Now showing items 1-20 of 12617

    • The genomic landscape of unsuspected, incidentally detected Gleason 7 prostate cancer found on autopsy

      Foucal, A.; Livingstone, J.; Salcedo, A.; Kuk, C.; Fraser, M.; Pushkar, D.; Govorov, A.; Kovylina, M.; Bristow, Robert G; Fleshner, N. E.; et al. (2021)
      Introduction & Objectives: Changes in our way of thinking in medicine are sometimes driven by observations in a small number of patients. For instance, when whole-genome sequencing used to track the lethal cell clone in a single patient who died of prostate cancer (PCa), surprisingly, revealed that it arose from a small, low-grade PCa focus. The genomic landscape of unsuspected, incidentally detected PCa on autopsy in men never found with the disease during their lifetime is virtually unknown. Intriguingly, while the field has anticipated that most autopsy-detected PCa are of low tumor volume and low Gleason score (GS), we and others have shown that nearly 25% of unsuspected autopsy detected PCa in Caucasian men were GS≥7. Materials & Methods: We used prostate glands prospectively collected during autopsy from Caucasian men, deceased with no known history of PCa, accrued by the University of Moscow, Russia and analyzed in Toronto, Canada. We limited the scope of our study to unifocal GS7 tumors with good DNA quantity and quality. DNA was isolated from the autopsy-detected tumors using QIAamp DNA Mini Kit (Hilden, Germany). To profile genome-wide copy number aberrations (CNAs), we used the OncoScan® FFPE Express v3 platform, optimized for highly degraded samples. BioDiscovery Nexus Express TM for OncoScan 3 was used to call CNAs using the SNP-FASST2 algorithm. We compared autopsy CNA data to intermediate-risk prostate cancer cases from the Canadian Prostate Cancer Genome Network (CPC-GENE project), all of whom underwent radiotherapy or radical prostatectomy for localized, non-indolent GS6-7 disease. Results: Three autopsy incidentally detected tumors were analyzed (ages 63, 70, 80) and compared to 300 surgical and biopsy-specimens from CPC-GENE. Driver gene hits were common in autopsy specimens: deletions in TP53 were observed in all three, BRCA2 in two and RB1 loss in two. A TMPRSS2:ERG fusion, caused by a deletion of chr21:39988436-42859011, was observed in one sample. Two of the three autopsy samples were indistinguishable from the diagnosed tumors in the CPC-GENE set. A limitation of this study is that although the three GS 7 were found incidentally on autopsy, they were not necessarily indolent: These men could have died of something else before their PCa became diagnosed. Conclusions: To our surprise, this study has shown, to the best of our knowledge, for the first time that unsuspected PCa GS7 detected incidentally on autopsy is genomically indistinguishable from clinically detected tumors. Autopsy studies have revealed the presence of a large reservoir of PCa, including GS7, which exist in the population and do not cause clinical symptoms or death. Most GS7 tumors found on autopsy in this study, intriguingly displayed mutations usually observed in more aggressive forms of the disease. This may suggest that other factors such as epigenetics could play an important role.
    • Tumor heterogeneity

      Pe'er, D.; Ogawa, S.; Elhanani, O.; Keren, L.; Oliver, T. G; Wedge, David C; Not available (2021)
      Tumor heterogeneity was traditionally considered in the genetic terms, but it has now been broadened into many more facets. These facets represent a challenge in our understanding of cancer etiology but also provide opportunity for us to understand prognosis and therapy response.
    • Epidemiology of anal human papillomavirus infection and high-grade squamous intraepithelial lesions in 29 900 men according to HIV status, sexuality, and age: a collaborative pooled analysis of 64 studies

