have been introduced for treatment of metastatic melanoma are active against brain metastases and offer new opportunities to improve disease outcomes. New challenges arise, including how to integrate or sequence multiple treatment modalities, and current practice varies widely. In this Review, we summarise evidence for the treatment of melanoma brain metastases, and discuss the rationale and evidence for combination modalities, highlighting areas for future research.

<h3>Objective</h3> This article explores how people with pancreatic cancer interpreted prediagnostic signs and symptoms, and what triggered them to seek medical help for symptoms that occurred intermittently. <h3>Design</h3> Thematic analysis of prediagnostic symptom descriptions drawn from a qualitative interview study of people with experiences of pancreatic cancer. <h3>Participants</h3> 40 people affected by pancreatic cancer (32 patients and 8 relatives of people who had died). Age at interview ranged from 35 to 84 years; 55% were men; and 57.5% of patients had been offered potentially curative surgery. <h3>Setting</h3> Respondents interviewed at home were recruited from different parts of the UK during 2009/2010. <h3>Results</h3> Analysis of the interviews suggested that <i>intermittent</i> symptoms were not uncommon in the months, or even years, before diagnosis but that the fact that the symptom did not persist was often taken by the patient as a reassuring indicator that it could not be ‘very important’. Such symptoms were rarely acted upon until a pattern became apparent, the frequency of symptom episodes increased, there was a change in the nature of the intermittent symptoms or additional symptom(s) appeared. These findings build on social science theories of consultation behaviour. <h3>Conclusions</h3> Our study—the largest reported collection of qualitative interviews with people with pancreatic cancer—reports for the first time that symptoms of an intermittent nature may precede a pancreatic cancer diagnosis. Patients (and potentially their doctors as well) may be falsely reassured by symptoms that come and go. Pancreatic cancer might be identified at a stage where curative treatment is more likely if there were greater awareness that intermittent gastrointestinal symptoms can have a serious cause, and if patients with intermittent pancreatitis-like symptoms were investigated more readily.

Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer.The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus gemcitabine (vandetanib group) or placebo plus gemcitabine (placebo group) according to pre-generated sequences produced on the principle of randomly permuted blocks with variable block sizes of two and four. Patients were stratified at randomisation by disease stage and ECOG performance status. All patients received gemcitabine 1000 mg/m2 as a 30-min intravenous infusion, weekly, for 7 weeks followed by a 1-week break, followed by a cycle of 3 weeks of treatment with a 1-week break, until disease progression, and either oral vandetanib 300 mg per day once daily or matching placebo. Patients and investigators were masked to treatment assignment. The primary outcome measure was overall survival (defined as the difference in time between randomisation and death from any cause or the censor date) in the intention-to-treat population. This trial has been completed and the final results are reported. The study is registered at EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434.Patients were screened and enrolled between Oct 24, 2011, and Oct 7, 2013. Of 381 patients screened, 142 eligible patients were randomly assigned to treatment (72 to the vandetanib group and 70 to the placebo group). At database lock on July 15, 2015, at a median follow-up of 24·9 months (IQR 24·3 to not attainable), 131 patients had died: 70 (97%) of 72 in the vandetanib group and 61 (87%) of 70 in the placebo group. The median overall survival was 8·83 months (95% CI 7·11-11·58) in the vandetanib group and 8·95 months (6·55-11·74) in the placebo group (hazard ratio 1·21, 80·8% CI 0·95-1·53; log rank χ21df 1·1, p=0·303). The most common grade 3-4 adverse events were neutropenia (35 [49%] of 72 patients in the vandetanib group vs 22 [31%] of 70 in the placebo group), thrombocytopenia (20 [28%] vs 16 [23%]), hypertension (nine [13%] vs 11 [16%]), leucopenia (12 [17%] vs 13 [19%]), and fatigue (17 [24%] vs 15 [21%]). No treatment-related deaths occurred during the study.The addition of vandetanib to gemcitabine monotherapy did not improve overall survival in advanced pancreatic cancer. Tyrosine kinase inhibitors might still have potential in the treatment of pancreatic cancer but further development requires the identification of biomarkers to specifically identify responsive cancer subtypes.Cancer Research UK and AstraZeneca.

Cytotoxic chemotherapy is widely used for advanced, unresectable pancreatic and other gastrointestinal foregut neuroendocrine tumours (NETs) and the most commonly used regimen combines 5-fluorouracil with streptozocin. The NET01 trial was designed to investigate whether capecitabine combined with streptozocin was an acceptable regimen with or without adding cisplatin.Patients with advanced, unresectable NETs of pancreatic, gastrointestinal foregut or unknown primary site were randomised to receive three-weekly capecitabine (Cap) 625 mg/m(2) twice daily orally, streptozocin (Strep) 1.0 g/m(2) intravenously on day 1, with or without cisplatin (Cis) 70 mg/m(2) intravenously on day 1. The primary outcome measure was objective response. Secondary outcome measures included progression-free and overall survival, quality of life, toxicity and biochemical response.86 (44 CapStrep, 42 CapStrepCis) patients were randomised. Best objective response rate was 12% (95% confidence interval (CI)=2-22%) with CapStrep and 16% (95% CI=4-27.4%) with CapStrepCis. Disease-control rate was 80% with CapStrep and 74% with CapStrepCis. The estimated median progression-free and overall survival were 10.2 and 26.7 months for CapStrep and 9.7 and 27.5 months for CapStrepCis. 44% of CapStrep and 68% of CapStrepCis patients experienced grade ≥3 adverse events.The efficacies of the novel CapStrep±Cis regimens were very similar. CapStrep was better tolerated than CapStrepCis. The trial was registered as EudraCT: 2004-005202-71 and ISRCTN: 35124268.

Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10-5) and overall survival (HR = 1.61, p = 1.67 × 10-4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC = 7.03 × 10-4), or published prognostic signatures (pAUROC < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = -0.75, p < 2.2 × 10-16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.

Blockade of vascular endothelial growth factor (VEGF) signaling with bevacizumab, a humanized anti-VEGF monoclonal antibody (mAb), or with receptor tyrosine kinase inhibitors, has improved progression-free survival and, in some indications, overall survival across several types of cancers by interrupting tumor angiogenesis. However, the clinical benefit conferred by these therapies is variable, and tumors from treated patients eventually reinitiate growth. Previously we demonstrated, in mouse tumor models, that galectin-1 (Gal1), an endogenous glycan-binding protein, preserves angiogenesis in anti-VEGF-resistant tumors by co-opting the VEGF receptor (VEGFR)2 signaling pathway in the absence of VEGF. However, the relevance of these findings in clinical settings is uncertain. Here, we explored, in a cohort of melanoma patients from AVAST-M, a multicenter, open-label, randomized controlled phase 3 trial of adjuvant bevacizumab versus standard surveillance, the role of circulating plasma Gal1 as part of a compensatory mechanism that orchestrates endothelial cell programs in bevacizumab-treated melanoma patients. We found that increasing Gal1 levels over time in patients in the bevacizumab arm, but not in the observation arm, significantly increased their risks of recurrence and death. Remarkably, plasma Gal1 was functionally active as it was able to reprogram endothelial cell biology, promoting migration, tubulogenesis, and VEGFR2 phosphorylation. These effects were prevented by blockade of Gal1 using a newly developed fully human anti-Gal1 neutralizing mAb. Thus, using samples from a large-scale clinical trial from stage II and III melanoma patients, we validated the clinical relevance of Gal1 as a potential mechanism of resistance to bevacizumab treatment.

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0–1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

Sirs, we read with interest the work of Walter and colleagues. 1 Walter T. Horgan A.M. McNamara M. et al. Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: a large retrospective study. Eur J Cancer. 2013; 49: 329-335 Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar We conducted a retrospective audit of patients undergoing second line chemotherapy at institutions across the UK that used the ABC02 standard of Cisplatin and Gemcitabine (CisGem) as first line treatment. 2 Valle J. Wasan H. Palmer D.H. et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010; 362: 1273-1281 Crossref PubMed Scopus (3055) Google Scholar Sixty-three patients were treated in second line with platinum based regimen, either a re-challenge of CisGem or an oxaliplatin and infused 5FU regimen although some patients received fluoropyrimidine or Gemcitabine alone. Patients with performance status 0–1 constituted 72% (Table 1). Table 1Results. Median progression free survival (PFS) following 1st line treatment 10.6 (95% CI: 9.8–12.6) months Median PFS following 2nd line treatment 4.0 (95% CI: 3.3–5.6) months Overall survival (OS) 19.5 (95% CI: 17.0–25.2) months Survival following 1st line progression 8.1 (95% CI: 5.3–11.4) months Open table in a new tab Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: A large retrospective studyEuropean Journal of CancerVol. 49Issue 2PreviewFirst-line chemotherapy (CT1) is effective in advanced biliary tract cancer (ABTC). The benefits of second-line chemotherapy (CT2) are unclear. Full-Text PDF

Recent advances in the study and clinical applications of circulating tumor DNA (ctDNA) are limited by practical considerations of sample collection. Whole-genome sequencing (WGS) is increasingly used for analysis of ctDNA, identifying copy-number alterations and fragmentation patterns. We hypothesized that low-depth/shallow WGS (sWGS) data may be generated from minute amounts of cell-free DNA, and that fragment-size selection may remove contaminating genomic DNA from small blood volumes. Dried blood spots have practical advantages for sample collection, may facilitate serial sampling, and could support novel study designs in humans and animal models.We developed a protocol for the isolation and analysis of cell-free DNA from dried blood spots using filter paper cards and bead-based size selection. DNA extracted and size-selected from dried spots was analyzed using sWGS and polymerase chain reaction (PCR).Analyzing a 50 μL dried blood spot from frozen whole blood of a patient with melanoma, we identified ctDNA based on the presence of tumor-specific somatic copy-number alterations, and found a fragment-size profile similar to that observed in plasma DNA. We found alterations in different chromosomes in blood spots from 2 patients with high-grade serous ovarian carcinoma. Extending this approach to serial dried blood spots from mouse xenograft models, we detect tumor-derived cell-free DNA and identified ctDNA from the originally grafted ascites.Our data suggest that ctDNA can be detected and monitored in dried blood spots from archived and fresh blood samples, enabling new approaches for sample collection and novel study/trial designs for both patients and in vivo models.

These guidelines for management of cutaneous melanoma present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation. To reflect the collaborative process for the UK, they are subject to dual publication in the British Journal of Dermatology and the British Journal of Plastic Surgery.

Current practice to diagnose pancreatic cancer is accomplished by endoscopic ultrasound guided fine needle aspiration (EUS–FNA) using a cytological approach. This method is time consuming and often fails to provide suitable specimens for modern molecular analyses. Here, we compare the cytological approach with direct formalin fixation of pancreatic EUS–FNA micro-cores and evaluate the potential to perform molecular biomarker analysis on these specimen. 130 specimens obtained by EUS–FNA with a 22G needle were processed by the standard cytological approach and compared to a separate cohort of 130 specimens that were immediately formalin fixed to preserve micro-cores of tissue prior to routine histological processing. We found that direct formalin fixation significantly shortened the time required for diagnosis from 3.6 days to 2.9 days (p < 0.05) by reducing the average time (140 vs 33 min/case) and number of slides (9.65 vs 4.67 slides/case) for histopathological processing. Specificity and sensitivity yielded comparable results between the two approaches (82.3% vs 77% and 90.9% vs 100%). Importantly, EUS–FNA histology preserved the tumour tissue architecture with neoplastic glands embedded in stroma in 67.89% of diagnostic cases compared to 27.55% with the standard cytological approach (p < 0.001). Furthermore, micro-core samples were suitable for molecular studies including the immunohistochemical detection of intranuclear Hes1 in malignant cells, and the laser-capture microdissection-mediated measurement of Gli-1 mRNA in tumour stromal myofibroblasts. Direct formalin fixation of pancreatic EUS–FNA micro-cores demonstrates superiority regarding diagnostic delay, costs, and specimen suitability for molecular studies. We advocate this approach for future investigational trials in pancreatic cancer patients.

&lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; The combination of 5-fluorouracil (5-FU), irinotecan and oxaliplatin (FOLFIRINOX) is considered the first-line chemotherapy for fit patients with advanced pancreatic ductal adenocarcinoma (PDAC) but carries an unfavourable adverse event (AE) profile. We retrospectively evaluated the tolerability and efficacy of a modified FOLFIRINOX (mFOLFIRINOX) regimen: intravenous oxaliplatin 85 mg/m&lt;sup&gt;2&lt;/sup&gt;, irinotecan 135 mg/m&lt;sup&gt;2&lt;/sup&gt;, folinic acid 400 mg/m&lt;sup&gt;2&lt;/sup&gt; and 5-FU infusion 2,400 mg/m&lt;sup&gt;2&lt;/sup&gt; over 46 h, with routine subcutaneous filgrastim on a 14-day cycle. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Records of 18 patients with advanced PDAC who received treatment with mFOLFIRINOX were reviewed. Imaging of measurable disease was assessed for response, and survival was measured from the date of commencing chemotherapy to disease progression and/or death. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Grade 3 or 4 AEs (n; %) included vomiting (5; 28), nausea (4; 22), diarrhoea (3; 17) and non-neutropaenic fever (3; 17). For patients with stage IV disease, 12/15 (80%) achieved at least stable disease as the best radiological response, with 7/15 (47%) objective responses. In this subgroup, median overall and progression-free survival were 9.3 months (95% CI 8.3-10.4) and 7.2 months (95% CI 4.7-9.6), respectively. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Compared to full-dose FOLFIRINOX, our modified regimen resulted in lower haematological but only marginally improved non-haematological toxicity rates, with comparable efficacy outcomes. Prospective studies are required to validate these findings.

Abstract Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.

