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Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Background 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. Methods 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. Results 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). Conclusions SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. Clinical trial registration ISRCTN71070888; ClinialTrials.gov (NCT03529175).

Hepatocellular carcinoma (HCC) remains a leading cause of cancer death worldwide, and despite recent immunotherapeutic advances there remains a need for improved diagnostic, prognostic, and therapeutic tools. UL-16 binding protein 1 (ULBP1) is a ligand of the activatory receptor Natural Killer cell Group 2 receptor D (NKG2D) and is found as a cell-surface protein on some malignant cells including on human hepatocellular carcinomas. We aimed to explore the biological and clinical significance of NKG2D ligands in the circulation of patients with HCC. We measured ULBP1 in the serum of two retrospective cohorts of patients with HCC from the PROLIFICA cohort in The Gambia (n = 43) and from a tertiary care setting in the UK (n = 72) by sandwich ELISA. Exosome isolation by size exclusion was used to compare ULBP1 concentration in exosomes and as free protein. Survival analysis was performed and multiple linear regression and Poisson regression were used to assess the independent effect of ULBP1 concentration. ULBP1 was raised in both cohorts with HCC regardless of the underlying liver disease, and was not associated with markers of cirrhosis such as platelet count or serum albumin. ULBP1 was present predominantly as free protein rather than bound to exosomes. Serum ULBP1 > 2000 pg/ml was associated with a significantly reduced survival in both cohorts (hazard ratios in Gambian and UK cohorts 2.37 and 2.1, respectively). The effect remained significant after adjustment for BCLC staging (p = 0.03). These data suggest that ULBP1 merits further investigation as a prognostic marker in HCC in diverse settings and should also be explored as a therapeutic target.

Background: Advanced biliary tract cancer (ABC) has a poor prognosis for which cisplatin-gemcitabine is the reference first-line chemotherapy. No robust evidence is available for second-line chemotherapy. Methods: Patients with ABC who progressed on first-line cisplatin-gemcitabine were randomised to active symptom control (ASC) and oxaliplatin and 5-fluorouracil (FOLFOX) or ASC alone. The primary end-point was overall survival (OS); recruitment of 162 patients was required, to deliver 148 events (hypothesised hazard ratio (HR) 0.63; 80% power; 5% two-sided alpha). Secondary end-points included progression-free survival (PFS) and response rate (ASC+FOLFOX arm only). Results: A total of 162 patients were randomised (81 in each arm) between 27-Mar-2014 and 04-Jan-2018). The median age was 65 years (range 26-84); 80 (49%) were male and the primary tumour sites were intrahepatic cholangiocarcinoma (CCA) 72 (44%), extrahepatic CCA 45 (28%), gallbladder 34 (21%) and ampullary cancer 11 (7%). After 150 OS events, the adjusted HR was 0.69 (95%CI-0.50-0.97; p=0.031; ASC+FOLFOX vs ASC). Median OS (months (m)), 6m and 12m OS-rate (%) were 6.2m, 50.6% and 25.9% for the ASC+FOLFOX and 5.3m, 35.5%, 11.4% for the ASC arm, respectively. The median PFS was 4.0 months (95%-CI 3.2-5.0); the response rate was 5% and the disease control rate 33%. Grade 3-5 adverse events were reported in 56 (69%) and 42 (52%) patients in the ASC+FOLFOX and ASC arm, respectively, including two chemotherapy-related deaths. Conclusion: FOLFOX improved OS after progression to cisplatin-gemcitabine with a clinically-meaningful increase in 6m and 12m OS rate. FOLFOX should become standard-of-care in second-line for ABC. Trial Registration: NCT01926236, EudraCT: 2013-001812-30. Funding Statement: The study was sponsored by The Christie NHS Foundation Trust. The ABC-6 study was funded by Cancer Research UK (CRUK/13/004), StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity) and The Christie Charity. The Cholangiocarcinoma Foundation provided funding translational research. Dr Angela Lamarca received funding from ESMO (European Society for Medical Oncology), SEOM (Sociedad Espanola de Oncologia Medica) and Conquer Cancer Foundation (Young Investigator Award) fellowship programs and from The Christie Charity. Declaration of Interests: Dr Angela Lamarca received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen and Incyte; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche; she is also a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. Prof Daniel H Palmer declares research grants from AstraZeneca, Bayer, BMS, Nucana, Sirtex; and Consulting or Advisory roles for AstraZeneca, Bayer, BMS, Eisai, MSD, Servier, Roche. Harpreet Singh Wasan declares no conflict of interest associated to this work. Dr Paul J Ross declares research grants from research grants from Sanofi, Bayer; Consulting or Advisory roles for Bayer, BMS, Eisai, Sirtex, Roche; speaker fees from Amgen, Roche, Servier; Travel grants from Bayer, Roche, Servier. Dr Yuk Ting Ma declares speaker honoraria and advisory roles for Bayer, Eisai and Roche. Dr Arvind Arora declares no conflict of interest. Dr Stephen Flak declares no conflict of interest. Dr Roopinder Gilmore declares no conflict of interest. Prof Jon Wadsley declares research grants from AstraZeneca and Sanofi-Genzyme and Consulting or Advisory roles for Lilly, AstraZeneca, Sanofi Genyme, Eisai, AAA, Roche, Novartis, Ipsen. Dr Kinnari Patel declares no conflict of interest. Alan Anthony declares no conflict of interest. Prof Anthony Maraveyas declares research grants from Pfizer, BMS and Bayer. Speaker fees from BMS. Bayer Ipsen, EUSA Pharma, Daiichi Sankyo and Pfizer and advisory roles for Bayer ,BMS, Leo, Pfizer, Merck and Ipsen. Dr Tim Iveson declares no conflict of interest. Dr Justin S Walters received educational support for travel and conference attendance from Mylan and Ipsen, and speaker honoraria from Mylan. Dr Claire Hobbs declares no conflict of interest. Safia Barber declares no conflict of interest. David Ryder declares no conflict of interest. Prof John Ramage declares research grants, speaker fees and advisory roles for Ipsen, Novartis and AAA. Linda M Davies declares no conflict of interest. Prof John Bridgewater declares Consulting or Advisory role for Merck Serono, SERVIER, Roche, Bayer, AstraZeneca, Incyte and Basilea; travel support from MSD oncology, Merck Serono, Servier and BMS. Prof Juan W Valle declares Consulting or Advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, PierisPharmaceuticals, QED and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited Ipsen Novartis Nucana; and Travel Grants from Celgene and Nucana. Ethics Approval Statement: The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by a research ethics committee and all patients were required to provide written informed consent.