      Wei, F.; Gaisa, M. M.; D'Souza, G.; Xia, N.; Giuliano, A. R.; Hawes, S. E.; Gao, L.; Cheng, S. H.; Donà, M. G.; Goldstone, S. E.; et al. (2021)
      Background: Robust age-specific estimates of anal human papillomavirus (HPV) and high-grade squamous intraepithelial lesions (HSIL) in men can inform anal cancer prevention efforts. We aimed to evaluate the age-specific prevalence of anal HPV, HSIL, and their combination, in men, stratified by HIV status and sexuality. Methods: We did a systematic review for studies on anal HPV infection in men and a pooled analysis of individual-level data from eligible studies across four groups: HIV-positive men who have sex with men (MSM), HIV-negative MSM, HIV-positive men who have sex with women (MSW), and HIV-negative MSW. Studies were required to inform on type-specific HPV infection (at least HPV16), detected by use of a PCR-based test from anal swabs, HIV status, sexuality (MSM, including those who have sex with men only or also with women, or MSW), and age. Authors of eligible studies with a sample size of 200 participants or more were invited to share deidentified individual-level data on the above four variables. Authors of studies including 40 or more HIV-positive MSW or 40 or more men from Africa (irrespective of HIV status and sexuality) were also invited to share these data. Pooled estimates of anal high-risk HPV (HR-HPV, including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), and HSIL or worse (HSIL+), were compared by use of adjusted prevalence ratios (aPRs) from generalised linear models. Findings: The systematic review identified 93 eligible studies, of which 64 contributed data on 29 900 men to the pooled analysis. Among HIV-negative MSW anal HPV16 prevalence was 1·8% (91 of 5190) and HR-HPV prevalence was 6·9% (345 of 5003); among HIV-positive MSW the prevalences were 8·7% (59 of 682) and 26·9% (179 of 666); among HIV-negative MSM they were 13·7% (1455 of 10 617) and 41·2% (3798 of 9215), and among HIV-positive MSM 28·5% (3819 of 13 411) and 74·3% (8765 of 11 803). In HIV-positive MSM, HPV16 prevalence was 5·6% (two of 36) among those age 15-18 years and 28·8% (141 of 490) among those age 23-24 years (ptrend=0·0091); prevalence was 31·7% (1057 of 3337) among those age 25-34 years and 22·8% (451 of 1979) among those age 55 and older (ptrend<0·0001). HPV16 prevalence in HIV-negative MSM was 6·7% (15 of 223) among those age 15-18 and 13·9% (166 of 1192) among those age 23-24 years (ptrend=0·0076); the prevalence plateaued thereafter (ptrend=0·72). Similar age-specific patterns were observed for HR-HPV. No significant differences for HPV16 or HR-HPV were found by age for either HIV-positive or HIV-negative MSW. HSIL+ detection ranged from 7·5% (12 of 160) to 54·5% (61 of 112) in HIV-positive MSM; after adjustment for heterogeneity, HIV was a significant predictor of HSIL+ (aPR 1·54, 95% CI 1·36-1·73), HPV16-positive HSIL+ (1·66, 1·36-2·03), and HSIL+ in HPV16-positive MSM (1·19, 1·04-1·37). Among HPV16-positive MSM, HSIL+ prevalence increased with age. Interpretation: High anal HPV prevalence among young HIV-positive and HIV-negative MSM highlights the benefits of gender-neutral HPV vaccination before sexual activity over catch-up vaccination. HIV-positive MSM are a priority for anal cancer screening research and initiatives targeting HPV16-positive HSIL+.
    • PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

      Alhalabi, K. T.; Stichel, D.; Sievers, P.; Peterziel, H.; Sommerkamp, A. C.; Sturm, D.; Wittmann, A.; Sill, M.; Jäger, N.; Beck, P.; et al. (2021)
      Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
    • Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity

      Ketola, K.; Kaljunen, H.; Taavitsainen, S.; Kaarijärvi, R.; Järvelä, E.; Rodriguez Martin, B.; Haase, K.; Woodcock, D. J.; Tubio, J.; Wedge, David C; et al. (2021)
      Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance Analysis (DSER), a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and post-treatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair-related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC-3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected post-castration in LuCaP 77 and LuCaP 105 xenograft models and post-chemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance.
    • Prostate cancer

      Sandhu, S.; Moore, C. M.; Chiong, E.; Beltran, H.; Bristow, Robert G; Williams, S. G.; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. (2021)
      The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.
    • Introduction to the National Cancer Imaging Translational Accelerator (NCITA): a UK-wide infrastructure for multicentre clinical translation of cancer imaging biomarkers

      McAteer, M. A.; O'Connor, James P B; Koh, D. M.; Leung, H. Y.; Doran, S. J.; Jauregui-Osoro, M.; Muirhead, N.; Brew-Graves, C.; Plummer, E. R.; Sala, E.; et al. (2021)
      The National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies.
    • Impact of SARS-CoV-2 on training and mental well-being of surgical gynecological oncology trainees