The APACT trial evaluated the safety and efficacy of adjuvant nab -P + Gem vs Gem alone in patients with resected PC. Between April 2014 and April 2016, 866 patients were randomized. As previously reported, APACT did not meet the primary endpoint of independently assessed disease-free survival (DFS); however, the prespecified sensitivity analysis for median investigator-assessed DFS was 16.6 months with nab -P + Gem and 13.7 months with Gem (HR, 0.82; 95% CI, 0.694–0.965; nominal P=0.0168). The overall survival (OS; secondary endpoint) at the time of the primary analysis trended in favor of nab -P + Gem: median 40.5 vs 36.2 months (427 events; 68% mature; HR, 0.82; 95% CI, 0.680–0.996; nominal P=0.045). The post hoc updated follow-up survival analysis outcomes were consistent with those observed in the primary analysis of nab -P + Gem vs Gem: median 41.8 vs 37.7 months (511 events; 81% mature; HR, 0.82; 95% CI, 0.687–0.973; nominal P=0.0232). Safety outcomes as previously presented were consistent with those reported in the treated population for the entire trial. Here, we present updated 5-year OS in the intent-to-treat population. Treatment-naive patients with histologically confirmed pancreatic adenocarcinoma, macroscopic complete resection (R0 or R1), Eastern Cooperative Oncology Group performance status 0 or 1, and carbohydrate antigen 19-9 levels < 100 U/mL were eligible. Stratification factors were resection status (R0 vs R1), lymph node status (positive vs negative) and region (North America, Europe, and Australia vs. Asia Pacific). Treatment was initiated ≤12 weeks postsurgery. Patients received nab-P 125 mg/m2 + Gem 1000 mg/m2 or Gem 1000 mg/m2 on days 1, 8, and 15 of six 28-day cycles. The primary endpoint was DFS by independent review. Secondary endpoints were OS and safety. Treatment-naive patients with histologically confirmed pancreatic adenocarcinoma, macroscopic complete resection (R0 or R1), Eastern Cooperative Oncology Group performance status of 0 or 1, and carbohydrate antigen 19-9 levels nab -P 125 mg/m2 + Gem 1000 mg/m2 or Gem 1000 mg/m2 on days 1, 8, and 15 of six 28-day cycles. The primary endpoint was DFS by independent review. Secondary endpoints were OS and safety. As of the data cutoff date (9 April 2021), all patients had been followed up for ≥5 years or discontinued from the study. The median follow-up time for OS was 63.2 months. In the intent-to-treat population, 268 and 287 events occurred in the nab -P + Gem and Gem arms, respectively (88% mature). The median OS in the nab -P + Gem arm was 41.8 months compared with 37.7 months in the Gem arm (HR, 0.80; 95% CI, 0.678–0.947; nominal P=0.0091). Five-year OS rates were 38% with nab -P + Gem and 31% with Gem. Patterns of OS in the prespecified subgroups were generally consistent with observations from the intent-to-treat population: R0 (HR, 0.85; 95% CI, 0.698–1.034); R1 (HR, 0.73; 95% CI, 0.534–1.003); LN+ (HR, 0.77; 95% CI, 0.636–0.922); LN− (HR, 0.97; 95% CI, 0.667–1.415). The 5-year OS outcomes in the APACT trial were consistent with those observed in both the primary analysis and the prior post hoc updated analysis for nab -P + Gem vs Gem alone. Although APACT did not meet its primary endpoint of independently assessed DFS in the primary analysis, these OS data suggest improved outcomes with nab -P + Gem.

No effective treatment currently exists for metastatic uveal melanoma. However, recent results obtained by an ATP-based tumor chemosensitivity assay have shown consistent activity of treosulfan+gemcitabine in up to 80% of tumor specimens tested. In this study we describe the first clinical results observed with this drug combination at different European centers in patients with metastatic uveal melanoma. Clinical case series of patients with metastatic uveal melanoma were treated with treosulfan+gemcitabine at seven different centers. Fourteen patients, 13 previously untreated and one pretreated with chemoimmunotherapy, were included in the study. Patients received treosulfan+gemcitabine in four different dose regimens. The response rates, progression-free and overall survival, and toxicity were evaluated. The analysis of 14 patients revealed one complete response, three partial responses and a stable disease in eight cases. The objective response rate was 28.6%, the median overall survival was 61 weeks [95% confidence interval (CI) 54–133 weeks], the progression-free survival was 28.5 weeks (95% CI 13–62 weeks) and the 1-year survival rate was 80%. The drugs were well tolerated. The most common side-effects were leuko- and thrombocytopenia. These preliminary results suggest potential therapeutic benefit of treosulfan+gemcitabine treatment in metastatic uveal melanoma and warrant further controlled studies.

The membrane associated MMP, MT1-MMP, is a critical pericellular protease involved in tumour cell invasion and angiogenesis and is highly up-regulated in numerous human cancers. It therefore represents an exciting new therapeutic cancer-specific target. We have generated recombinant human scFv antibodies against the non-catalytic, hemopexin domain of MT1-MMP that modulate its interactions with collagen. One of these is an effective inhibitor of the invasive capacity of cancer cells and of angiogenesis in model systems. This demonstrates that targeting sites outside the catalytic domain presents a potential novel approach to proteinase inhibition that could have applications in cancer therapeutics.

Care closer to home is being explored as a means of improving patient experience as well as efficiency in terms of cost savings. Evidence that community cancer services improve care quality and/or generate cost savings is currently limited. A randomised study was undertaken to compare delivery of cancer treatment in the hospital with two different community settings.Ninety-seven patients being offered outpatient-based cancer treatment were randomised to treatment delivered in a hospital day unit, at the patient's home or in local general practice (GP) surgeries. The primary outcome was patient-perceived benefits, using the emotional function domain of the EORTC quality of life (QOL) QLQC30 questionnaire evaluated after 12 weeks. Secondary outcomes included additional QOL measures, patient satisfaction, safety and health economics.There was no statistically significant QOL difference between treatment in the combined community locations relative to hospital (difference of -7.2, 95% confidence interval: -19·5 to +5·2, P=0.25). There was a significant difference between the two community locations in favour of home (+15·2, 1·3 to 29·1, P=0.033). Hospital anxiety and depression scale scores were consistent with the primary outcome measure. There was no evidence that community treatment compromised patient safety and no significant difference between treatment arms in terms of overall costs or Quality Adjusted Life Year. Seventy-eight percent of patients expressed satisfaction with their treatment whatever their location, whereas 57% of patients preferred future treatment to continue at the hospital, 81% at GP surgeries and 90% at home. Although initial pre-trial interviews revealed concerns among health-care professionals and some patients regarding community treatment, opinions were largely more favourable in post-trial interviews.Patient QOL favours delivering cancer treatment in the home rather than GP surgeries. Nevertheless, both community settings were acceptable to and preferred by patients compared with hospital, were safe, with no detrimental impact on overall health-care costs.

<h3>Importance</h3> Melanoma is among the most lethal skin cancers; it has become the fifth most common cancer in the United Kingdom, and incidence rates are rising. Population approaches to reducing incidence have focused on mass media campaigns to promote earlier presentation and potentially improve melanoma outcomes; however, interventions using smartphone applications targeting those with the greatest risk could promote earlier presentation to health care professionals for individuals with new or changing skin lesions. <h3>Objective</h3> To study the effect of a commercially available skin self-monitoring (SSM) smartphone application among individuals with increased risk of melanoma on their decision to seek help for changing skin lesions. <h3>Design, Setting, and Participants</h3> This phase 2 randomized clinical trial was conducted in 12 family practices in Eastern England between 2016 and 2017. A total of 238 participants, aged 18 to 75 years and with an increased risk of melanoma, were identified using a real-time melanoma risk assessment tool in family practice waiting rooms. Analysis was intention to treat. Participants were observed for 12 months, and data analysis was conducted from January to August 2018. <h3>Intervention</h3> The intervention and control groups received a consultation with standard written advice on sun protection and skin cancer detection. The intervention group had an SSM application loaded on their smartphone and received instructions for use and monthly self-monitoring reminders. <h3>Main Outcomes and Measures</h3> The coprimary outcomes were skin consultation rates with family practice physicians and patient intervals, measured as the time between noticing a skin change and consulting with a family practice clinician. Follow-up questionnaires were sent at 6 and 12 months, and consultation rates were extracted from family practice records. Secondary outcomes included skin self-examination benefits and barriers, self-efficacy for consulting without delay, perceived melanoma risk, sun protection habits, and potential harms. <h3>Results</h3> A total of 238 patients were randomized (median [interquartile range] age, 55 [43-65] years, 131 [55.0%] women, 227 [95.4%] white British; 119 [50.0%] randomized to the intervention group). Overall, 51 participants (21.4%) had consultations regarding skin changes during the 12 months of follow-up, and 157 participants (66.0%) responded to at least 1 follow-up questionnaire. There were no significant differences in skin consultation rates (adjusted risk ratio, 0.96; 95% CI, 0.56 to 1.66;<i>P</i> = .89), measures of SSM (adjusted mean difference, 0.08; 95% CI, −0.83 to 1.00;<i>P</i> = .86), or psychological harm (eg, Melanoma Worry Scale: adjusted mean difference, −0.12; 95% CI, −0.56 to 0.31;<i>P</i> = .58). <h3>Conclusions and Relevance</h3> In this study, recruitment, retention, and initial delivery of the intervention were feasible, and this research provided no evidence of harm from the SSM smartphone application. However, no evidence of benefit on skin self-examination or health care consulting was found, and there is no reason at this stage to recommend its implementation in this population at increased risk of melanoma. <h3>Trial Registration</h3> isrctn.org Identifier:ISRCTN16061621

The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis (NMA).A systematic literature review (SLR) identified studies in Medline, Embase and Cochrane published until November 2020. Screening used prespecified eligibility criteria. Following a transitivity assessment across included studies, Bayesian NMA was conducted.A total of 43 publications reporting 15 targeted therapy trials and 42 reporting 18 immunotherapy trials were retained from the SLR and considered for the NMA. Due to substantial between-study heterogeneity with immunotherapy trials, the analysis considered a network restricted to targeted therapies. Among combination therapies, encorafenib + binimetinib was superior to dabrafenib + trametinib for overall response rate (OR = 1.86; 95 % credible interval [CrI] 1.10, 3.17), superior to vemurafenib + cobimetinib with fewer serious adverse events (SAEs) (OR = 0.51; 95 % CrI 0.29, 0.91) and fewer discontinuations due to AEs (OR = 0.45; 95 % CrI 0.21, 0.96), and superior to atezolizumab + vemurafenib + cobimetinib with fewer SAEs (OR = 0.41; 95 % CrI 0.21, 0.82). Atezolizumab + vemurafenib + cobimetinib and encorafenib + binimetinib were generally comparable for efficacy endpoints. Among double combination therapies, encorafenib + binimetinib showed high probabilities of being better for all efficacy and safety endpoints.This NMA confirms that combination therapies are more efficacious than monotherapies. Encorafenib + binimetinib has a favourable efficacy profile compared to other double combination therapies and a favourable safety profile compared to both double and triple combination therapies.

<h2>Abstract</h2> Cytotoxic chemotherapy drugs damage proliferating cells primarily by interfering with mitosis and we now know the molecular target of most of the drugs in clinical use. Even so, non-specificity of cytotoxic agents is a major drawback and their ability to damage normal as well as malignant cells means that cure with chemotherapy is not often achieved. Various strategies have been adopted to enhance the antitumour effect. These include combining drugs with different mechanisms of action, delivering drug directly to the tumour and overcoming cellular resistance mechanisms. With advances in science, rational drug design is now becoming a reality, and mechanism-driven, targeted anticancer agents are being used alongside conventional cytotoxic chemotherapy. Cancer treatment is therefore increasing in complexity, so the challenge for clinicians and scientists now is to manipulate the various treatment options to maximize benefit and minimize harm for individual patients.

Pyridoxine is frequently used to treat capecitabine-induced hand-foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes.A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily.Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15-1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival.Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.

Angiogenesis is thought to be critical for tumor metastasis. However, inhibiting angiogenesis using antibodies such as bevacizumab (Avastin), has had little impact on melanoma patient survival. We have demonstrated that both angiogenesis and metastasis are increased in older individuals, and therefore sought to investigate whether there was an age-related difference in response to bevacizumab, and if so, what the underlying mechanism could be.We analyzed data from the AVAST-M trial of 1,343 patients with melanoma treated with bevacizumab to determine whether there is an age-dependent response to bevacizumab. We also examined the age-dependent expression of VEGF and its cognate receptors in patients with melanoma, while using syngeneic melanoma animal models to target VEGF in young versus old mice. We also examined the age-related proangiogenic factor secreted frizzled-related protein 2 (sFRP2) and whether it could modulate response to anti-VEGF therapy.We show that older patients respond poorly to bevacizumab, whereas younger patients show improvement in both disease-free survival and overall survival. We find that targeting VEGF does not ablate angiogenesis in an aged mouse model, while sFRP2 promotes angiogenesis in vitro and in young mice. Targeting sFRP2 in aged mice successfully ablates angiogenesis, while the effects of targeting VEGF in young mice can be overcome by increasing sFRP2.VEGF is decreased during aging, thereby reducing response to bevacizumab. Despite the decrease in VEGF, angiogenesis is increased because of an increase in sFRP2 in the aged tumor microenvironment. These results stress the importance of considering age as a factor for designing targeted therapies.

Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 μg m−2. In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44–68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1–29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole–blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.

4080 Background: SP1049C (a block co-polymer incorporating doxorubicin) has demonstrated broad in vitro activity and superior anti-tumour activity in 9/9 in vivo animal tumour models compared to doxorubicin. Methods: Chemotherapy- or radiotherapy-naïve patients with measurable, inoperable, recurrent or metastatic adenocarcinoma of the oesophagus; KP ≥60; normal cardiac LVEF; adequate swallowing and adequate renal, hepatic and bone marrow function were eligible. SP1049C 75mg/m 2 IV 30-minute infusion was given q3w, for up to 6 cycles. Radiological response was assessed after cycles 2, 4 and 6. Upon disease progression (PD) patients were offered standard chemotherapy. QoL (by QLQ-C30 and QLQ-OES24 questionnaires), toxicity, disease-related symptoms and cardiac function were also prospectively assessed. Results: From February 2002 to December 2004, 21 patients (all male), median age 62 years (range 38–78) with stage 3 (n = 1) of stage IV (n = 20) disease were enrolled. Response rate (WHO criteria) in 19 patients eligible for efficacy analysis (radiologically re-assessed after ≥2 cycles of treatment) included: PR 9/19 (47%), SD (8/19) 42% and PD (2/19) 11% by investigator assessment (confirmed PR 41%, unconfirmed PR 12% and SD 29% by independent review, RECIST criteria). One responding patient underwent salvage resection of a pT2N0 (Stage 2A) tumour. All patients are evaluable for toxicity. Toxicity (Gd 1–2/3–4, by patient) included: neutropaenia 24%/62%, leucopaenia 19%/29%, anaemia 38%/5% and thrombocytopaenia 9.5%/0% (resulting in 9 (43%) patients being dose-reduced to 55 mg/m 2 at cycle 2), nausea 81%/19%, vomiting 62%/24%, anorexia 52.4%/14%, lethargy 81%/14%, febrile neutropaenia -/29%, mucositis 48%/5%, and Gd 1–2 alopecia in 67%. Grade I cardiotoxicity (fall in LVEF by 10–19% from baseline, CTC v2.0) was seen in 4 (19%) patients. The median overall survival (all patients) is 10 months; four patients received 2 nd -line chemotherapy. Conclusions: SP1049C appears to have activity in monotherapy in this patient group and combination studies with other active agents are warranted. [Table: see text]

<h3>Abstract</h3> <h3>Objective</h3> Estimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer’s disease. <h3>Methods</h3> In a cohort of 336 older adults, ranging in cognitive functioning, we estimated the time of initial changes of Aβ, tau, and decreases in cognition with respect to the time of Aβ-positivity. <h3>Results</h3> Small effect sizes of change in CSF Aβ42 and regional Aβ PET were estimated to occur several decades before Aβ-positivity. Increases in CSF tau occurred 11-12 years before Aβ-positivity. Temporoparietal tau PET showed increases 4-5 years before Aβ-positivity. Subtle cognitive dysfunction was observed 7-9 years before Aβ-positivity. <h3>Conclusions</h3> Increases in tau and cognitive dysfunction occur years before the presence of significant Aβ. Explicit estimates of the time for these events provide a clearer picture of the time course of the amyloid cascade and identify potential windows for specific treatments.

