Yuk Ting Ma

Smoking initiation is followed by the early acquisition of epigenetic change in cervical epithelium: a longitudinal study

Background:To prove a causal link between an epigenetic change and an environmental or behavioural risk factor for a given disease, it is first necessary to show that the onset of exposure precedes the first detection of that epigenetic change in subjects who are still free of disease.Methods:Towards this end, a cohort of women aged 15–19 years, recruited soon after they first had sexual intercourse, were used to provide sequential observations on the relationship between cigarette smoking and the detection in cervical cytological samples of methylated forms of CDKN2A (p16) using nested methylation-specific polymerase chain reaction.Results:Among women who remained cytologically normal and who tested negative for human papillomavirus DNA in cervical smears during follow-up, those who first started to smoke during follow-up had an increased risk of acquiring CDKN2A methylation compared with never-smokers (odds ratio=3.67; 95% confidence interval 1.09–12.33; P=0.04).Conclusion:Smoking initiation is associated with the appearance of methylated forms of CDKN2A.

Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial.

BACKGROUND Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo. METHODS We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (<400 ng/mL and ≥400 ng/mL). Only the trial coordinator was unmasked to treatment allocation before patient progression during the study. The primary endpoint was progression-free survival defined as the interval between randomisation and progression according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) or death due to any cause, and was analysed by intention-to-treat. Safety was analysed by intention-to-treat. The trial has been completed and the final results are reported. The trial is registered at EudraCT, number 2008-005073-36, and ISRCTN, number ISRCTN93375053. FINDINGS Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group. INTERPRETATION The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes. FUNDING Bayer PLC and BTG PLC.

A multicentre comparison between Child Pugh and Albumin-Bilirubin scores in patients treated with sorafenib for Hepatocellular Carcinoma

The Albumin‐Bilirubin (ALBI) grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma (HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh (CP) A class. However, the original publication did not provide comparison with the subclassification by points (5–15) within the CP classification.

Management of metastatic germ cell tumors

Germ cell tumors are the most common solid malignancies to affect young adult men and incidence is increasing worldwide. The introduction of cisplatin-based combination chemotherapy in the late 1970s resulted in a dramatic improvement in the prognosis of patients with metastatic germ cell tumors, and overall cure rates in this group now exceed 80%. Randomized clinical trials and prognostic factors have guided treatment strategies over the last two decades. Clinical research for most advanced adult malignant diseases is driven by the need to improve response rates and prolong survival. The remarkable chemotherapy sensitivity of testicular germ cell cancers has revolutionized treatment results in the last 20 years, substantially altering the landscape in these tumors with greater than 80% cure rates routinely achievable. Furthermore, it seems unlikely that modifications in dose or scheduling of currently available drugs will improve the outlook for the small minority of poor-prognosis metastatic disease cases. Failing this there are real changes in our approach to these tumors that could enhance outcomes, including better supportive care, better service delivery and better public education. The choice of different platinum, and total dose of etoposide and bleomycin and their impact on the clinical outcome in context of various trials is discussed in detail in this review.

Biology of testicular germ cell tumors.

Germ cell tumors are derived from cells of the germ cell lineage and are the most common solid malignancies to affect young Caucasian men between the ages of 15 and 40 years. All testicular germ cell tumors develop from the same precursor lesion, intratubular germ cell neoplasia unclassified, which in turn is thought to arise from malignant transformation of a primordial germ cell or gonocyte. These tumors are characterized by extreme chemosensitivity and are considered a model for curative disease. In spite of this, a small subset of patients with metastatic disease fail to achieve a complete response with cisplatin-based chemotherapy or relapse from complete remission. Understanding the molecular biology may help the design of new therapies for those patients with a poor prognosis and could also improve the treatment of cancer in general. Current understanding of the role of genetic and epigenetic factors in the etiology of germ cell tumors and the biochemical mechanisms underlying chemotherapy sensitivity and resistance is discussed in detail in this review.

TACE 2: A randomized placebo-controlled, double-blinded, phase III trial evaluating sorafenib in combination with transarterial chemoembolisation (TACE) in patients with unresectable hepatocellular carcinoma (HCC)—Background.