We report a rare presentation of metastatic renal cell carcinoma (RCC) in a 71-year-old man who presented with persistent shoulder pain. MRI revealed widespread lytic lesions within the bones suggestive of metastatic disease but extensive imaging including CT chest, abdomen and pelvis with contrast and fluorodeoxyglucose-positron emission tomography did not identify a primary cancer. The diagnosis was ultimately made from a targeted bone and subsequently targeted liver biopsy, whereby immunohistochemistry was consistent with metastatic RCC (mRCC). While bone metastases in RCC are very common, it is extremely rare for patients to present with mRCC and no identifiable renal primary.

ABSTRACT Aims: Sorafenib is the only standard therapy for advanced hepatocellular carcinoma, but has a low response rate. Leucovorin and oxaliplatin (FOLFOX) has a superior response rate versus doxorubicin among Asian sorafenib-naive patients. We aimed to retrospectively review the outcome of 20 consecutive patients treated with FOLFOX at a single European center. Materials & methods: Patients had symptomatic disease burdens unlikely to regress with sorafenib or had no proven treatment options (sorafenib-refractory or recurrence post liver transplantation). Results: One sorafenib-refractory patient had a complete response and two liver transplant patients experienced partial responses. Median overall survival was 6.3 months. There was one chemotherapy death due to neutropenic sepsis. Conclusion: In advanced hepatocellular carcinoma, FOLFOX can induce clinically relevant responses, but needs prospective validation.