Metastatic melanoma (MM) carries a dismal prognosis, as it is largely resistant to conventional cytotoxic chemotherapy, biochemotherapy and immunotherapy. There is, therefore, a pressing need to identify new, effective treatments to improve outcomes from MM. Innovative approaches in oncology drug development include anti-angiogenic strategies, in the form of monoclonal antibodies and small-molecule kinase inhibitors. In this review we aim to present current concepts and controversies surrounding the role of angiogenesis and anti-angiogenic therapies in MM, alluding to other tumor types in which increasing knowledge may supply avenues for future directions in melanoma research and management. An overview of angiogenesis and its importance in melanoma progression is presented, highlighting the key molecules that represent potential therapeutic targets. The results of using anti-angiogenic strategies in preclinical and clinical trials are discussed and future perspectives for anti-angiogenic therapies in MM are considered.

Cutaneous and uveal melanoma both have a poor prognosis and chemotherapy is usually unsuccessful. We have previously reported the activity of a number of cytotoxic agents against metastatic cutaneous and primary choroidal uveal melanoma using an ex vivo adenosine triphosphate (ATP)-based chemosensitivity assay (ATP-TCA). In this study we compare the results obtained with the two types of melanoma. Cutaneous melanoma deposits in skin and lymph nodes (n = 58) and choroidal melanomas (n = 77) were tested using the ATP-TCA. Analysis of the data based on an arbitrary threshold for sensitivity shows that both types of melanoma exhibit heterogeneity of sensitivity to all the agents and combinations tested. With all the single agents except gemcitabine, cutaneous melanomas showed greater sensitivity in the assay, though this did not achieve statistical significance. This was also true with the drug combinations, with the exception of treosulfan + gemcitabine, which had similar activity in each type of melanoma. Of all the single agents tested, doxorubicin (47% of specimens classed as sensitive), vinorelbine (43%), treosulfan (41%) and paclitaxel (33%) showed the greatest activity with cutaneous melanoma. In the uveal melanoma samples, mitoxantrone (33%), gemcitabine (22%) and treosulfan (21%) showed the greatest activity. In contrast to the cutaneous melanomas, 13% of the uveal melanomas were sensitive to paclitaxel, 4% were sensitive to doxorubicin and 11% were found to be sensitive to vinorelbine. Both tumour types showed greater sensitivity to combinations of cytotoxic agents. The combination of treosulfan + gemcitabine was universally effective, with 72% of cutaneous melanomas and 80% of uveal melanomas exhibiting activity at the level selected to indicate sensitivity in the assay, though this will not necessarily indicate a similar level of clinical sensitivity.

Metastatic melanoma has a very poor prognosis and systemic therapies - both cytotoxic and biological - have not improved outcome in this disease so far. For this reason, novel therapeutic strategies are urgently required. Angiogenesis represents a relevant process to modulate in melanoma, as pro-angiogenic ligands and their receptors are overexpressed and have been found to correlate with disease progression and prognosis. The angiogenic axis may be targeted at many different levels, which are still being defined. This article presents an overview of the importance of angiogenesis in melanoma and draws attention to some of the key molecules that are currently being targeted rationally within clinical studies. We discuss a number of anti-angiogenic and anti-vascular agents and their mechanisms of action. An overview of the efficacy and toxicity of these treatments in clinical trials performed so far in melanoma is presented and future directions for anti-angiogenic strategies in melanoma are considered. Keywords: Angiogenesis, melanoma, molecularly targeted therapy, monoclonal antibodies, tyrosine kinase inhibitors, vascular endothelial growth factor (VEGF), Metastatic melanoma, systemic therapies, anti-angiogenic strategies, pro-angiogenic ligands, melanoma disseminates, VEGF isoforms, angiogenic signalling, Intra-tumoral hypoxia, malignant melanocytes

Endothelin-1 (ET-1) acting through endothelin A and B receptors (ETAR and ETBR) has been implicated in the development of cancer. The endothelin axis has not previously been characterised in human pancreatic adenocarcinoma (PAC).Expression of ET-1, ETAR, ETBR, vascular endothelial growth factor and microvessel density (MVD) was determined by immunohistochemistry in 45 surgically resected human PACs and 15 non-cancer human pancreas samples.PAC had the highest staining intensity for ET-1 and ETBR: 38% PAC samples scored 2+ or more compared with 7% non-cancer sample in ET-1; 58% PAC samples scored 2+ compared with 0% non-cancer samples in ETBR. MVD was significantly lower in PAC compared with non-cancer tissue (p<0.0001).PAC was characterised by greater expression of ET-1 and ETBR compared with normal pancreas.

The ageing population poses new challenges globally. Cancer care for older patients is one of these challenges, and it has a significant impact on societies. In the United Kingdom (UK), as the number of older cancer patients increases, the management of this group has become part of daily practice for most oncology teams in every geographical area. Older cancer patients are at a higher risk of both under- and over-treatment. Therefore, the assessment of a patient's biological age and effective organ functional reserve becomes paramount. This may then guide treatment decisions by better estimating a prognosis and the risk-to-benefit ratio of a given therapy to anticipate and mitigate against potential toxicities/difficulties. Moreover, older cancer patients are often affected by geriatric syndromes and other issues that impact their overall health, function and quality of life. Comprehensive geriatric assessments offer an opportunity to identify and address health problems which may then optimise one's fitness and well-being. Whilst it is widely accepted that older cancer patients may benefit from such an approach, resources are often scarce, and access to dedicated services and research remains limited to specific centres across the UK. The aim of this project is to map the current services and projects in the UK to learn from each other and shape the future direction of care of older patients with cancer.

Background: Whether outcomes following consolidative chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC) are improved by radiotherapy dose escalation or sensitization using the protease inhibitor nelfinavir is uncertain.Methods: In this multi-centre, two stage study (SCALOP-2) patients received capecitabine (830mg/m2 twice daily)-based CRT following four 28-day cycles of day 1, 8 and 15 gemcitabine (1000mg/m2)/nab-paclitaxel (125mg/m2). In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4Gy in 28 fractions) was identified. The subsequent open-label, randomized 2x2 factorial + 1 phase II second stage compared standard-dose CRT to high-dose CRT (60Gy in 30 fractions), with or without nelfinavir at MTD (1250mg twice daily). The co-primary endpoints were progression-free survival (PFS) with or without nelfinavir, and overall survival (OS) with or without radiotherapy dose escalation. Secondary endpoints included health-related quality of life (HRQoL) measures assessed using the QLQ-C30, PAN26 and EQ5D tools.Findings: There was no improvement in median OS with high compared with standard dose CRT (16.9 (60% confidence interval, CI 16.2-17.7) vs. 15.6 (60%CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60%CI 0.91-1.40; p=0.68)). Similarly, median PFS was not improved with the addition of nelfinavir compared to no nelfinavir (10.0 (60%CI 9.9-10.2) vs. 11.1 (60%CI 10.3-12.8) months respectively; adjusted HR 1.71 (60%CI 1.38-2.12; p=0.98)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or the rate of grade 3/4 adverse events. The rate of local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n=11/46 (23.9%) vs. n=15/45 (33.3%)). There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment.Interpretation: In patients with LAPC receiving consolidative CRT, there is no improvement in OS or PFS from radiotherapy dose escalation or nelfinavir. Dose-escalated CRT may nevertheless improve local tumour control and is well tolerated.Trial Registration: This trial is registered with International Standard Randomised Controlled Trial Number (ISRCTN) 50083238.Funding: The SCALOP-2 trial was sponsored by the University of Oxford and funded by Cancer Research UK (CRUK/07/040). Trial management was provided by the Oncology Clinical Trials Office (OCTO) at the University of Oxford as part of the UKCRC Oxford Clinical Trials Research Unit (OCTRU). Statistical input was provided by Centre for Statistics in Medicine (CSM) at the University of Oxford. This work was funded by Cancer Research UK (C28958/A17139). Celgene provided additional financial support and nab-paclitaxel free of charge. Radiotherapy Trials Quality Assurance by National Radiotherapy Trials (RTTQA) Group.Celgene provided an education grant and nab-paclitaxel without charge. CMJ is supported by a Clinical Lectureship part-funded by Cancer Research UK RadNet Cambridge (C17918/A28870). MAH is supported by funding from the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. PC received support from the NIHR Cambridge Biomedical Research Centre.Declaration of Interest: The authors declare that they have no conflicts of interest.Ethical Approval: The study was approved by the South Central – Oxford A Research Ethics Committee and by the UK Medicines and Healthcare Products Regulatory Agency. Data are reported here in compliance with the CONsolidated Standards of Reporting Trials (CONSORT) statement.

Angiogenesis has been identified as a relevant target for melanoma experimental therapeutics, based on preclinical and clinical studies. A variety of angiogenesis inhibitors are currently being tested in both metastatic and adjuvant melanoma clinical trials. To date, the most promising evidence of benefit is based on a statistically nonsignificant trend in survival gain reported in a randomized phase II trial combining bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, with cytotoxic chemotherapy. Larger phase III studies are required to determine the true extent of clinical benefit with this class of agents. Key to these clinical trials is the need to include translational endpoints, since correlation of biological and clinical data will provide the opportunity to identify biomarkers predictive of treatment response. These biological studies will also aid our, as yet, poor understanding of the mechanism of action of angiogenesis inhibitors, as well as drug-related side effects. Finally, if these trials show meaningful clinical benefit, then careful consideration will need to be given when designing second-generation trials, in the light of novel gene-directed therapies currently showing promise in melanoma.

Vemurafenib, a BRAF inhibitor, has been associated with a number of cutaneous adverse effects, mainly through the activation of MAP kinases. Pyogenic granuloma was seen in a patient with melanoma who had a response to the agent.

NIVO + IPI and NIVO showed superior clinical activity vs IPI in a phase 3 trial of MEL patients (pts), irrespective of PD-L1 tumor expression. Among pts with high PD-L1 expression (≥5%), median progression-free survival (mPFS) was similar between NIVO + IPI and NIVO, but overall response rate (ORR) was higher with NIVO + IPI. We describe PD-L1 as a biomarker for NIVO + IPI and NIVO efficacy across phase 2 (CheckMate 069) and phase 3 (CheckMate 066 and 067) trials. Treatment-naïve pts (N = 832) with MEL received NIVO 1 mg/kg + IPI 3 mg/kg Q3W × 4 or NIVO 3 mg/kg Q2W, followed by NIVO 3 mg/kg Q2W until progression or unacceptable toxicity. Tumor tissue from primary or metastatic sites, obtained at screening, was assessed for PD-L1 expression using a validated Dako immunohistochemistry assay. Minimum pt follow-up was 18 months (mos). Survival data remain immature. The proportion of pts with PD-L1 expression ≥5% was 26% (92/358) for NIVO + IPI and 29% (139/474) for NIVO. Pt characteristics were similar between PD-L1 subgroups, although fewer pts had LDH > ULN in the PD-L1 ≥5% subgroup. Among pts with PD-L1 expression ≥5%, mPFS of NIVO + IPI was not reached (NR) and was 22.0 mos for NIVO alone (hazard ratio [HR]: 0.99, 95% CI: 0.66─1.46). For pts with low to no PD-L1 (<5%), mPFS was 11.1 mos for NIVO + IPI and 4.9 mos for NIVO (HR: 0.70, 95% CI: 0.57─0.87). ORR was higher with NIVO + IPI vs NIVO in pts with ≥5% (68.5% vs 59.0%) and <5% (54.9% vs 39.7%) PD-L1 expression. Median duration of response was NR in both PD-L1 subgroups for NIVO + IPI, and 20.8 and 22.3 mos in NIVO ≥5% and <5% PD-L1 subgroups, respectively. The frequency and types of treatment-related grade 3-4 adverse events were consistent with earlier reports (NIVO + IPI: 56.5%, NIVO: 18.2%) and did not differ by PD-L1 expression. While pts with ≥5% PD-L1 tumor expression have better efficacy outcomes, those with <5% PD-L1 expression still benefit from NIVO + IPI or NIVO. Among pts with high PD-L1, mPFS of NIVO + IPI and NIVO were similar, but the ORR of NIVO + IPI was numerically higher across PD-L1 subgroups. As OS data have not yet matured, caution is advised when applying these results to assess the relative benefit of NIVO + IPI vs NIVO.

Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial.Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers.In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47-0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65-1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13-0.70).SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS.ISRCTN71070888; ClinialTrials.gov (NCT03529175).

<h2>Abstract</h2> Patients with <i>BRAF</i>-mutant melanoma commonly develop resistance to BRAF inhibitor and MEK inhibitor (BRAF/MEKi) treatment, resulting in disease recurrence or progression. Repeated treatment after a break or an intervening therapy may provide clinical benefit. To ensure a common understanding when discussing the treatment of <i>BRAF</i>-mutant melanoma, we propose consensus definitions for retreatment and rechallenge. 'Retreatment' should be defined as 'repeated treatment with the same therapeutic class following relapse after adjuvant treatment has ended.' Retreatment may be an option for patients with unresectable or metastatic disease who have completed prior adjuvant therapy or discontinued adjuvant therapy early due to toxicity or patients with locoregional recurrence after adjuvant treatment who subsequently underwent resection. 'Rechallenge' should be defined as 'repeated treatment with the same therapeutic class following disease progression in patients who had clinical benefit with prior treatment for unresectable or metastatic disease<i>.</i>' Rechallenge may be an option for patients who had disease progression after an initial response and received an alternative intervening treatment or patients with unresectable or metastatic melanoma who had a treatment break after responding to BRAF/MEKi therapy. Clinical benefits may be possible with repeated BRAF/MEKi treatment because of the role of the MAPK pathway in melanoma oncogenesis and resistance mechanisms specific to BRAF/MEKi, which are discussed in this article. The concepts of retreatment and rechallenge may also be relevant for treatment with immune checkpoint inhibitors in patients with melanoma. Use of consistent terminology will help to stimulate and align further research in this area.