1 UCL Cancer Institute, University College London, UK 2 Royal Free London NHS Foundation Trust, London, UK 3 Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, UK 4 Queen Elizabeth Hospital Birmingham, UK 5 Guys Hospital, London, UK 6 University of Nottingham, Nottingham, UK 7 Aintree University Hospital, Liverpool, UK 8 Newcastle Clinical Trials Unit, Newcastle, UK 9 Western General Hospital, Edinburgh, UK 10 The Royal Devon and Exeter Hospital, Exeter, UK 11 Southampton University Hospitals NHS Trust, Southampton, UK 12 ,University of Glasgow, Glasgow UK 13 Bristol Royal Infirmary, Bristol, UK 14 Christie Hospital NHS Foundation Trust, Manchester, UK 15 The Royal Marsden NHS Foundation Trust, Sutton and London Hospital, Surrey,

Impact of restricting access to high-cost medications for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, and its incidence is increasing in the West, including the UK, with the increasing burden of chronic liver disease. Until recently, systemic treatment options for advanced disease were limited. However, randomized clinical trials have demonstrated that the multikinase inhibitor sorafenib prolongs survival in appropriately selected patients, and this drug has become the standard of care for patients with advanced HCC. However, a single-technology appraisal by the NICE recommended that the UK National Health Service should not fund sorafenib on the grounds of cost–effectiveness. A number of other novel agents and combinations are currently in clinical trials, the results of which may further expand the treatment options and indications for systemic therapy in HCC. This review discusses the impact of restricting access to high-cost medications for patients with HCC in the UK, and describes potential strategies and future directions that may improve the cost–effectiveness of such drugs. It also describes the potential impact, pending national guidance, of variations in local funding decision-making on patient outcomes.

Biology of Germ Cell Tumors

Testicular cancer has been a model for a curable malignancy. The existence of an array of potential new therapies is the result of a prodigious effort in the researching and defining of the molecular components of the cancer phenotype and the subsequent rational design of agents to target candidate pathways. A better understanding of the molecular biology of cancer may also aid in guiding the most appropriate use of existing therapies, such as conventional chemotherapy.

Metastatic Serous Carcinoma of the Testis: A Case Report and Review of the Literature

Serous tumours of the testis and paratestis are rare, with fewer than 50 cases reported in the literature. The majority of the reported cases have been borderline serous tumours, and these tend not to recur or metastasize. Conversely, serous carcinomas can metastasize but this is often a late event. The presence of invasion in an otherwise borderline tumour has also been associated with the development of metastatic disease several years later, thus highlighting the importance of extensive sampling of all cases of borderline serous tumours. We report a case of a young man diagnosed with serous carcinoma of the testis, occurring 18 years after first diagnosis of a testicular germ cell tumour in the contralateral testis. This pattern has not previously been reported.

Abstract 2354: Cancer vaccine development for hepatocellular carcinoma - HEPAVAC

The HEPAVAC Consortium aims to develop a highly innovative, novel cancer vaccine approach for hepatocellular carcinoma (HCC). The international project consortium consists of 9 European Partners from academia and the biotech industry with complementary and substantial expertise in developing immunotherapeutic strategies to treat cancer. The project has started in September 2013 and is supported by the European Commission9s 7th Framework Program (www.hepavac.eu). HCC/normal adjacent tissue matched samples have been collected for HLA immunopeptidome analysis. 17 HCC samples from HLA-A*02+ patients and 15 samples from HLA-A*24+ patients have been analysed by mass spectrometry (LC-MS/MS). RNA-expression profiles have been established for 12 HCC samples. HLA-presentation/expression of peptides and mRNA on primary HCC samples are compared to >140 normal tissue samples from relevant organs (including heart, brain, lung, kidney, liver, nerve, skin etc.) from Immatics’ database. A total of 9051 HLA-A*02-restricted different tumor-associated peptides (TUMAPs) have been identified from HLA-A*02+ samples, while a total of 3286 different HLA-A*24-restricted TUMAPs have been identified from HLA-A*24+ samples. Of these, 33 HLA-A*02+ TUMAPS and 33 HLA-A*24+ TUMAPs have been validated, including peptide synthesis, immunogenicity testing and pharmaceutical evaluation. Most promising TUMAP candidates show selective expression only in HCC samples and no expression in normal tissues. In parallel, more than 6600 HLA-DR TUMAPs have been identified in Hep3B cells transfected with CIITA as well as an average of 1500 HLA-DR TUMAPs have been identified in HCC samples. A total of 16 newly identified HCC-specific epitopes have been selected for the HEPAVAC vaccine cocktail and are currently synthesized according to GMP standard. Of these, 7 are restricted to HLA- class I A*02; 5 HLA-A*24 and 4 HLA class II. In parallel, preclinical studies assessing the formulation and combination of the immunological RNA-based adjuvant (RNAdjuvant®) with peptide cocktails are underway. A multi Center phase I/II clinical trial in early HCC patients is predicted to start in July 2016. Citation Format: Sarah Kutscher, Roberto Accolla, Yuk T. Ma, Regina Heidenreich, Francesco Izzo, Alfred Koenigsrainer, Markus Loeffler, Phillip Mueller, Andrea Mayer, Hans-Georg Rammensee, Bruno Sangro, Sven Francque, Danila Valmori, Toni Weinschenk, Harpreet Singh-Jasuja, Luigi Buonaguro. Cancer vaccine development for hepatocellular carcinoma - HEPAVAC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2354.