4003 Background: Level A evidence supports use of CisGem as first-line chemotherapy for ABC; no robust evidence is available for second-line chemotherapy. Methods: Pts diagnosed with ABC with disease progression after prior CisGem were randomised (1:1) to either ASC+mFOLFOX or ASC. Randomisation was stratified by serum albumin levels ( < 35 vs ≥35 g/L), platinum sensitivity (determined from first-line CisGem) and disease extent (locally advanced vs metastatic). Pts with ECOG PS0-1, adequate haematological, renal and liver function, and adequate biliary drainage were eligible. Primary end-point was overall survival (OS) (multivariable Cox regression adjusted for stratification factors); sample size: 162 pts delivering 148 events were required (80% power; 5% two-sided alpha) for a hypothesised hazard ratio (HR) of 0.63. Assumed median survival for ASC was 4 months. Results: 162 pts (81 in each arm) were randomised (27 March ‘14 - 04 Jan ‘18); median age 65 yrs (range 26-84); sex: 80 (49%) male, 82 (51%) female; primary site: intrahepatic 72 (44%), extrahepatic 45 (28%), gallbladder 34 (21%) and ampullary 11 (7%). Baseline characteristics were balanced between arms except platinum sensitivity (ASC+mFOLFOX 27 pts (33%); ASC 34 pts (42%)). After 150 OS events, the adjusted HR was 0.69 (95% CI 0.50-0.97; p = 0.031; ASC+mFOLFOX vs ASC). Median OS (months (m)), 6m and 12m OS-rate (%) were 6.2m, 50.6% and 25.9% for the ASC+mFOLFOX and 5.3m, 35.5%, 11.4% for the ASC arm, respectively. Grade 3/4 toxicities were reported in 48 (59%) and 32 (39%) pts in the ASC+mFOLFOX and ASC arm, respectively; these were balanced between arms except for fatigue and neutropenia (more frequent in ASC+mFOLFOX arm); data cleaning is ongoing. No chemotherapy-related deaths were reported. Conclusion: Survival with ASC was greater than assumed; ASC+mFOLFOX improved OS after progression to CisGem with a clinically meaningful increase in 6m and 12m OS rate. ASC+mFOLFOX should become standard of care in second-line for ABC. Clinical trial information: NCT01926236.

IntroductionThe presence of positive nodal disease (LND) and the number of lymph nodes involved (LNB) are known to be significant prognostic markers for resected adenocarcinoma of the pancreas. In addition, the ratio of the number of involved nodes to the number of nodes resected known as the lymph node ratio (LNR) is emerging as an important prognostic marker. The role of the resection margin (RM) as presently defined (R1 ≤ 1 mm) is unclear as results differ based on the dataset. The aim of this study was to assess the impact of nodal disease and a redefined RM on outcome.Material and methodsRetrospective analysis of pancreatic head resections for adenocarcinomas from 2003–2009. The RM was re‐analysed based on tumour clearance and categorized into: histopathological evidence of a tumour; ≤0.5 mm, ≤1 mm, ≤1.5 mm, or ≤2.0 mm of the actual surgical resection margin. The impact of histopathological variables on cancer‐specific survival (CSS) and disease‐free survival (DFS) was analysed.ResultsLND, LNB and LNR were independent prognostic markers for CSS (P = 0.048, 0.003, 0.016) but, did not influence DFS. A LNR < 0.143 was associated with a higher CSS [38.16 ± 4.69 versus 20.59 ± 2.20 months, P = 0.0042, hazard ratio (HR) 3.74 (95% confidence interval (CI) 1.52–9.23)]. An R1 RM was not associated with CSS or DFS on multivariate analysis, irrespective of the distance. LNB and LNR maintained independent significance irrespective of the size of the RM.ConclusionLNB and LNR are the only prognostic factors for CSS in patients with pancreatic head adenocarcinoma, but do not predict recurrence. Microscopic RMs does not seem to influence the outcome even when redefined. Further prospective studies are indicated to substantiate these findings.

Background: Transarterial chemoembolisation (TACE) has not been shown to be superior to bland embolisation (TAE) for treatment of hepatocellular carcinoma (HCC). Methods: We conducted a randomised phase II/III trial in patients with untreated HCC. Patients were randomised to TAE with polyvinyl alcohol (PVA) particles alone or sequential TACE (sTACE) in which cisplatin 50 mg was administered intrarterially 4–6 h before PVA embolisation. Treatment was repeated 3-weekly for up to three treatments. The primary endpoint was overall survival and secondary endpoints were progression-free survival, toxicity and response. Target sample sizes for phase II and III were 80 and 322. Results: The trial was terminated at phase II after 86 patients had been randomised. Patients were well matched for prognostic criteria. All three planned treatments were given to 57.1% (TAE) and 56.8% (TACE) patients. Grade 3/4 toxicity occurred in 63.5% and 83.7%, respectively (P=0.019). End-of-treatment RECIST response (CR+PR) was 13.2 and 32.6% (P=0.04) (mRECIST 47.3% and 67.4) and median overall survival and progression-free survival was 17.3 vs 16.3 (P=0.74) months and 7.2 vs 7.5 (P=0.59), respectively. Conclusion: Transarterial chemoembolisation according this novel schedule is feasible and associated with a higher response rate than TAE alone. The survival benefit of TACE over TAE remains unproven.