Before a new treatment can be widely used on patients, it must be proven to be safe and effective. Clinical trials are a means of conducting experiments on humans to yield reliable results. For this reason, they are in the best interests of patients, clinicians, pharmaceutical companies and society as a whole. Evidence suggests that patients treated in a trial do better than similar patients treated outside a trial, and the government has made clinical trials a priority in cancer care. In the UK in 2000, only 3.5% of cancer patients entered a clinical trial. The National Cancer Research Network, the Wales Cancer Trials Network and the Scottish Cancer Therapy Network aim to achieve a target of 10% accrual over the next few years. Regional clinical research networks are now actively recruiting patients across the UK.

Pancreatic adenocarcinoma is the fourth most common cause of cancer-related mortality in the developed world. The nucleoside analogue gemcitabine is established standard therapy for advanced disease. Gemcitabine can occasionally cause non-dose-dependent pulmonary toxicity, and the systemic complication of capillary-leak syndrome, which may mimic cardiogenic pulmonary oedema. Here, we present a case of capillary-leak syndrome in a patient with pancreatic cancer treated with gemcitabine, with a past history of severe cardiovascular dysfunction and coronary arteriosclerosis.

BackgroundPopulation-wide screening for melanoma is unlikely to be cost-effective. Nevertheless, targeted surveillance of high-risk individuals may be.ObjectivesTo estimate the cost-effectiveness of various surveillance strategies in the UK population, stratified by risk using a simple self-assessment tool scoring between 0 and 67.MethodsA decision model comparing alternative surveillance policies from the perspective of the UK National Health Service over 30 years was developed. The strategy with the highest expected net benefit for each risk score was identified, resulting in a compound risk-stratified policy describing the most cost-effective population-wide strategy. The overall expected cost and quality-adjusted life-years (QALYs), the incremental cost-effectiveness ratio, and associated uncertainty were reported.ResultsThe most cost-effective strategy is for those with a Williams score of 15 to 21 (relative risk [RR] of 0.79–1.60 vs. a mean score of 17 in the United Kingdom) to be offered a one-off full-body skin examination, and for those with a score of 22 or more (RR 1.79+) to be enrolled into a quinquennial monitoring program, rising to annual recall for those with a risk score greater than 43 (RR 20.95+). Expected incremental cost would be £164 million per annum (~0.1% of the National Health Service budget), gaining 15,947 additional QALYs and yielding an incremental cost-effectiveness ratio of £10,199/QALY gained (51.3% probability <£30,000).ConclusionsThe risk-stratified policy would be expensive to implement but cost-effective compared with typical UK thresholds (£20,000–£30,000/QALY gained), although decision uncertainty is high. Phased implementation enrolling only higher risk individuals would be substantially less expensive, but with consequent foregone health gain.

Expression of the DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) correlates with resistance to irinotecan in colorectal cancer cell lines. This phase I study evaluated the maximum tolerated dose (MTD) of lomeguatrib, an inactivating pseudosubstrate of MGMT, in combination with irinotecan in patients with metastatic colorectal cancer and assessed the safety, toxicity and clinical pharmacology of combination treatment.Patients with metastatic colorectal cancer received lomeguatrib (10-80 mg PO) on days 1-5 with irinotecan (250-350 mg/m(2) IV) on day 4 of a 21-day cycle.Twenty-four patients, pre-treated with a median of 2 lines of chemotherapy, received 104 cycles of treatment. The MTD was defined as 80 mg/day lomeguatrib with 300 mg/m(2) irinotecan. The main toxicities observed were neutropaenia and diarrhoea. Lomeguatrib of 80 mg/day produced complete MGMT depletion in all available peripheral blood mononuclear cells (PBMCs) and paired tumour biopsies (one patient). There was no pharmacokinetic interaction between the drugs. In 22 patients assessable for tumour response, one achieved a partial response and 16 had stable disease.This study defined a tolerable dose of irinotecan in combination with lomeguatrib in patients with metastatic colorectal cancer. Combination treatment gave a similar response rate to irinotecan monotherapy in this heavily pre-treated patient group.

Summary Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15‐year‐old female diagnosed with AJCC stage IB non‐ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAF V 600E mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C&gt;T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma‐predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable.

BackgroundExpert elicitation is required to inform decision making when relevant “better quality” data either do not exist or cannot be collected. An example of this is to inform decisions as to whether to screen for melanoma. A key input is the counterfactual, in this case the natural history of melanoma in patients who are undiagnosed and hence untreated.ObjectivesTo elicit expert opinion on the probability of disease progression in patients with melanoma that is undetected and hence untreated.MethodsA bespoke webinar-based expert elicitation protocol was administered to 14 participants in the United Kingdom, Australia, and New Zealand, comprising 12 multinomial questions on the probability of progression from one disease stage to another in the absence of treatment. A modified Connor-Mosimann distribution was fitted to individual responses to each question. Individual responses were pooled using a Monte-Carlo simulation approach. Participants were asked to provide feedback on the process.ResultsA pooled modified Connor-Mosimann distribution was successfully derived from participants’ responses. Feedback from participants was generally positive, with 86% willing to take part in such an exercise again. Nevertheless, only 57% of participants felt that this was a valid approach to determine the risk of disease progression. Qualitative feedback reflected some understanding of the need to rely on expert elicitation in the absence of “hard” data.ConclusionsWe successfully elicited and pooled the beliefs of experts in melanoma regarding the probability of disease progression in a format suitable for inclusion in a decision-analytic model.

Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2). Patients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19–9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme. SCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen. Eudract No: 2013–004968-56; ClinicalTrials.gov : NCT02024009.

Abstract Purpose Despite recent advances, approximately 50% of patient with metastatic melanoma eventually succumb to the disease. Patients with melanomas harboring a BRAF mutation (BRAF Mut ) have a worse prognosis than those with wildtype (BRAF WT ) tumors. Unexpectedly, interim AVAST-M Phase III trial data reported benefit from adjuvant anti-VEGF bevacizumab only in the BRAF Mut group. We sought to find mechanisms underpinning this sensitivity. Methods We investigated this finding in vitro and in vivo using melanoma cell lines and clones generated by BRAF V600E knock-in on a BRAF WT background. Results Compared with BRAF WT cells, isogenic BRAF V600E clones secreted more VEGF and exhibited accelerated growth rates as spheroids and xenografts, which were more vascular and proliferative. Recapitulating AVAST-M findings, bevacizumab affected only BRAF V600E xenografts, inducing significant tumor growth delay, reduced vascularity and increased necrosis. We identified 814 differentially expressed genes in isogenic BRAF V600E /BRAF WT clones. Of 61 genes concordantly deregulated in clinical melanomas ROR2 was one of the most upregulated by BRAF V600E . ROR2 was shown to be RAF-MEK regulated in BRAF V600E cells and its depletion suppressed VEGF secretion down to BRAF WT levels. The ROR2 ligand WNT5A was also overexpressed in BRAF Mut melanomas, and in ROR2-overexpressing BRAF V600E cells MEK inhibition downregulated WNT5A and VEGF secretion. Conclusions These data implicate WNT5A-ROR2 in VEGF secretion, vascularity, adverse outcomes and bevacizumab sensitivity of BRAF Mut melanomas, suggesting that this axis has potential therapeutic relevance.

The national Cancer Reform Strategy recommends delivering care closer to home whenever possible. Cancer drug treatment has traditionally been administered to patients in specialist hospital-based facilities. Technological developments mean that nowadays, most treatment can be delivered in the out-patient setting. Increasing demand, care quality improvements and patient choice have stimulated interest in delivering some treatment to patients in the community, however, formal evaluation of delivering cancer treatment in different community settings is lacking. This randomised trial compares delivery of cancer treatment in the hospital with delivery in two different community settings: the patient's home and general practice (GP) surgeries.Patients due to receive a minimum 12 week course of standard intravenous cancer treatment at two hospitals in the Anglia Cancer Network are randomised on a 1:1:1 basis to receive treatment in the hospital day unit (control arm), or their own home, or their choice of one of three neighbouring GP surgeries. Overall patient care, treatment prescribing and clinical review is undertaken according to standard local practice. All treatment is dispensed by the local hospital pharmacy and treatment is delivered by the hospital chemotherapy nurses. At four time points during the 12 week study period, information is collected from patients, nursing staff, primary and secondary care teams to address the primary end point, patient-perceived benefits (using the emotional function domain of the EORTC QLQC30 patient questionnaire), as well as secondary end points: patient satisfaction, safety and health economics.The Outreach trial is the first randomised controlled trial conducted which compares delivery of out-patient based intravenous cancer treatment in two different community settings with standard hospital based treatment. Results of this study may better inform all key stakeholders regarding potential costs and benefits of transferring clinical services from hospital to the community.ISRCTN: ISRCTN66219681.

4195 Background: SP1049C is a block co-polymer incorporating doxorubicin resulting in broad in vitro activity and superior anti-tumour activity in 9 out of 9 in vivo animal tumour models compared to doxorubicin. Methods: Chemotherapy- or radiotherapy-naïve patients with measurable, inoperable or metastatic, biopsy-proven, adenocarcinoma of the oesophagus; KP ≥60; normal cardiac LVEF; adequate swallowing and adequate renal, hepatic and bone marrow function were eligible. Treatment: SP1049C 75mg/m2 IV 30-minute infusion was given q3w, for up to 6 cycles. Radiological response was assessed after cycles 2, 4 and 6. Upon disease progression (PD) patients were offered standard chemotherapy. Other assessments included: QoL (by QLQ-C30 and QLQ-OES24 questionnaires), toxicity, disease-related symptoms and cardiac function. Results: From February 2002 to date, 17 male patients; median age 62 years (range 49 – 78); 16 with stage IV disease and 1 unknown stage (TxN1M0); were enrolled. 10 patients are eligible for efficacy analysis. Radiological response after 2 cycles: one (10%) PR, 8 (80%) SD (including 4 (40%) with minor responses) and one (10%) PD. Further partial responses have been seen after cycles 4 and 6 (by investigator assessment) and will be reported in due course. One responding patient underwent salvage resection (pT2N0 (Stage 2A) tumour). Toxicity data is available for 2 cycles for the first 11 patients. Gd 3–4 haematological toxicity (by patient): neutropaenia 8 (73%), leucopaenia 7 (64%), anaemia (0%) and platelets (0%) resulting in six (55%) patients being dose-reduced to 55 mg/m2 at cycle 2. Non-haematological toxicity (Gd1–2,Gd3–4): nausea (73%,0%), anorexia (45%,9%), lethargy (55%,18%), febrile neutropaenia (0%,36%), weight loss (35%,0%), vomiting (45%,18%), mucositis (55%,9%), and Gd 1–2 alopecia in 55%. A significant fall in LVEF (pre-defined as an absolute ≥15% drop from baseline value) was seen in 2 patients. Conclusions: SP1049C appears to be active in advanced oesophageal adenocarcinoma based on the preliminary results of the first 10 patients and the study will continue accrual to a total of 24 evaluable patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Supratek Pharma, Inc. Supratek Pharma, Inc. Supratek Pharma, Inc. Supratek Pharma, Inc.

Objective A qualitative sub-study was carried out within a larger phase II feasibility trial, to identify and describe the burden experienced by advanced melanoma patients participating in a clinical trial and the factors affecting their capacity to cope with the burden. Methods Semi-structured interviews were conducted with fourteen patients with advanced melanoma recruited from National Health Service hospitals in the United Kingdom. Qualitative analysis was undertaken using a framework analysis approach. Normalisation process theory was applied to the concept of research participation burden in order to interpret and categorise findings. Results Burdens of participation were identified as arising from making sense of the trial and treatment; arranging transport, appointment and prescriptions; enacting management strategies and enduring side effects; reflecting on trial documents and treatment efficacy, and emotional and mental effects of randomisation and treatment side effects. Factors reported as influencing capacity include personal attributes and skills, physical and cognitive abilities and support network. Discussion This is the first study to highlight the substantial burden faced by patients with advanced melanoma in a clinical trial and factors that may lessen or worsen the burden. Consideration of identified burdens during trial design and execution will reduce the burden experienced by research participants.

Background: The ECOG and Karnofsky performance status (PS) scales are routinely used to assess cancer patients for treatment and disease monitoring, but are problematic to use in older people. The Rockwood clinical frailty scale (CFS) is established in geriatric medicine as a quick and easy 9 point frailty scale and has been shown to predict for mortality as well as inpatient length of stay. It has not been evaluated in a cancer setting. We sought to compare the use of CFS with ECOG and Karnofsky PS to assess cancer patients attending routine outpatient clinics.

Pancreatic adenosquamous carcinoma has a poor prognosis, with limited prospective trial data to guide optimal treatment. The potential impact of drug metabolism on the treatment response of patients with pancreatic adenosquamous carcinoma is largely unknown.We describe the case of a 51 year old woman with pancreatic adenosquamous carcinoma who, following surgical resection, experienced early disease relapse during adjuvant gemcitabine therapy. Paradoxically, this was followed by an exceptional response to capecitabine therapy lasting 34.6 months. Strong expression of cytidine deaminase was detected within the tumour.This case study demonstrates that early relapse during adjuvant chemotherapy for pancreatic adenosquamous carcinoma may be compatible with a subsequent exceptional response to second line chemotherapy, an important observation given the poor overall prognosis of patients with adenosquamous carcinoma. Cytidine deaminase is predicted to inactivate gemcitabine and, conversely, catalyze capecitabine activation. We discuss strong intra-tumoural expression of cytidine deaminase as a potential mechanism to explain this patient's disparate responses to gemcitabine and capecitabine therapy, and highlight the benefit that may be gained from considering similar determinants of response to chemotherapy in clinical practice.