Summary Background The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. Methods We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m 2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m 2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. Findings Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5–31·5) compared with 25·5 months (22·7–27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68–0·98], p=0·032). 608 grade 3–4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3–4 adverse events in 196 of 366 patients in the gemcitabine group. Interpretation The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. Funding Cancer Research UK.

Background: There is no specific quality of life (QoL) measurement tool to quantify QoL in patients with biliary tract cancer. Quality of life measurement is an increasingly crucial trial end point and is now being incorporated into clinical practice. Methods: This International Multicentre Phase IV Validation Study assessed the QLQ-BIL21 module in 172 patients with cholangiocarcinoma and 91 patients with cancer of the gallbladder. Patients completed the questionnaire at baseline pretherapy and subsequently at 2 months. Following this, the psychometric properties of reliability, validity, scale structure and responsiveness to change were analysed. Results: Analysis of the QLQ-BIL21 scales showed appropriate reliability with Cronbach's α-coefficients >0.70 for all scales overall. Intraclass correlations exceeded 0.80 for all scales. Convergent validity >0.40 was demonstrated for all items within scales, and discriminant validity was confirmed with values

Goblet cell carcinoid tumours are often considered a subset of appendiceal neuroendocrine tumours which behave more aggressively. They usually metastasize through transcoelomic/peritoneal invasion and common sites include the ovaries, peritoneum, and liver. Metastases may have goblet cell carcinoid, signet ring cell carcinoma or classic carcinoid histology. We report the first case in the literature of a patient with a goblet cell carcinoid with lung metastasis, which was associated with unfavourable outcome.

BACKGROUND: The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen.METHODS: We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mgm(-2)), cisplatin (70 mgm(-2)) and streptozocin (1000 mgm(-2)) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival.RESULTS: In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3-4 toxicity was neutropaenia (28% patients) but grade 3-4 infection was rare (7%). The most frequent non-haematological grade 3-4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and a-fetoprotein.CONCLUSION: FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response. British Journal of Cancer (2010) 102, 1106-1112. doi:10.1038/sj.bjc.6605618 www.bjcancer.com Published online 16 March 2010 (C) 2010 Cancer Research UK

Patients presenting with ascites associated with peritoneal disease have a wide differential diagnosis including both malignant and non-malignant related causes. We present the unusual case of a patient, clinically deteriorating, whose malignant peritoneal disease was due to an underlying follicular lymphoma. An urgent staging CT scan followed by a peritoneal biopsy allowed the patient to start chemotherapy within days of acute presentation to the hospital. This case emphasises the importance of obtaining tissue diagnosis urgently in these patients to ensure that the correct treatment can be started in a timely manner.

Reference A 78-year-old man with locally advanced adenocarcinoma of he pancreas presented to the emergency department with an acute istory of fresh rectal bleeding. He had signs of hypovolaemic shock nd his haemoglobin decreased from 9.3 to 6.9 g/dL over 12 h. He ad previously received chemotherapy and chemo-radiotherapy nd 4 months prior had undergone an endoscopic retrograde holangio-pancreatography (ERCP) and biliary stenting for jaunice. The patient had a computerised tomography (CT) angiogram hich demonstrated a blush of contrast adjacent to the covered etal biliary stent. This was arising from a pseudoaneurysm of the astroduodenal artery at the level of the head of pancreas tumour djacent to the metal stent, with radiological evidence of active xtravasation (Fig. 1).

Cytotoxic T lymphocytes (CTLs) specific for an HLA-A2–presented peptide epitope of the Wilms tumor antigen-1 (WT1) can selectively kill immature human leukemia progenitor and stem cells in vitro. In this study we have used retroviral gene transfer to introduce a WT1-specific T-cell receptor (TCR) into T lymphocytes obtained from patients with leukemia and from healthy donors. TCR-transduced T cells kill leukemia cells in vitro and display WT1-specific cytokine production. Intravenous injection of TCR-transduced T cells into nonobese diabetic–severe combined immunodeficiency (NOD/SCID) mice harboring human leukemia cells resulted in leukemia elimination, whereas transfer of control T cells transduced with an irrelevant TCR was ineffective. The data suggest that adoptive immunotherapy with WT1-TCR gene–modified patient T cells should be considered for the treatment of leukemia.

The willow tree has been a source of remedies against fever and inflammation since ancient times. Just over a century ago, Hoffman isolated and modified an active compound from the willow tree and offered it for sale as aspirin. Subsequently, a number of similar compounds have been derived, and these have been classified as non-steroidal anti-inflammatory drugs or NSAIDs. These drugs inhibit the enzyme cyclo-oxygenase (COX), which catalyses the conversion of arachidonic acid to prostaglandins (PGs). PGs are important mediators of signal transduction pathways, and are involved in cellular adhesion, growth and differentiation. Aspirin and other NSAIDs are extensively used in cancer patients, primarily for analgesia. However, since the late 1970s, researchers have been interested in whether regular ingestion of aspirin and other NSAIDs can decrease cancer risk. The most persuasive evidence to date relates to colorectal cancer. Is there a role for these drugs in the primary prevention of cancer, or even the treatment of established disease? Here, we review the theoretical, experimental, epidemiological and clinical data relevant to this question. Two isoforms of COX exist, with distinct tissue distributions and physiological functions. COX-1 is constitutively expressed in many tissues and cell types, whereas the inducible isoenzyme COX-2 is pro-inflammatory in nature, and expressed only in response to certain stimuli such as mitogens, cytokines and growth factors. NSAIDs may achieve different degrees of inhibition of COX-1 and COX-2. Specific COX-2 inhibitors such as celecoxib and rofecoxib have been developed, and these largely avoid the gastrointestinal side-effects associated with NSAID use, which are thought to be due mainly to COX-1 inhibition. A number of studies have demonstrated over-expression of COX-2 in solid malignancies including colon,1 prostate,2 and breast3, as well as pancreas, non-small-cell lung, bladder, endometrium and skin basal and squamous cell.4 A significant relation … Address correspondence to Professor J. Waxman, Department of Cancer Medicine, Faculty of Medicine, Imperial College of Science, Technology & Medicine, Hammersmith Campus, Du Cane Road, London W12 0NN. email: j.waxman{at}ic.ac.uk

SummaryAdoptive antigen-specific immunotherapy is an attractive concept for the treatment of cancer because it does not require immunocompetence of patients, and the specificity of transferred lymphocytes can be targeted against tumour-associated antigens that are poorly immunogenic and thus fail to effectively trigger autologous T cell responses. As the isolation and in vitro expansion of antigen-specific lymphocytes is difficult, ‘conventional’ adoptive T cell therapy can only be carried out in specialized centres in small numbers of patients. However, T cell receptor (TCR) genes isolated from antigen-specific T cells can be exploited as generic therapeutic molecules for ‘unconventional’ antigen-specific immunotherapy. Retroviral TCR gene transfer into patient T cells can readily produce populations of antigen-specific lymphocytes after a single round of polyclonal T cell stimulation. TCR gene modified lymphocytes are functionally competent in vitro, and can have therapeutic efficacy in murine models in vivo. TCR gene expression is stable and modified lymphocytes can develop into memory T cells. Introduction of TCR genes into CD8+ and CD4+ lymphocytes provides an opportunity to use the same TCR specificity to produce antigen-specific killer and helper T lymphocytes. Thus, TCR gene therapy provides an attractive strategy to develop antigen-specific immunotherapy with autologous lymphocytes as a generic treatment option.

We report two cases of carcinoma of the prostate metastasising to the dura. It is unusual for dural metastases from carcinoma of the prostate to cause clinical manifestation. We review late stage prostatic carcinoma metastasising the dura, and its symptomatic response to treatment.

The admission of critically unwell patients with cancer to the intensive care unit (ICU) often presents physicians and intensivists with a clinical and ethical dilemma. Studies in the 1990s cited ICU mortality rates of 75–91% for cancer patients who required intubation, and up to 95% in patients