At present, SARS-CoV-2 infection rates among UK oncology health care workers are unknown. The COVID-19 Serology in Oncology Staff (CSOS) study is a multicentre UK study investigating oncology staff SARS-CoV-2 exposure following 2 months of the UK national pandemic lockdown. Participants are patient-facing staff working in secondary care oncology departments during the COVID-19 pandemic. Samples are being collected at multiple time points and analysed for SARS-CoV-2 antibodies (blood-based tests) as well as antigens (nasopharyngeal swab test). To increase accuracy, two different methods are being used to detect SARS-CoV-2 IgG antibodies. The study's primary objective is to measure the prevalence of SARS-CoV-2 IgG antibodies in oncology staff following 2 months of national pandemic lockdown. Secondary outcomes comprise the rate of persistent asymptomatic SARS-CoV-2 antigen positivity over time, the proportion of previously symptomatic and asymptomatic SARS-CoV-2 IgG seropositivity and the proportion of those who do not become antibody-positive following a positive antigen polymerase chain reaction (PCR) result. Here, we summarise the initial results from our pilot study [1Favara D.M. Cooke A. Doffinger R. Houghton S. Budriunaite I. Bossingham S. et al.First results from the UK COVID-19 Serology in Oncology Staff study (CSOS).medRxiv. 2020; https://doi.org/10.1101/2020.06.22.20136838Crossref Scopus (0) Google Scholar]. Seventy health care workers (from a total of 82 eligible staff; 85.4%) were recruited from the oncology department at the Queen Elizabeth Hospital in Kings Lynn – a 515-bed district general hospital in the East of England serving a population of about 331 000 people. Samples were collected during the first week of June 2020 from both oncology and haemato-oncology staff: antibodies were assayed using a rapid point of care (POC) test (manufacturer reported sensitivity 98.5% and specificity 97.9%), as well as a laboratory-based Luminex test (sensitivity 84% and specificity 100%); antigen status was measured by PCR. Most of the participants were nurses (45/70; 64.3%), followed by doctors (15/70; 21.2%) and patient-facing administrative staff (10/70; 14.3%). Prior symptoms were reported in 25/70 (35.7%) participants, with the highest incidence in nurses (17/45; 37.7%). Symptom duration was similar across all staff groups (median and mean 11 days; range 1–35 days). Eleven of the 25 (44%) who reported previous symptoms reported undergoing PCR nasopharyngeal swab testing when symptomatic: of these, 4/11 (36.4%) tested positive. Only 5/17 (29.4%) previously symptomatic nurses received a prior PCR test (2/5; 40% were positive), in contrast to 4/5 (80%) previously symptomatic doctors (2/4; 50% were positive). The mean time from resolution of reported previous symptoms to the CSOS study sample collection date was 48.4 days (95% confidence interval 39.3–57.46). Most participants (45/70; 64.3%) reported no prior symptoms during the pandemic, which was similar across all groups. All tested participants were nasopharyngeal swab PCR negative for SARS-CoV-2 antigen. A positive SARS-CoV-2 IgG was detected in 15/70 (21.4%) of participants using the Luminex test, and in 10/70 (14.3%) using the rapid POC test. All participants positive using the rapid POC test were positive using the Luminex test. Due to its ability to detect lower antibody concentration levels (because of the assay type), the results from the Luminex assay were used as the final result. Nurses had the highest percentage of SARS-CoV-2 antibodies (13/45; 28.9%). The percentage prevalence in doctors was less than half that in nurses (2/15; 13.3%), although this difference was not significant (Fischer's exact test P = 0.3). No SARS-CoV-2 antibodies were detected in the receptionists. All participants with a positive nasopharyngeal PCR result prior to the study tested positive for antibodies (4/4; 100%). Sixty per cent (9/15) of antibody-positive participants reported previous symptoms, consistent with SARS-CoV-2 infection during the pandemic: a 3.6-fold higher odds than antibody-negative participants (16/55; 29.1%) (Fischer's exact test P = 0.03). Of the total number of previously symptomatic participants, 9/25 (36%) had detectable SARS-CoV-2 antibodies. In those who reported no prior symptoms during the pandemic, 6/45 (13.3%) had antibodies, indicating asymptomatic prior infection. Of seven participants who had no prior symptoms but had been exposed to a suspected infected household member, 4/7 (57.1%) had positive antibodies. See Figure 1 for the results. To the best of our knowledge, this is the first UK study specifically investigating SARS-CoV-2 exposure in patient-facing oncology staff who were at work within a secondary care non-surgical oncology department during the COVID-19 pandemic between March and the start of June 2020. Nearly a quarter of oncology staff assessed were SARS-CoV-2 antibody-positive, suggesting a substantial past infection rate, although we found that no participants were SARS-CoV-2 PCR positive at the time of sampling. Although only 6% (9/150) of the patients admitted to the pilot site's oncology in-patient ward during the first 3 months of the UK lockdown were found to be PCR positive, by the nature of the hospital admission process it is possible that some of the infections among staff (both previously symptomatic and asymptomatic) could have arisen from exposure to these patients, especially as earlier on during the pandemic, personal protective equipment was less readily available within the National Health Service. Nurses were the staff group with the highest percentage of positive SARS-CoV-2 antibodies (double that of doctors, although this difference was not statistically significant at this sample size), which if borne out in a larger sample size, may be the result of a higher frequency and duration of physical contact between nurses and patients by the nature of their work. That none of the receptionist group were antibody positive fits with this hypothesis. A higher proportion of those who reported prior symptoms suggestive of SARS-CoV-2 infection were antibody positive. This emphasises the correlation between symptoms and SARS-CoV-2 serology and highlights the importance of SARS-CoV-2 testing. The National Health Service has now begun to initiate large-scale SARS-CoV-2 testing in staff (using multiple different assays), which will be invaluable in determining exposure rates. Until a vaccine or functional treatment becomes available, serial testing of both oncology staff and patients is likely to be clinically useful, especially when taking into account managing immunocompromised oncology and haemato-oncology patients. Our finding of a 13.3% previous asymptomatic infection rate (evidenced by positive antibodies and a negative PCR) is higher than reported elsewhere in health care workers [for example: 3/230 (1.3%) in a French study and 11/578 (1.9%) in a Spanish Study] [2Solodky M.L. Galvez C. Russias B. Detourbet P. N'Guyen-Bonin V. Herr A.L. et al.Lower detection rates of SARS-COV2 antibodies in cancer patients vs healthcare workers after symptomatic COVID-19.Ann Oncol. 2020; https://doi.org/10.1016/j.annonc.2020.04.475Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,3Garcia-Basteiro A.L. Moncunill G. Tortajada M. Vidal M. Guinovart C. Jimenez A. et al.Seroprevalence of antibodies against SARS-CoV-2 among health care workers in a large Spanish reference hospital.medRxiv. 2020; https://doi.org/10.1101/2020.04.27.20082289Crossref Scopus (0) Google Scholar]. However, it remains unclear whether such antibodies are protective against future repeat SARS-CoV-2 infection. New data in this regard appear promising [4Sekine T. Perez-Potti A. Rivera-Ballesteros O. Strålin K. Gorin J.-B. Olsson A. et al.Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19.bioRxiv. 2020; https://doi.org/10.1101/2020.06.29.174888Crossref Scopus (0) Google Scholar]. Two different antibody assays were used in order to limit the possibility of erroneous results. The rapid POC antibody test was reported by the manufacturer to have high sensitivity and specificity and not to cross-react with the four other main coronavirus types, whereas the Luminex test was able to detect antibodies at a lower concentration level (by the nature of the method). This was evidenced by a previously SARS-CoV-2 PCR-positive participant, who was confirmed to be low level anti-SARS-CoV-2 (IgG)-positive by the Luminex test, but not by the rapid POC method. If we had used the rapid test only, the overall positive antibody percentage would have been 8% lower. Although there is the possibility that some of our study participants were recently SARS-CoV-2 infected and thus were not yet producing SARS-CoV-2 IgG or had fully seroconverted, the mean time from the reported resolution of previous symptoms to the start of the study was 1.5 months. This is something that will be explored with additional sample collection at a later time point. This study is ongoing and will be collecting further samples at later time points from both our pilot site as well as other National Health Service hospitals. We report these interim results in the expectation that they will be of importance for planning UK national guidance on SARS-CoV-2 testing of patients due to start or having started anticancer non-surgical treatments, as well as the oncology staff treating them. The authors declare no conflict of interest. This study was funded by the Oncology Department Charity Fund at the Queen Elizabeth Hospital Kings Lynn NHS Foundation Trust, the Oncology Department Research Fund at Peterborough City Hospital, North West Anglia NHS Foundation Trust, and the Addenbrooke's Charitable Trust.

The ambition of the UK Government's 10-year cancer plan consultation document to transform cancer outcomes is highly welcome. 1 UK Department of Health and Social Care10-Year Cancer Plan: call for evidence. https://www.gov.uk/government/consultations/10-year-cancer-plan-call-for-evidence/10-year-cancer-plan-call-for-evidenceDate: March 31, 2022 Date accessed: May 27, 2022 Google Scholar This consultation must reflect on the extraordinary role played by the UK research community in responding to COVID-19—a response enabled by clinical research delivery infrastructure embedded within the National Health Service (NHS), which allowed rapid clinical evaluation of novel treatments and vaccines to save and transform lives. This unique national research delivery capability is the legacy of more than two decades of national clinical research networks, with co-operation between government agencies, charitable funders, and many others. This national capability started in cancer with the inception of the National Cancer Research Network and the National Cancer Research Institute (NCRI) in 2001. Now, through the National Institute for Health and Care Research (NIHR) Clinical Research Network (CRN), it extends across the full spectrum of health and social care. Cancer outcomes have been radically improved during this time, but further gains will require reinvigoration and realignment of our research capability at multiple levels, starting with the health-care workforce.

Melanoma is the most aggressive form of skin cancer, with tendency to spread to any organ of the human body, including the gastrointestinal tract (GIT). The diagnosis of metastases to the GIT can be difficult, as they may be clinically silent for somewhile and may occur years after the initial melanoma diagnosis. CT imaging remains the standard modality for staging and surveillance of melanoma patients, and in most cases, it will be the first imaging modality to identify GIT lesions. However, interpretation of CT studies in patients with melanoma can be challenging as lesions may be subtle and random in distribution, as well as sometimes mimicking other conditions. Even so, early diagnosis of GIT metastases is critical to avoid emergency hospitalisations, whilst surgical intervention can be curative in some cases. In this review, we illustrate the various imaging presentations of melanoma metastases within the GIT, discuss the clinical aspects and offer advice on investigation and management. We offer tips intended to aid radiologists in their diagnostic skills and interpretation of melanoma imaging scans.

Advanced melanoma is a life-threatening cancer with limited life expectancy. The recent introduction of new targeted systemic therapies has provided clinicians with the means to potentially extend survival for the first time. However, the chance of cure remains very low and treatment-induced toxicity is well described. This qualitative study was undertaken to evaluate clinicians’ assessment regarding the key concerns in managing advanced melanoma following the introduction of these new treatments. Three hundred and forty-three oncologists were surveyed online between August and November 2012 (in 11 countries) and March and April 2013 (in an additional country). Analysis of free-text responses identified 23 clinical issues of concern across all countries. Of these, the most common clinical concerns were drug toxicity and tolerability, followed by limited treatment effectiveness and limited treatment options. These results suggest that despite the promise of the two new agents in the field, clinicians are still concerned about the limitations of current treatment options, recognising that there remains a significant unmet need in the treatment of advanced melanoma.

Abstract Background: IMCgp100 is an affinity-enhanced T cell receptor (TCR) specific for the HLA-A2 restricted melanoma gp100 peptide (YLEPGPVTA) fused to an anti-CD3 antibody fragment. Binding of IMCgp100 to melanoma cells redirects T cell cytotoxicity even in the presence of significant levels of PD-1 and PD-L1. Due to its high affinity, IMCgp100 enables T cells to kill HLA down-regulated melanoma cells otherwise invisible to natural T cell recognition. During phase I dose escalation of a weekly schedule, the Maximum Tolerated Dose (MTD) was 600ng/kg or 50mcg absolute dose. An expanded cohort is accruing at the MTD, and a second dose escalation was initiated to determine the MTD, toxicity and potential activity of a daily x 4 q3w schedule. Methods: Patients enrolled are HLA A2 positive, stage IV or unresectable stage III melanoma, with an ECOG Performance Status (PS) ≤1 and a lymphocyte count of ≥0.5×109/L. The phase II expansion of weekly dosing has a target of 10 patients; accrual will continue until a trio of evaluable biopsies are available from at least six patients. Dose escalation for the daily x 4 q3w regimen began at 10mcg/daily. One cycle is 6 weeks. Results: 16 patients have been treated weekly at MTD (600ng/kg or 50mcg). 63% were male, median age 58 yrs, ECOG PS 0 in 56%. All but one patient had stage IV disease. 63% of patients received ≥2 prior systemic therapies; some patients had prior ipilimumab (56%), RAFi (31%) and anti-PD1 or other immunotherapies (13%). Two patients were subsequently shown to be gp100 negative by IHC. Common toxicities included transient grade 3 pruritic rash and grade 2 pyrexia/edema. Lymphocytes migrated to skin and tumor as evidenced by biopsy analysis, accompanied by chemokine/cytokine release. Three partial responses (PR) and one complete response (CR) were observed and are still ongoing. Two PRs continue after &amp;gt;12 months, one, in an ipilimumab refractory patient continues after &amp;gt;3 months and a CR continues after &amp;gt;4 months; these include responses in the two ocular melanoma patients enrolled (long term PR and CR). Sites of response include lung, liver, lymphatic system and various soft tissues. For the daily x 4 regimen, the 20mcg daily dose is complete, toxicities are tolerable and escalation continues. Conclusions: Toxicities of IMCgp100 were consistent with the mode of action of the drug i.e. IMCgp100 mediated T cell mobilisation, activation and tumor killing. Objective durable responses were observed including in ocular melanoma patients. Additional patients are being accrued at 50mcg weekly. For the daily x 4 regimen, the 20mcg dose was completed, which equates to 80mcg every 3 weeks, or just over half the dose achievable in this period with weekly dosing. Dose escalation in the d x 4 regimen continues. Citation Format: Mark R. Middleton, Pippa Corrie, Mario Sznol, Jeffrey Infante, Clive Mulatero, Jeff Evans, Neil Steven, David Krige, William H. Shingler, Yvonne McGrath, Namir J. Hassan, Bent K. Jakobsen. A phase I/IIa study of IMCgp100: Partial and complete durable responses with a novel first-in-class immunotherapy for advanced melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT106. doi:10.1158/1538-7445.AM2015-CT106

Pancreatic cancer is known for its typically late presentation and poor survival rates, with overall 5-year survival of less than 5%. The role of chemotherapy alone or with radiotherapy in the management of locally advanced tumors continues to be an area of debate. We report a case of locally advanced, pancreatic adenosquamous carcinoma that was initially deemed unresectable intraoperatively. Nonetheless, the tumor was resected after radiological response to gemcitabine-capecitabine chemoradiotherapy regimen similar to the Selective Chemoradiation in Advanced LOcalised Pancreatic cancer trial. Histological examination revealed complete pathological response with extensive fibrosis (ypT0 N0). On 12-month follow-up CT, a single liver lesion in the left lateral segment was identified and confirmed to be a metastasis with cytological diagnosis via EUS and FNA. The disease remained stable and confined to the solitary hepatic metastasis after further gemcitabine chemotherapy. Therefore, a further successful resection was performed. The 2 main strategies for the management of locally advanced unresectable pancreatic cancer are chemotherapy induction followed by consolidation chemoradiotherapy or chemotherapy alone, with conflicting published evidence. Evidence for the optimal management of the rare histological type of adenosquamous carcinoma is scant. We present a case of such tumor with a complete pathological response to chemoradiotherapy. The results of future studies in the area are eagerly awaited.