4100 Background: NabP+GEM chemotherapy improves survival compared with GEM monotherapy as treatment for mPDAC. A PDAC mouse model suggested that nabP potentiates GEM activity by reducing cytidine deaminase levels and scheduling may be critical to optimise clinical benefit. Methods: Patients (pts) were randomised to receive standard concomitant (CON) nabP+GEM or sequential (SEQ) administration, with nabP given 24 hours before GEM. After 6 cycles, pts benefiting from treatment could continue the same regimen until disease progression. The primary endpoint was progression-free survival (PFS) by RECIST v1.1; secondary endpoints included safety, objective response rate (ORR), overall survival (OS) and quality of life (QoL). Serial blood and baseline tumour samples were collected for exploratory biomarkers. Results: Between March 2014 and 2016, 146 pts (71 SEQ, 75 CON) were recruited. Median age (range) was 66 (45-82) years; Karnofsky performance status was 70 (in 12% pts), 80 (27%), 90 (38%) or 100 (24%); 47% had pancreatic head primaries; 84% had liver metastases. Median no. cycles received was 4 SEQ, 3 CON; 51 pts (35%) received ≥6 cycles of treatment (42% SEQ, 28% CON). A 24+2hr interval was achieved in > 90% SEQ admin. Grade ≥3 adverse events experienced by ≥10% pts (SEQ, CON) were neutropaenia (54%, 30%; p = 0.003), febrile neutropaenia (12%, 12%), fatigue (22%, 15%), vomiting (7%, 11%) and anaemia (10%, 5%). G-CSF was administered at local investigator's discretion to 35 pts (23 SEQ, 12 CON; p = 0.015). To date, 112 pts have died. 6 month (m) PFS by SEQ and CON arms were 47% and 33%; median PFS were 5.8 and 4.0m; hazard ratio (HR) = 0.66, 95% CI = 0.46-0.95; 12m OS by SEQ and CON arms were 29% and 26%; median OS were 10.1 and 7.9m; HR = 0.88, 95% CI = 0.61-1.29. ORR was 50% SEQ and 33% CON (p = 0.065). Mean baseline QoL Global health status score was 60.6 SEQ and 63.4 CON. The mean change in QoL score from baseline at 24 weeks was -2.1 SEQ and -12.1 CON. Conclusions: Sequential delivery of nabP combined with GEM trended towards improving all clinically relevant efficacy end points: PFS, OS, and ORR. Translational correlates will be reported in due course. Clinical trial information: ISRCTN71070888.

342 Background: NabP+GEM chemotherapy improves survival compared with standard GEM monotherapy as treatment for advanced PDAC. A PDAC mouse model showed that delivery of nabP prior to GEM generated a higher intratumoural dFdC:dFdU ratio, which correlated with improved outcome. Therefore, scheduling may be critical to optimise clinical benefit. Methods: Patients were randomised to receive nabP+GEM, either concomitantly (CON) or sequentially (SEQ), 24 hours apart. After 6 cycles, patients benefiting from treatment could continue the same regimen until disease progression. The primary endpoint was progression-free survival (PFS) assessed by 8-weekly CT scanning; secondary endpoints included safety, response rate, overall survival (OS) and quality of life (QoL). Results: Between March 2014 and 2016, 146 patients (71 SEQ, 75 CON) from 19 UK sites were randomly assigned. Median age (range) was 66 (45-82) years; Karnofsky performance status was 70 (in 12% of patients), 80 (27%), 90 (38%) or 100 (24%); 47% of primary tumours were situated in the pancreatic head; 84% had liver metastases. Median number of cycles was 4 SEQ, 3 CON; 50 patients (34%) received ≥ 6 cycles of treatment (41% SEQ, 28% CON). A 24+2hr interval was achieved in over 90% SEQ administrations. Most patients stopped treatment prior to 6 cycles due to disease progression/death (42%) or toxicity (41%). Grade ≥ 3 adverse events experienced by ≥ 10% patients (SEQ, CON) were neutropaenia (54%, 30%), febrile neutropaenia (12%, 12%), fatigue (22%, 16%), vomiting (7%, 11%) and anaemia (10%, 5%). G-CSF was administered to 35 patients (23 SEQ, 12 CON). To date, 109 patients have died. 6-month PFS by SEQ and CON arms was 46.7% and 33.8%; median PFS was 5.8 and 4.3 months. 12-month OS by SEQ and CON arms was 29.1% and 20.1%; median OS was 10.1 and 7.9 months. The objective response rate was 44% SEQ and 30% CON. Mean baseline QoL Global health status was 60.6 SEQ and 63.4 CON. The change from baseline (mean) at 24 weeks was -2.1 SEQ and -12.1 CON. Conclusions: Sequential delivery of nabP and GEM improves progression-free and overall survival. Although more myelosuppressive, QoL was maintained. Clinical trial information: ISRCTN71070888.

A 77-year-old man with known adenocarcinoma of the gastro-oesophageal junction presented with symptoms of general deterioration associated with right-sided retro-orbital pain and visual disturbance. The visual acuity in the right eye was normal but there was paralysis of the lateral gaze. Furthermore, the left eye was deviated medially and inferiorly and there was very little preserved coordinated movement. Twenty months prior to this presentation he had been diagnosed with a locally advanced unresectable moderately differentiated adenocarcinoma of the GOJ. The patient had been treated initially with chemotherapy consisting of epirubicin, oxaliplatin and 5-fluorouracil …

Since malignant cells are derived from normal cells, many tumour-associated antigens are also expressed in normal tissues. For examples, WT1 is expressed at elevated levels in most leukaemias, but it is also expressed at reduced levels in normal CD34+ haematopoietic stem cells and in progenitor cells of other tissues. Antigen expression in normal tissues is likely to trigger immunological tolerance and thus blunt T cell responses. This could explain the observation that WT1 vaccination in mice frequently fails to stimulate high avidity cytotoxic T cell responses. In order to circumvent tolerance, we have isolated from HLA-A2-negative donors high avidity CTL specific for HLA-A2-presented peptide epitopes of WT1. These allorestricted CTL efficiently kill HLA-A2-positive leukaemia cells but not normal CD34+ haematopoietic stem cells. However, adoptive cellular therapy with allorestricted CTL could only be performed in leukaemia patients rendered tolerant to the infused CTL by prior allogeneic stem cell transplantation. In order to circumvent this limitation, we propose to exploit the TCR of allorestricted CTL as therapeutic tool. TCR gene transfer can be used to take advantage of the specificity of allorestricted CTL and transfer it to patient CTL, while avoiding the transfer of immunogenic alloantigens from the donor CTL to the patient.

Background & Aims Standard RECIST criteria may not be the optimal method to assess response to loco-regional therapy for hepatocellular cancer (HCC). EASL and mRECIST, which measure changes in arterialized tumor, have been proposed. Here we compare the three criteria and their associations with survival. Methods Response was determined using RECIST 1.1, EASL, and mRECIST criteria in 83 consecutive patients with HCC undergoing palliative therapy with transarterial (chemo) embolization. Results were compared at the first assessment after therapy. Cox regression and Kaplan–Meier survival analyses were used to explore differences in overall survival between the responders and non-responders defined by each method. Results There was a good correlation between EASL and mRECIST with overall response rates; 58% and 57%, and target lesion responses; 74% and 73%, respectively. There was a poor correlation with RECIST 1.1 with overall and target response rates of 7%. Overall and target lesion progression rates were similar for all three assessments; 27% and 2% for both EASL and mRECIST and 28% and 6% for RECIST 1.1. There was a significant association between survival and overall EASL and mRECIST responses, which was retained in multivariate analysis. EASL response was associated with a 44% risk reduction and mRECIST with a 42% reduction. There was no significant association between survival for RECIST 1.1 responses or target EASL and mRECIST responses. Conclusions When measured at a single, early time point post-therapy, EASL and mRECIST overall response rates are associated with survival and should be used in preference to RECIST 1.1 or target responses.

Background The Wilms’ tumor antigen (WT1) is an attractive target for immunotherapy of leukemia. In the past, we isolated and characterized the specificity and function of a WT1-specific T-cell receptor. The goal of this translational study was to develop a safe and efficient WT1-T-cell receptor retroviral vector for an adoptive immunotherapy trial with engineered T cells.Design and Methods We generated a panel of retroviral constructs containing unmodified or codon-optimized WT1-T-cell receptor α and β genes, linked via internal ribosome entry sites or 2A sequences, with or without an additional inter-chain disulfide bond in the T-cell receptor constant domains. These constructs were functionally analyzed in vitro, and the best one was tested in an autologous primary leukemia model in vivo.Results We identified a WT1-T-cell receptor construct that showed optimal tetramer staining, antigen-specific cytokine production and killing activity when introduced into primary human T cells. Fresh CD34+ cells purified from a patient with leukemia were engrafted into NOD/SCID mice, followed by adoptive immunotherapy with patient’s autologous T cells transduced with the WT1-T-cell receptor. This therapeutic treatment evidently decreased leukemia engraftment in mice and resulted in a substantial improvement of leukemia-free survival.Conclusions This is the first report that patient’s T cells, engineered to express the WT1-T-cell receptor, can eliminate autologous leukemia progenitor cells in an in vivo model. This study provides a firm basis for the planned WT1-T-cell receptor gene therapy trial in leukemia patients.