For all primary cutaneous squamous cell carcinomas (cSCCs), physical examination should include full skin examination, recording of tumour diameter and regional lymph-node-basin status. Surgery is the treatment of choice, with a minimal 5-mm margin. For elderly patients with well-differentiated tumours, other surgical modalities can be explored. Surgery for organ-transplant recipients should not be delayed. The issue with cSCC is identifying high-risk tumours with staging, as this may alter treatment and follow-up schedules. Adjuvant radiation therapy should be considered for incomplete resection, when re-excision is impossible or there are poor-prognosis histological findings. Recommendations are at least biannual dermatological surveillance for 2 years, but in elderly patients with small, well-differentiated tumours long-term follow-up is not always necessary. In case of positive lymph nodes, radical dissection is needed, with regional postoperative adjuvant radiation. Advanced cSCCs are defined as unresectable local, regional or distant disease requiring systemic treatment. Their only approved treat-ment is the PD-1 inhibitor, cemiplimab. Trials evaluating adjuvant or neo-adjuvant anti-PD-1 are ongoing. Platin-based chemo or anti-epidermal growth-factor-receptor therapies are possible second-line treatments. For transplant patients, minimizing immunosuppression and switching to sirolimus must be considered at first appearance of cSCC.

SUMMARY In melanoma, transcriptional profiling has revealed multiple co-existing cell states, including proliferative versus invasive sub-populations that have been posited to represent a “go or grow” tradeoff. Both of these populations are maintained in tumors, but how they physically interact to promote metastasis is unknown. We demonstrate that these subpopulations form spatially structured heterotypic clusters that cooperate in the seeding of metastasis. We unexpectedly found that INV cells were tightly adherent to each other, and formed clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation between these populations, in which the INV cells facilitated the spread of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of both clustering and the PRO/INV states. Our data suggest a framework for the co-existence of these two divergent cell populations, in which differing cell states form heterotypic clusters that promote metastasis via cell-cell cooperation.

Background: The ECOG and Karnofsky performance status (PS) scales are routinely used to assess cancer patients for treatment and disease monitoring, but are problematic to use in older people. The Rockwood clinical frailty scale (CFS) is established in geriatric medicine as a quick and easy 9 point frailty scale and has been shown to predict for mortality as well as inpatient length of stay. It has not been evaluated in a cancer setting. We sought to compare the use of CFS with ECOG and Karnofsky PS to assess cancer patients attending routine outpatient clinics.

4133 Background: Pazopanib (paz) is a tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGF-α, -β, and c-kit. Inhibition of angiogenic pathways in combination with chemotherapy has been shown to benefit patients (pts) with colorectal cancer (CRC). Methods: Pts with previously untreated advanced or metastatic CRC and adequate organ function were assigned to paz with FOLFOX6 (FO) or capeOx (CO) by their physician. Doses of paz were escalated with full strength chemotherapy, starting at 400mg daily. The optimally tolerated regimen (OTR) was the combination dose at which &lt;1/6 pts experienced dose-limiting toxicity (DLT). Results: Fifty pts were enrolled in FO (paz 400 mg, n=6; 800, 15), CO (400, 12; 800, 9) and reduced capecitabine (rc) CO (800, 8) cohorts: median age = 55.5, M/F = 37/13. Pts have remained on therapy for a median of 3 (range 0–17) months. Three pts remain on study. Safety data is available on 41. The most common AEs are summarized in the table below. The OTR was exceeded with CO in combination with 800 mg and 400 mg of pazopanib, but was not exceeded with 800 mg pazopanib when capecitabine was reduced to 850 mg/m 2 twice daily or with FO with 800 mg pazopanib. Efficacy and pharmacokinetic analyses are ongoing. Conclusions: The OTRs were achieved at 800 mg paz with full-dose FO, and at 800mg paz with rcCO. [Table: see text] [Table: see text]

4195 Background: SP1049C is a block co-polymer incorporating doxorubicin resulting in broad in vitro activity and superior anti-tumour activity in 9 out of 9 in vivo animal tumour models compared to doxorubicin. Methods: Chemotherapy- or radiotherapy-naïve patients with measurable, inoperable or metastatic, biopsy-proven, adenocarcinoma of the oesophagus; KP ≥60; normal cardiac LVEF; adequate swallowing and adequate renal, hepatic and bone marrow function were eligible. Treatment: SP1049C 75mg/m2 IV 30-minute infusion was given q3w, for up to 6 cycles. Radiological response was assessed after cycles 2, 4 and 6. Upon disease progression (PD) patients were offered standard chemotherapy. Other assessments included: QoL (by QLQ-C30 and QLQ-OES24 questionnaires), toxicity, disease-related symptoms and cardiac function. Results: From February 2002 to date, 17 male patients; median age 62 years (range 49 – 78); 16 with stage IV disease and 1 unknown stage (TxN1M0); were enrolled. 10 patients are eligible for efficacy analysis. Radiological response after 2 cycles: one (10%) PR, 8 (80%) SD (including 4 (40%) with minor responses) and one (10%) PD. Further partial responses have been seen after cycles 4 and 6 (by investigator assessment) and will be reported in due course. One responding patient underwent salvage resection (pT2N0 (Stage 2A) tumour). Toxicity data is available for 2 cycles for the first 11 patients. Gd 3–4 haematological toxicity (by patient): neutropaenia 8 (73%), leucopaenia 7 (64%), anaemia (0%) and platelets (0%) resulting in six (55%) patients being dose-reduced to 55 mg/m2 at cycle 2. Non-haematological toxicity (Gd1–2,Gd3–4): nausea (73%,0%), anorexia (45%,9%), lethargy (55%,18%), febrile neutropaenia (0%,36%), weight loss (35%,0%), vomiting (45%,18%), mucositis (55%,9%), and Gd 1–2 alopecia in 55%. A significant fall in LVEF (pre-defined as an absolute ≥15% drop from baseline value) was seen in 2 patients. Conclusions: SP1049C appears to be active in advanced oesophageal adenocarcinoma based on the preliminary results of the first 10 patients and the study will continue accrual to a total of 24 evaluable patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Supratek Pharma, Inc. Supratek Pharma, Inc. Supratek Pharma, Inc. Supratek Pharma, Inc.

Background:NabP+GEM chemotherapy improves survival as treatment for mPDAC, compared with GEM alone. The UK randomised phase 2 SIEGE trial showed that sequential (SEQ) delivery of nabP+GEM (with nabP given 24 hours before GEM) trended towards improved efficacy compared with standard concomitant (CON) delivery. Preclinical models suggest that nabP potentiates GEM activity by either impacting on stroma or reducing CDA levels. Methods: 146 pts were randomised to receive CON or SEQ nabP+GEM. Baseline whole blood (wb) CDA activity was measured using an endpoint read, spectrometric, plate based assay. Baseline tumour IHC assessed stromal content (H&E), CDA (ab137605) and nucleoside transporter protein, hENT1 (Ventana SP120) expression. Results: 6-month (m) progression-free survival (PFS, primary end point) by SEQ and CON arms was 47% and 33%; median PFS was 5.8 and 4.1m (HR 0.68, 95%CI 0.48-0.97); median overall survival (OS) was 10.1 and 7.9m, respectively. Baseline wb CDA activity correlated only with ANC (R2 0.70, p<.0001) after adjustment for other baseline factors including KPS, disease burden, CRP and did not predict for PFS, OS or toxicity. Of 105 tumours evaluable by IHC, 34 had diffuse strong (ds) CDA staining which predicted for improved PFS with SEQ therapy (HR 0.43, 95%CI 0.20-0.91); this was not evident for other staining patterns or ds-CDA staining for pts on CON therapy. Ds-CDA staining trended towards improved OS with SEQ compared with CON therapy (HR 0.73, 95%CI 0.35-1.52). On disease progression, 34 pts (13 SEQ, 21 CON) received further anti-cancer treatment. Stroma or hENT1 expression did not predict for PFS or OS with SEQ or CON therapy. Tumour stroma staining, but not CDA or hENT1, was an independent prognostic factor for improved OS (moderate/extensive vs none/little, HR 0.55, 95%CI 0.37-0.84). Conclusions: Whole blood CDA activity was not a useful predictive biomarker, due to the dominant neutrophil effect. Instead, strong tumour CDA expression predicted for pts most likely to have a survival benefit from SEQ therapy and warrants further exploration. Clinical trial identification: EudraCT Nr: 2013-001868-40 Sponsors Protocol ID: AX-PANC-PI-0101 ISRCTN: ISRCTN71070888 Legal entity responsible for the study: Cambridge University Hospitals NHS Foundation Trust Funding: Celgene UK Disclosure: P. Corrie: Funding for the SIEGE clinical trial from Celgene Advisory boards in the last 2 years for BMS, Novartis, MSD, Pierre Fabre, Baxalta. J.W. Valle: Speakers' Bureau, Travel, acommodations and expenses from Celgene. B. Basu: Research funding and provision of trial drug from Celgene. Travel, accommodation and registration expenses for ASCO and ESMO Congresses from Bayer. Consulting and advisory role with Baxter Healthcare, Astex, Celgene, Nordic. Honararium from BTG Itrnl. H. Wasan: Honoraria, Speakers bureau and research funding from Celgene and Merck KGA. D. Palmer: Honoraria from Celgene, Nucana, BMS, Sirtex, Bayer. J. Wadsley: Honoraria from Celgene for participation in advisory boards, financial support Celgene to attend conferences. D. Jodrell: Receipt of grants/research supports: Support for Educational Symposium (Celgene) Receipt of honoraria or consultation fees: Support for Scientific Meeting attendance (Celgene). All other authors have declared no conflicts of interest.

Abstract Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal that metastatic cells may depart the primary tumour very early in the disease course and follow a branched pattern of evolution. Truncal UV-induced mutations that often swamp downstream analyses of heterogeneity, were found to be replaced by APOBEC-associated mutations in the branches of the evolutionary tree. Multi-sample analyses from a further 7 patients confirmed that branched evolution was pervasive, representing an important mode of melanoma dissemination. Our analyses illustrate that combining cancer cell fraction estimates across multiple metastases provides higher resolution phylogenetic reconstructions relative to single sample analyses and highlights the limitations of accurately inferring inter-tumoural heterogeneity from a single biopsy.

<h3>Background</h3> Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented. <h3>Methods</h3> C-144-01 is a global Phase 2 open-label, multicenter study of the safety and efficacy of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 66) patients with Stage IIIC/IV unresectable melanoma who received lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. All responses were assessed by RECIST 1.1. <h3>Results</h3> 66 patients had the following baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), relatively high tumor burden (106 mm mean target lesion sum of diameters), 44% with liver and/or brain lesions, median LDH 244 U/L. Objective Response Rate (ORR) by investigator was 36.4% (2 CR, 22 PR, 1 previously confirmed PR is now changed to SD) and Disease Control Rate (DCR) of 80.3%. At a median follow up of 9.7 months, median Duration of Response (DOR) has not been reached. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. The ORR per IRC was 34.8% (2 CR, 21 PR) and DCR was 72.7%. At a median follow up of 6.9 months, the median IRC DOR has not been reached. Overall concordance rate of investigator and IRC read of response was 89.4%. The concordance compares favorably with literature reports in a metastatic disease.¹ <h3>Conclusions</h3> Lifileucel treatment resulted in a 36.4% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who had received prior anti-PD1 and BRAF/MEK inhibitors, if tumor BRAF mutated. The high concordance of 89.4% between investigator and IRC confirms the original assessment of lifileucel efficacy in metastatic melanoma.² <h3>Acknowledgements</h3> The authors would like to thank the patients and their families for participation in the study. The authors would also like to acknowledge the support and dedication of all investigators and site team members from all participating clinical trial institutions. <h3>Trial Registration</h3> ClinicalTrials. gov Identifier: NCT02360579 <h3>Ethics Approval</h3> Ethics Approval This trial was approved by Western Institutional Review Board - IRB Tracking Number: 20160198. <h3>References</h3> Ghiorghiu DC, et al. Comparison of central and site review of RECIST data in an open randomised phase II trial in advanced melanoma. 10.1594.ecr 2009/C-075. Sarnaik A, et al. Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1. <i>J Clin Oncol</i> 2019;37:2518–2518.

Abstract Background International guidelines for testing potentially immunosuppressed cancer patients receiving non-surgical anticancer therapies for SARS-CoV-2 (COVID-19) are currently lacking. The value of routinely testing staff treating cancer patients is not known. Methods Patient-facing oncology department staff at work during the COVID-19 pandemic consented to have a nasopharyngeal swab SARS-CoV-2 antigen test by polymerase chain reaction (PCR) and blood tests for SARS-CoV-2 antibody using a laboratory Luminex-based assay and a rapid point-of-care (POC) assay on 2 occasions 28 days apart in June and July 2020. Findings 434 participants were recruited: nurses (58·3%), doctors (21·2%), radiographers (10·4%) and administrators (10·1%). 82% were female; median age 40-years (range 19-66). 26·3% reported prior symptoms suggestive of SARS-CoV-2 infection and 1·4% tested PCR-positive prior to June 2020. All were PCR-negative at both study day 1 and 28. 18·4% were SARS-CoV-2 sero-positive on day 1 by Luminex, of whom 42·5% also tested positive by POC. 47·5% of Luminex sero-positives had antibodies to both nucleocapsid (N) and surface (S) antigens. Nurses (21·3%) and doctors (17·4%) had higher prevalence trends of Luminex sero-positivity compared with administrators (13·6%) and radiographers (8·9%) ( p =0.2). 38% of sero-positive participants reported previous symptoms suggestive of SARS-CoV-2 infection, a 1·9-fold higher odds than sero-negative participants ( p =0·01). 400 participants re-tested on day 28: 13·3% were Luminex sero-positive of whom 92·5% were previously positive and 7·5% newly positive. Nurses (16·5%) had the highest seroprevalence trend amongst staff groups ( p =0·07). 32·5% of day 1 sero-positives became sero-negative by day 28: the majority being previously reactive to the N-antigen only ( p &lt;0·0001). Interpretation The high prevalence of SARS-CoV-2 IgG sero-positivity in oncology nurses, and the high decline of positivity over 4 weeks supports regular antigen and antibody testing in this staff group for SARS-CoV-2 as part of routine patient care prior to availability of a vaccine. Funding ACT, NHS Evidence before this study To identify studies involving oncology healthcare workers and SARS-CoV-2 exposure during the COVID-19 pandemic, we searched PubMed and Medrxiv for articles published between January 1 and July 31 using the following search terms “COVID-19”, “SARS-CoV-2”, “oncology staff”, “healthcare workers” without language restriction. To date, no large study has specifically reported and tracked patient-facing oncology staff SARS-CoV-2 exposure. Added value of this study To the best of our knowledge, this is the first study specifically investigating SARS-CoV-2 exposure in UK patient-facing oncology staff who were at work during the peak of the COVID-19 pandemic between March and June 2020. 18·4% of staff were SARS-CoV-2 antibody positive at the start of June 2020 suggesting prior SARS-CoV-2 infection, while 32·5% of those antibody-positive cases became antibody-negative 28 days after the first sample collection. The highest seroprevalence rates at both time points were recorded in nurses. Implications of all the available evidence These results justify incorporating SARS-CoV-2 PCR and antibody testing of oncology nurses into international guidelines for managing cancer patients treated with non-surgical anticancer treatments prior to availability of a functional vaccine.

<h3>Background</h3> The gut microbiome of cancer patients appears to be associated with response to Immune Checkpoint Inhibitor (ICIs) treatment.^1–4 However, the bacteria linked to response differ between published studies. <h3>Methods</h3> Longitudinal stool samples were collected from 69 patients with advanced melanoma receiving approved ICIs in the Cambridge (UK) MELRESIST study. Pretreatment samples were analysed by Microbiotica, using shotgun metagenomic sequencing. Microbiotica’s sequencing platform comprises the world’s leading Reference Genome Database and advanced Microbiome Bioinformatics to give the most comprehensive and precise mapping of the gut microbiome. This has enabled us to identify gut bacteria associated with ICI response missed using public reference genomes. Published microbiome studies in advanced melanoma,^1–3renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC)⁴ were reanalysed with the same platform. <h3>Results</h3> Analysis of the MELRESIST samples showed an overall change in the microbiome composition between advanced melanoma patients and a panel of healthy donor samples, but not between patients who subsequently responded or did not respond to ICIs. However, we did identify a discrete microbiome signature which correlated with response. This signature predicted response with an accuracy of 93% in the MELRESIST cohort, but was less predictive in the published melanoma cohorts.^1–3 Therefore, we developed a bioinformatic analytical model, incorporating an interactive random forest model and the MELRESIST dataset, to identify a microbiome signature which was consistent across all published melanoma studies. This model was validated three times by accurately predicting the outcome of an independent cohort. A final microbiome signature was defined using the validated model on MELRESIST and the three published melanoma cohorts. This was very accurate at predicting response in all four studies combined (91%), or individually (82–100%). This signature was also predictive of response in a NSCLC study and to a lesser extent in RCC. The core of this signature is nine bacteria significantly increased in abundance in responders. <h3>Conclusions</h3> Analysis of the MELRESIST study samples, precision microbiome profiling by the Microbiotica Platform and a validated bioinformatic analysis, have enabled us to identify a unique microbiome signature predictive of response to ICI therapy in four independent melanoma studies. This removes the challenge to the field of different bacteria apparently being associated with response in different studies, and could represent a new microbiome biomarker with clinical application. Nine core bacteria may be driving response and hold potential for co-therapy with ICIs. <h3>Ethics Approval</h3> The study was approved by Newcastle &amp; North Tyneside 2 Research Ethics Committee, approval number 11/NE/0312. <h3>References</h3> Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. <i>Science</i> 2018;359(6371):104–108. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. <i>Science</i> 2018;359(6371):97–103. Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. <i>Neoplasia</i> 2017;19(10):848–855. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. <i>Science</i> 2018;359(6371):91–97.

We present the case of a 34-year old woman who initially presented with obesity and back pain. She was eventually diagnosed with Cushing's syndrome secondary to an adrenocortical carcinoma that had metastasised to her spine, causing cauda equina compression. The delays in reaching the correct diagnosis caused significant morbidity and exemplify the pitfalls of premature closing, a common cognitive error in diagnostic reasoning.

TPS4183 Background: Durvalumab/cis/gem improved overall survival (OS) in pts with advanced BTC versus placebo/cis/gem (Oh et al. NEJM Evid 2022). Disruption of the microbiota may impair tumour response to immunotherapy and chemotherapy and a better understanding of its role in the efficacy of these therapeutics in advanced BTC is required. Methods: This is a multi-centre, single arm trial exploring the microbiome in pts receiving durvalumab 1500 mg intravenously (IV) Q3w, in combination with cis 25 mg/m 2 , gem 1000 mg/m 2 (Days 1 and 8, Q3w) up to 8 cycles, followed by durvalumab 1500 mg as monotherapy Q4w, until progression or intolerable toxicity. Pts with an ECOG performance status of ≤1 and histologically-proven BTC, including cholangiocarcinoma and gallbladder carcinoma, who have had no prior systemic chemotherapy for locally advanced or metastatic disease are eligible. Pts must provide a saliva and stool sample prior to commencement of durvalumab/cis/gem and at 18 weeks, or at progression (if earlier than 18 weeks). Taxonomic profiling via 16S Ribosomal ribonucleic acid gene sequencing will examine the differences in the diversity and composition of the pt gut microbiome. Pts must also have availability of a tumour biopsy. This study plans to recruit 70 pts from 10 UK centres (over 12 months). The primary objective is to determine the difference in baseline alpha diversity between “responders” (partial or complete response) and “non-responders” at 18 weeks (RECIST 1.1) in patients treated with durvalumab/cis/gem. Secondary objectives include investigation of the association between microbiome parameters and objective response rate, tumour control (partial + complete response + stable disease), progression-free and OS, and to investigate the interaction between treatment effect and microbiome parameters on clinical outcomes. The tumour biopsy will be used for research into the tumour microbiome and/or factors that may influence response to chemotherapy/immunotherapy, including, but not limited to tumour mutation burden, programmed cell death 1/programmed death-ligand 1 status, and microsatellite instability status. Clinical trial information: ISRCTN11210442 .

Most cytotoxic chemotherapy drugs exert their effect by inhibiting one or more of the processes involved in cell division. It appears that the fate of cells damaged by chemotherapy is to die primarily by induction of apoptosis (programmed cell death). Chemotherapy is generally used to treat cancer at an advanced or early stage.

Abstract Recent advances in the research and clinical applications of circulating tumour DNA (ctDNA) is limited by practical considerations of sample collection. Whole genome sequencing (WGS) is increasingly used for analysis of ctDNA, identifying copy-number alterations, fragment size patterns, and other genomic features. We hypothesised that low-depth WGS data may be generated from minute amounts of cell-free DNA, and that fragment-size selection may be effective to remove contaminating genomic DNA (gDNA) from small volumes of blood. There are practical advantages to using dried blood spots as these are easier to collect, facilitate serial sampling, and support novel study designs in prospective human studies, animal models and expand the utilisation of archival samples by the removal of gDNA in small volumes. We therefore developed a protocol for the isolation and analysis of cell-free DNA from dried blood spots. Analysing a dried blood spot of 50μL frozen whole blood from a patient with melanoma, we identified ctDNA based on tumour-specific somatic copy-number alterations, and found a fragment size profile similar to that observed in plasma DNA processed by traditional methods. We extended this approach to detect tumour-derived cell-free DNA in a dried blood spot from a mouse xenograft model and were able to identify ctDNA from the originally grafted ascites. Together, our data suggests that ctDNA can be detected and monitored in dried blood spots. This will enable new approaches for sample collection from patients and in vivo models.

Over the past five years, three anticancer drugs (ipilimumab, pembrolizumab and nivolumab) belonging to a new class known as immune checkpoint inhibitors have become available, which are already having an impact on survival in patients with metastatic melanoma and offering promise in the treatment of other malignancies. However, close monitoring for immune-related adverse events, which can occasionally be severe or fatal, is an important component of treatment.

Poor outcome in pancreatic ductal adenocarcinoma (PDA) is associated partly with stromal hyaluronan (HA) accumulation, which may compromise chemotherapy access to tumors. In animal models, PEGPH20 degrades HA in tumors. Interim data from a phase 2 study showed that PEGPH20 plus chemotherapy improved efficacy over chemotherapy alone in tumors retrospectively identified to accumulate HA (“HA-High”). The objectives of this phase 3 study are to compare efficacy and safety of standard-dose nab-paclitaxel (NAB) and gemcitabine (GEM) combined with either PEGPH20 or placebo in patients with HA-High, previously untreated, Stage IV PDA. Primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints are objective response rate, duration of response, and safety. Trial design: 420 patients ≥18 years with untreated HA-High metastatic PDA, ECOG PS 0-1 will be randomized (stratified by geographic region: North America/Europe/Other) 2:1 to NAB 125 mg/m2 + GEM 1000 mg/m2 + PEGPH20 3.0 µg/kg or to placebo. Patients with HA-High tumors will be prospectively identified by a companion diagnostic test and scoring algorithm (Ventana Medical Systems, Inc.), which defines HA-High staining in the extracellular matrix as ≥50% of the tumor surface. Treatment will be provided in 4-week cycles (Wk 1-3, Wk 4 rest) until disease progression, unacceptable toxicity, death, or consent withdrawal. PEGPH20 or placebo will be given twice weekly (Cycle 1) then weekly (Cycles 2+), NAB + GEM once weekly for all cycles. Dexamethasone will be given before and after PEGPH20 to reduce treatment-related musculoskeletal symptoms and enoxaparin will be given to minimize thromboembolic events. Tumor response will be assessed by an independent central reader by RECIST v1.1. Adverse events will be graded per NCI CTCAE v4.03. An independent Data Monitoring Committee will evaluate safety and interim data for PFS and OS analyzed by an independent statistical analysis center. Clinical trial identification: EudraCT 2015-004068-13; NCT02715804 Legal entity responsible for the study: Halozyme Therapeutics Halozyme Therapeutics

Abstract Background: IMCgp100 comprises an affinity-enhanced T cell receptor (TCR) specific for the HLA-A2 restricted melanoma gp100 peptide (YLEPGPVTA) fused to an anti-CD3 antibody fragment. Binding of IMCgp100 to melanoma cells redirects T cell cytotoxicity even in the presence of significant levels of PD-1 and PD-L1. Importantly, IMCgp100 enables T cells to kill HLA down-regulated melanoma cells otherwise invisible to cancer specific T cells. A Phase I study was conducted to determine the Maximum Tolerated Dose (MTD) and toxicity of IMCgp100 in patients with metastatic melanoma. Methods: HLA A2 positive patients with Stage IV or unresectable Stage III melanoma, with an ECOG Performance Status (PS) ≤1 and a lymphocyte count of ≥0.5x109/L were enrolled. Those with symptomatic, unstable brain metastases requiring steroids and those who might benefit from immediate vemurafenib treatment were excluded. IMCgp100 was administered on day 1 and patients followed to day 30. Those who tolerated the first dose received repeated cycles of six weekly doses. The dose of IMCgp100 was escalated in cohorts of 3 (+3) patients until criteria for MTD were met. MTD was defined as the highest dose level with an observed incidence of Dose Limiting Toxicity (DLT) in fewer than 33% of patients enrolled at that level. Transient Grade 3 lymphopenia and Grade 3 skin toxicity were excluded from the definition of a DLT. Results: 31 patients were enrolled in 8 cohorts (doses from 5 to 900ng/Kg). 58% were male, median age was 61, ECOG PS 0 in 52% and 1 in 48%. All but 1 patient had stage IV disease. 60% of patients had received systemic treatment with DTIC (29%), ipilimumab (6%), vemurafenib (3%) or one or more experimental therapies (22%) prior to enrolment. At dose 900ng/Kg, 2/4 patients developed Grade 3 hypotension, therefore the MTD was defined at 600ng/Kg. Common toxicities included transient grade 3 pruritic rash and grade 2 pyrexia. Patients experienced profound lymphocyte trafficking to skin as evidenced by immunohistochemical analysis of skin biopsies, accompanied by chemokine/cytokine release. Rash was initially observed at dose level 45ng/Kg. Tumor flare was observed in patients with cutaneous or subcutaneous disease. Four partial responses (PR) and multiple lesser responses (not meeting RECIST PR) have been documented to date. One PR was achieved after a single dose. Two PRs continue after &amp;gt;9 months of continued treatment. One patient continues with stable disease for &amp;gt;10 months. Sites of response included the lung, the liver, the lymphatic system and various soft tissues. Conclusions: Toxicities of IMCgp100 were consistent with the mode of action of the drug i.e. IMCgp100 mediated T cell mobilisation, activation and tumor killing. Objective durable responses were observed. The study has been expanded to accrue additional patients at 600ng/Kg and to explore potentially superior dosing regimens. Citation Format: Mark Middleton, Jeff Evans, Neil Steven, Pippa Corrie, Clive Mulatero, Mario Sznol, William H. Shingler, Dominic Smethurst, Namir Hassan, Yvonne McGrath, Bent Jakobsen. A Phase I study of IMCgp100: durable responses with a novel first-in-class immunotherapy for advanced melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT329. doi:10.1158/1538-7445.AM2014-CT329

Pippa Corrie speaks to Natasha Galukande, Assistant Commissioning Editor. Dr Corrie undertook a PhD in anticancer drug development before qualifying in medicine at Oxford University (Oxford, UK) and training in medical oncology at the University of Birmingham (Birmingham, UK). Pippa is now a Consultant Medical Oncologist and University Associate Lecturer at Cambridge University Hospitals NHS Foundation Trust (Cambridge, UK). She is Clinical Director for Systemic Therapies in the Cancer Division at Addenbrooke’s Hospital (Cambridge, UK), which sees over 3000 new patients each year, and lead Oncologist for the pancreatic cancer service at Addenbrooke’s Hospital and across the Anglia Cancer Network. She is Deputy Director of the Cambridge Cancer Trials Centre (Cambridge, UK) and a member of the National Cancer Research Institute Pancreatic Cancer Clinical Studies Group. Her goal is to improve outcomes for patients with chemoresistant cancers through the conduct of clinical trials. Her specialist interests are pancreaticobiliary cancers and melanoma, researching mechanisms of response and resistance to anticancer drugs.

<h3>Background</h3> Current guidelines set out when to start anticancer treatments but not when to stop as disease progresses and death approaches. Older cytotoxic agents are administered intravenously. Most newer drugs, such as Tyrosine-Kinase Inhibitors (TKIs), are oral and widely used in incurable disease with evidence of a few months9 survival benefit. New generation agents are considerably more expensive, typically around £5K per month, and perceived as easier to start than to stop. <h3>Aims</h3> Systematic literature review examining decisions to stop oral and parenteral anticancer agents in clinical practice, focusing on: a) How are decisions made? b) When are they made? c) Why are they made? d) Who makes them? <h3>Methods</h3> Seven electronic databases (Embase, Medline, PsycINFO, CINAHL, ASSIA, Web-of-Knowledge, Cochrane Collaboration), grey literature, references and citations were searched. <h3>Results</h3> Forty-nine eligible papers were located. No studies were found concerning criteria for stopping TKIs in practice: most studies examined palliative chemotherapy generally. Key findings: The complexity of chemotherapy regimes means that decisions are not one-off, but rather an on-going process, before all treatments are finally stopped. This may involve switching to alternative therapies and taking breaks. Treatment was stopped when side-effects or burdens became too great. Non-clinical factors were also influential, including physicians9 personal experiences, emotions and history. While decision-making was part of the on-going physician-patient interaction, there was variation in who made the final decision: in some studies decisions to continue were patient-led, in others physicians continued treatment if there was evidence of benefit. Some studies presented stopping as ‘biological fact’, treatment being stopped when the patient became too ill. <h3>Conclusions</h3> Evidence to inform decision-making concerning stopping palliative anticancer therapy is variable and absent for new generation oral agents such as TKIs. Further research is urgently needed in this area to inform optimal patient care decisions in a resource-constrained NHS.