Purpose: The Wilms' tumor antigen 1 (WT1) is overexpressed in several leukemias and solid tumors, but there is currently limited information regarding its role in prostate cancer. This study aimed to investigate WT1 expression in prostate cancer, and to determine the number and function of WT1-specific T cells in the peripheral blood of patients. Experimental Design: Immunohistochemistry was used to assess WT1 expression in cancer tissues. Human leukocyte antigen A2 (HLA-A2) tetramers served to detect WT1-specific T cells, and peptide-specific stimulation was used to assess T-cell function in vitro. Results: Immunohistochemistry of tissue arrays comprising 36 cancer and 8 normal prostate samples revealed nuclear WT1 staining in 39% of cancer samples, but not in normal prostate tissues. Tetramer analysis revealed a low frequency of WT1-specific T cells in 20 of 38 HLA-A2–positive patients. In vitro stimulation with WT1 peptide plus interleukin 2(IL2) and interleukin 7 (IL7) did not lead to an accumulation of WT1-specific T cells in any of the patient samples, although all patients were able to generate T-cell responses against Melan-A/MART1 control peptide. Stimulation with WT1 peptide in the presence of interleukin 15 (IL15), a cytokine that was shown to reverse tolerance of murine tumor-specific T cells, was able to restore the expansion and IFNγ production of WT1-specific T cells in a subgroup of prostate cancer patients. Conclusion: The observation that IL15 can restore the function of WT1-specific T cells that were unresponsive to IL2 has implications for vaccination and immunotherapeutic strategies that aim to enhance WT1-specific T cell immunity in patients.

A 63-year-old man, a wheelchair user, from primary progressive multiple sclerosis (MS), presented with an episode of expressive dysphasia and confusion. Cerebral imaging revealed a solitary cerebral mass that was radiologically felt to be a primary brain tumour, but a brain biopsy demonstrated an adenocarcinoma in keeping with brain metastasis. Further immunohistochemistry suggested a probable colorectal primary. Subsequent staging confirmed a primary cancer within the caecum/terminal ileum, with extensive bilobar unresectable liver metastases. Unfortunately, as a consequence of the heavy tumour burden and rapid disease progression, the patient deteriorated rapidly and, due to his poor performance status, palliative chemotherapy was not deemed suitable. He was offered palliative whole brain radiotherapy to help control his symptoms, but he declined. He subsequently died at home a few weeks later, as per his wishes.

Purpose: The Wilms' tumor antigen (WT1) is overexpressed in ∼90% of breast tumors and, thus, is a potential target antigen for the immunotherapy of breast cancer. We have tested the working hypotheses that WT1 can be immunogenic in patients with breast cancer and can stimulate CTL of sufficient avidity to kill tumor cells.Experimental Design: Paired tumor-draining lymph node and peripheral blood samples were analyzed from five HLA-A2-positive patients with stage I/II breast cancer. Fluorescent HLA-A*0201/WT1 tetramers were used to quantify WT1-specific CTL and the functional capacity of the CTL was assessed using cytotoxicity assays and intracellular cytokine staining.Results: WT1 tetramer–binding T cells expanded from all lymph node samples but none of the corresponding peripheral blood samples. Functional assays were carried out on T cells from the patient who had yielded the highest frequency of HLA-A*0201/WT1 tetramer–positive cells. The cytotoxicity assays showed WT1 peptide–specific killing activity of the CTL, whereas intracellular cytokine staining confirmed that the tetramer–positive T cells produced IFN-γ after stimulation with WT1 peptide. These WT1-specific T cells killed HLA-A2-positive breast cancer cell lines treated with IFN-γ but no killing was observed with untreated tumor cells.Conclusions: These results show that WT1-specific CTL can be expanded from the tumor-draining lymph nodes of breast cancer patients and that they can display peptide-specific effector function. However, the CTL only killed IFN-γ-treated tumor targets expressing high levels of HLA-A2 and not tumor cells with low HLA expression. This suggests that induction of autologous WT1-specific CTL may offer only limited tumor protection and that strategies that allow a high level of peptide/MHC complex presentation and/or improve CTL avidity may be required.

After termination of pregnancy for non-medical reasons, the products of conception are often not routinely examined for gestational trophoblastic neoplasia. Between 1995 and 2001 we identified 15 women without and 36 women with a pathological diagnosis of gestational trophoblastic neoplasia at the time of their pregnancy termination. Women without a diagnosis were significantly more likely to have subsequent life-threatening complications of gestational trophoblastic neoplasia (four of 15 vs none of 36; p=0.003), and to require surgical intervention (15 of 15 vs one of 36; p