Abstract Despite significant advances in the treatment of metastatic melanoma long-term remission for the majority of patients remains elusive. Kinase inhibitors provide potent but short-term responses for a significant proportion of patients and immunotherapy elicits long-term responses but only in a minority. IMCgp100 is a novel bi-specific immunotherapy comprising a soluble, affinity-enhanced, T cell receptor (TCR) specific for the melanoma-associated antigen gp100, fused to an anti-CD3 specific antibody fragment (scFv). The engineered TCR portion of the drug targets the gp100 peptide 280-288 antigen, which is over-expressed and presented by HLA-A2 on the surface of melanoma cells, thereby effectively coating these cells with CD3-specific antibody fragments. The anti-CD3 scFv portion captures and redirects T cells in physical contact with the melanoma cell to kill it. In vitro IMCgp100 potently redirects T cells from the blood of late stage cancer patients to target melanoma cells exhibiting substantial HLA-down regulation, even in the presence of high numbers of regulatory T cells. Target cell killing is observed within hours, and is associated with the release of pro-inflammatory cytokines and dendritic cell cross-presentation of gp100 and other melanoma-specific antigens. Thus, IMCgp100 demonstrates the potential to elicit potent short-term responses and trigger longer-term anti melanoma activity. As part of a Phase 1 dose-finding study in HLA-A2 positive patients with advanced melanoma, 18 patients have received single IV infusions of 5, 15, 45, 135, 270 or 405ng/Kg of IMCgp100. Seven patients have subsequently received weekly IMCgp100 infusions for 6 weeks, with a brief clinical response in 1 patient at 270ng/Kg. To date, the most frequent drug related toxicities observed are rash (12 patients), pruritus (7), hypotension (5) and oedema (7), starting at the 45ng/Kg dose level. The frequency, severity and duration of adverse events demonstrate a clear dose response relationship. Pharmacodynamic data show a transient reduction in peripheral lymphocyte count 24h after dosing, consistent with the proposed mechanism of action of IMCgp100. Pharmacokinetic analysis indicates a linear dose relationship, with Cmax at 4h and T1/2 of approximately 9h. IMCgp100 is well-tolerated, with evidence of T-cell trafficking after dosing. Toxicity to date has been consistent with on target effects. Citation Format: Mark Middleton, Jeff Evans, Neil Steven, Pippa G. Corrie, Clive Mulatero, Debbie Baker, Giovanna Bossi, Katherine Adams, Jane Harper, Andy Johnson, William Shingler, Dominic Smethurst, Namir Hassan, Yvonne McGrath, Bent Jakobsen. IMCgp100: a novel bispecific biologic for the treatment of malignant melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1238. doi:10.1158/1538-7445.AM2013-1238

BackgroundCirculating tumour DNA (ctDNA) is released by cancer cells into the bloodstream, which can be analysed via liquid biopsy. Analysis of liquid biopsy samples provides a real-time snapshot of tumour burden. After treatment, ctDNA concentrations can be low, making detection challenging. To study clonal evolution during treatment in patients with melanoma with high sensitivity, we sought to maximise the number of mutations targeted through individualised next-generation sequencing panel design.Methods72 patients with stage III or IV melanoma were recruited to MelResist, a translational, multicentre research study. Serial plasma samples were taken from patients at monthly intervals during treatment (median 6·7 samples per patient). Clinical events were scored according to Response Evaluation Criteria In Solid Tumors (RECIST) (version 1.1) criteria. Exome and targeted sequencing were carried out on tumour samples at baseline and progression for nine patients, whose identified mutations were used to design an individualised targeted sequencing panel.FindingsMultiple mutations per patient were tracked to monitor response to therapy. The percentage change in ctDNA mutant allele fraction after treatment initiation agreed with RECIST response for seven out of eight evaluable patients. ctDNA concentration strongly correlated with lactate dehydrogenase (LDH) concentration, a currently used measure of melanoma tumour burden (r2=0·64, p=9·93 × 10−7). ctDNA dynamics were compared against rising LDH, which showed a median lead-time to biochemical progression (rising LDH) of 70 days (IQR 28–152·3). Targeting multiple mutations could improve sensitivity compared with individual mutations.InterpretationIn this study, we applied an individualised targeted sequencing panel on ctDNA from patients with melanoma. As tumour sequencing becomes more routine, individualised sequencing panel design might become more feasible, facilitating a more sensitive approach for ctDNA analysis than targeting individual loci. Tracking clonal evolution during therapy non-invasively may facilitate personalised treatment decisions with molecularly targeted agents.FundingCancer Research UK, Lewis Family Charitable Trust, Addenbrooke's Charitable Trust, Cambridge Cancer Trials Centre, NIHR Cambridge Biomedical Research Centre and Human Research Tissue Bank.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The potential for researchers and patients to work together in designing and doing clinical trials you allude to in your editorial1Editorial. How consumers can and should improve clinical trials.Lancet. 2001; 357: 1721Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar might not be rocket science, but the practicalities of implementing such collaborations are nonetheless complex. The Consumers' Advisory Group for Clinical Trials (CAGCT), cofounded in 1995 by Michael Baum (breastcancer surgeon) and Hazel Thornton (cancer patient), with a primary interest in cancer research, exemplifies these predicaments. Now under new chairmanship, following Thornton's retirement in 1999, the current CAGCT executive can no longer boast any member who has had cancer. However, most have, at one time or another, participated in clinical trials. Lay and professional members of the group are committed to improving accrual of patients to clinical trials, but our success in achieving this goal to date is disappointing. Although many cancer consumer groups exist in the UK, so far none has achieved the success of the American Breast Cancer Coalition group in encouraging women to participate in the Herceptin trials, which has proved to be an effective treatment. However, one success story in the USA is not a great track record, since research suggests that only 5% of new cancer patients enter therapeutic trials, the same as in the UK. So where is advocacy for patients going wrong? The public cannot continue to blame barred access to the clinical and scientific communities involved in designing and doing clinical trials. This predicament has been overcome, largely thanks to the acknowledgment of the importance of the consumer voice by the Medical Research Council, the UK Coordinating Committee on Cancer Research, and the National Cancer Research Network. Thus, for example, the national Standardisation of Breast Radiotherapy (START) trial, done to assess adjuvant radiotherapy for breast cancer, has been designed with representation from the action group Rage. However, most of society holds strong, commonly negative, views on research done on human beings, yet few individuals bother to get involved with the process. Apathy, ignorance, and in the case of cancer patients, shortened life expectancy, are key predicaments for consumer groups, which are generally small with negligible independent funding. We need the assistance of experienced research bodies to identify consumers, and to train them to become influential voices. We also need these bodies to acknowledge our contribution, not least in monetary terms. Furthermore, communication among such groups is minimal. Better interaction could lead to the development of strong consensus consumer views more likely to affect the research community.

Background Patients with advanced cutaneous melanoma and persistent disease after checkpoint inhibitor therapy have poor outcomes and limited treatment options, highlighting a significant unmet medical need. 1 Autologous TIL cell therapies have shown promise in this population attributable, in part, to their intrinsic and patient-specific antitumor activity 2 ; however, no such therapies are approved. Made from each patient‘s digested and cryopreserved tumor, ITIL-168 is an autologous TIL cell therapy manufactured to offer an unrestricted T-cell receptor repertoire. A single-center compassionate use clinical series demonstrated the feasibility and clinical utility of an earlier version of ITIL-168. 3 DELTA-1 is a global, multicenter phase 2 study to evaluate efficacy and safety of ITIL-168. DELTA-1 will enroll patients with melanoma relapsed after or refractory to PD-1 inhibitors (PD-1i), patients intolerant to PD-1i, and patients whose best response to PD-1i was stable disease. Methods Patients aged ≥18 years with histologically confirmed advanced cutaneous melanoma, ECOG performance status 0–1, and adequate organ function will be enrolled in 1 of 3 cohorts. Cohort 1 (n≈80) will include patients who relapsed after or were refractory to ≥1 prior line of systemic therapy, including a PD-1i and, if BRAF-mutated, a BRAFi ± MEKi. Cohorts 2 and 3 (n≈25 each) will include patients intolerant to PD-1i and those with stable disease after ≥4 doses of PD-1i, respectively. After tumor resection for TIL harvest, patients must have ≥1 remaining measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patients with uveal, acral, or mucosal melanoma, prior allogeneic transplant or cell therapy, and with central nervous system (CNS) disorder or symptomatic and/or untreated CNS metastases are ineligible. Patients will receive 5 days of lymphodepleting chemotherapy (cyclophosphamide ×2 days overlapping with fludarabine ×5 days) followed by a single ITIL-168 infusion (≥5×109 cells) and supportive short course high-dose IL-2. The primary endpoint is objective response rate (ORR) per central review. Key secondary endpoints include duration of response, progression-free survival, overall survival, disease control rate, TIL persistence, and safety. Hypothesis testing of ORR will be performed for cohort 1. Two interim analyses will occur after 20 patients in cohort 1 have been followed for ≥28 days (safety) and evaluated for response ≥3 months after ITIL-168 infusion (futility). The primary analysis will occur when all patients in the cohort 1 modified intent-to-treat population have been followed for ≥6 months after the first posttreatment disease assessment. Acknowledgements Medical writing support was provided by Christopher Waldapfel, PharmD, of Instil Bio, Inc, and Phylicia Aaron, PhD, of Nexus GG Science, with funding from Instil Bio, Inc. References Schadendorf D, van Akkoi ACJ, Berking C, et al. Melanoma. Lancet 2018; 392 (10151):971–984. Borch TH, Anderson R, Ellebaek E, et al. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer 2020; 8 (2):e000668. Hawkins RE, Jiang Y, Lorigan PC, et al. Clinical feasibility and treatment outcomes with unselected autologous tumor infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma. Cancer Res 2021; 81 (13):LB150. Ethics Approval All patients will provide written informed consent. The study will be approved by the Institutional Review Board/Independent Ethics Committee at each site and conducted in accordance with the Good Clinical Practice Guidelines of the International Conference on Harmonisation. Consent N/A; the abstract does not contain sensitive or identifiable patient information.

Primary mediastinal large B-cell lymphoma (PMLBCL) is a distinct clinical and biological disease from other types of DLBCL. It is more frequent in young female and constitutes 6%-10% of all DLBCL. PMLBCL is characterized by a diffuse proliferation of medium to large B-cells associated with sclerosis. Molecular analysis shows it to be a distinct entity from other DLBCL. Rituximab CHOP/MACOP-B-like regimens followed by mediastinal radiotherapy (RT) were associated with a 5-years PFS of 75%–85%. More intensive regimens, as DA-EPOCH-R without mediastinal RT, have shown very promising results, but this therapeutic advance needs to be confirmed in further prospective trials. The role of consolidative mediastinal RT should be still better assess in prospective comparative studies. PET-CT scan is a powerful tool to define the real quality of response and it is hoped that future prospective trials may allow its role in the de-escalation of mediastinal RT.

Chemotherapy followed by consolidation chemoradiotherapy (CRT) is a treatment option for locally advanced non-metastatic pancreatic cancer (LAPC), but outcome remains poor. The SCALOP trial identified a feasible, safe, and effective CRT regimen for LAPC: capecitabine (830mg/m2 oral bd) as radiosensitisation + 50.4Gy in 28 fractions. The two-stage SCALOP-2 trial aims to improve this regimen by increasing radiotherapy dose intensity and adding nelfinavir as an additional radiosensitising AKT inhibitor.

Abstract Improving outcomes in pancreatic adenocarcinoma remains a key challenge, and few advances have yet impacted significantly on life expectancy; the overall 5-year survival rate remains less than 5%, even including patients undergoing surgical resection. This case history illustrates the difficulties in diagnosis and the complexity of this disease. Most patients present too late for curative surgery, and symptom palliation involves multidisciplinary approaches to relieve common problems associated with obstructive jaundice, pain, cachexia, and ascites. Venous thromboembolism is also common, and its management discussed here. Although responses to chemotherapy and radiotherapy are poor, systemic therapy has been established as an effective adjuvant for those patients identified early enough to undergo surgery, whilst, in advanced disease, recent approaches to combination chemotherapy may offer modest improvements in life expectancy. However, drug-induced toxicity limits patients &amp;lt;tolerance of treatment. Considerable hope lies in a better understanding of the molecular characteristics of this disease, which may yield novel targets for therapeutic intervention.

Antiangiogenesis in Cancer Therapy Mechanism of action of approved antiangiogenesis agents: overview for cliniciansSarah J Welsh, Tobias Janowitz & Pippa CorrieSarah J WelshSarah J Welsh is an Academic Clinical Lecturer in medical oncology at the University of Cambridge (UK) and Cambridge University Hospitals NHS Foundation Trust (UK). Her research is based in the Cancer Research UK Cambridge Institute where her research focuses on exploiting pathways within the tumor microenvironment as a treatment strategy in solid malignancies.Search for more papers by this author, Tobias JanowitzTobias Janowitz holds an Academic Clinical Lecturer post in medical oncology at the University of Cambridge (UK). His research and clinical post are funded by the Wellcome Trust Translational Medicine and Therapeutics program. His main research interests are host responses to cancer and development of new cancer treatments.Search for more papers by this author & Pippa CorriePippa Corrie is Consultant and Associate Lecturer in medical oncology at Cambridge University Hospitals NHS Foundation Trust. Her main interest is improving outcomes for chemoresistant cancers: in particular, melanoma and pancreatic cancer. She is Chief Investigator of the AVAST-M (adjuvant bevacizumab in high-risk melanoma) NIHR portfolio trial.Search for more papers by this authorPublished Online:25 Aug 2014https://doi.org/10.2217/ebo.13.732AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View chapterAbstract: Summary Angiogenesis plays a key role in the development and progression of a number of solid malignancies. Understanding the molecular pathways of angiogenesis has been a crucial step towards the development of treatments for these cancers. Blocking angiogenesis pathways has led to several direct and indirect angiogenesis inhibitors being licensed for clinical use. This chapter introduces the process of angiogenesis and highlights key aspects relevant to treatment of cancer. It also briefly introduces drugs that have been approved for the treatment of solid malignancies, which will be discussed in further detail in subsequent chapters. References1 Folkman J . Tumor angiogenesis: therapeutic implications . N. Engl. J. Med. 285 , 1182 – 1186 (1971) . Google Scholar2 Hanahan D , Weinberg RA . Hallmarks of cancer: the next generation . Cell 144 , 646 – 674 (2011) . Google Scholar3 Carmeliet P , Jain R . Molecular mechanisms and clinical applications of angiogenesis . Nature 473 , 298 – 307 (2011) . Google Scholar4 Denekamp J . 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