      Gaba, F.; Blyuss, O.; Rodriguez, I.; Dilley, J.; Wan, Yee-loi L; Saiz, A.; Razumova, Z.; Zalewski, K.; Nikolova, T.; Selcuk, I.; et al. (2021)
      Introduction: The SARS-CoV-2 global pandemic has caused a crisis disrupting health systems worldwide. While efforts are being made to determine the extent of the disruption, the impact on gynecological oncology trainees/training has not been explored. We conducted an international survey of the impact of SARS-CoV-2 on clinical practice, medical education, and mental well-being of surgical gynecological oncology trainees. Methods: In our cross-sectional study, a customized web-based survey was circulated to surgical gynecological oncology trainees from national/international organizations from May to November 2020. Validated questionnaires assessed mental well-being. The Wilcoxon rank-sum test and Fisher's exact test were used to analyse differences in means and proportions. Multiple linear regression was used to evaluate the effect of variables on psychological/mental well-being outcomes. Outcomes included clinical practice, medical education, anxiety and depression, distress, and mental well-being. Results: A total of 127 trainees from 34 countries responded. Of these, 52% (66/127) were from countries with national training programs (UK/USA/Netherlands/Canada/Australia) and 48% (61/127) from countries with no national training programs. Altogether, 28% (35/125) had suspected/confirmed COVID-19, 28% (35/125) experienced a fall in household income, 20% (18/90) were self-isolated from households, 45% (57/126) had to re-use personal protective equipment, and 22% (28/126) purchased their own. In total, 32.3% (41/127) of trainees (16.6% (11/66) from countries with a national training program vs 49.1% (30/61) from countries with no national training program, p=0.02) perceived they would require additional time to complete their training fellowship. The additional training time anticipated did not differ between trainees from countries with or without national training programs (p=0.11) or trainees at the beginning or end of their fellowship (p=0.12). Surgical exposure was reduced for 50% of trainees. Departmental teaching continued throughout the pandemic for 69% (87/126) of trainees, although at reduced frequency for 16.1% (14/87), and virtually for 88.5% (77/87). Trainees reporting adequate pastoral support (defined as allocation of a dedicated mentor/access to occupational health support services) had better mental well-being with lower levels of anxiety/depression (p=0.02) and distress (p<0.001). Trainees from countries with a national training program experienced higher levels of distress (p=0.01). Mean (SD) pre-pandemic mental well-being scores were significantly higher than post-pandemic scores (8.3 (1.6) vs 7 (1.8); p<0.01). Conclusion: SARS-CoV-2 has negatively impacted the surgical training, household income, and psychological/mental well-being of surgical gynecological oncology trainees. The overall clinical impact was worse for trainees in countries with no national training program than for those in countries with a national training program, although national training program trainees reported greater distress. COVID-19 sickness increased anxiety/depression. The recovery phase must focus on improving mental well-being and addressing lost training opportunities.
    • Comprehensive library generation for identification and quantification of endometrial cancer protein biomarkers in cervico-vaginal fluid

      Njoku, Kelechi; Chiasserini, D.; Geary, Bethany; Pierce, Andrew; Jones, E. R.; Whetton, Andrew D; Crosbie, Emma J; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 5th Floor Research, St Mary's Hospital, Oxford Road, Manchester M13 9WL (2021)
      Endometrial cancer is the most common gynaecological malignancy in high-income countries and its incidence is rising. Early detection, aided by highly sensitive and specific biomarkers, has the potential to improve outcomes as treatment can be provided when it is most likely to effect a cure. Sequential window acquisition of all theoretical mass spectra (SWATH-MS), an accurate and reproducible platform for analysing biological samples, offers a technological advance for biomarker discovery due to its reproducibility, sensitivity and potential for data re-interrogation. SWATH-MS requires a spectral library in order to identify and quantify peptides from multiplexed mass spectrometry data. Here we present a bespoke spectral library of 154,206 transitions identifying 19,394 peptides and 2425 proteins in the cervico-vaginal fluid of postmenopausal women with, or at risk of, endometrial cancer. We have combined these data with a library of over 6000 proteins generated based on mass spectrometric analysis of two endometrial cancer cell lines. This unique resource enables the study of protein biomarkers for endometrial cancer detection in cervico-vaginal fluid. Data are available via ProteomeXchange with unique identifier PXD025925.
    • Biguanides drugs: Past success stories and promising future for drug discovery

      Grytsai, Oleksandr; Myrgorodska, I.; Rocchi, S.; Ronco, C; Benhida, R.; Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 28 Avenue Valrose, 06108, Nice, France; Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, (2021)
      Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment.
    • Definition of biologically distinct groups of conjunctival melanomas according to etiological factors and implications for precision medicine

      Gardrat, S.; Houy, A.; Brooks, Kelly; Cassoux, N.; Barnhill, R.; Dayot, S.; Bièche, I.; Raynal, V.; Baulande, S.; Marais, Richard; et al. (2021)
      Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations in BRAF, NRAS, HRAS, and KIT were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with BRAF and CDKN2A-mutated ConjMel tended to be younger while the NF1-mutated one tended to be older. The eight tumors arising from nevi were enriched in CTNNB1 mutations (63% vs. 8%; Fisher's exact p-test = 0.001) compared to non-nevi ConjMel and five were devoid of BRAF, RAS, NF1, or KIT mutations, suggesting a specific oncogenic process in these tumors. The two KIT-mutated cases carried SF3B1 mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in ERBB2, IDH1, MET, and MAP2K1 (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. CTNNB1 mutations were associated with nevus-derived ConjMel. Concomitant KIT/SF3B1 mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.
    • High versus low sun protection factor sunscreens and cutaneous squamous cell carcinoma risk: a population-based cohort study

      Lergenmuller, S.; Ghiasvand, R.; Robsahm, T. E.; Green, Adèle C; Lund, E.; Rueegg, C. S; Veierød, M. B.; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (2021)
      Evidence on sunscreen use and cutaneous squamous cell carcinoma (cSCC) risk is limited. Most studies did not take sun protection factor (SPF) into consideration, and used nonusers of sunscreen as the reference group. Nonusers are likely a priori at lower cSCC risk than users. No study has investigated the effect of high versus low SPF sunscreens on cSCC appropriately adjusting for time-varying confounding. Using data from the Norwegian Women and Cancer study (1991-2016), we investigated whether use of SPF≥15+ versus SPF<15+ sunscreens reduces cSCC risk. We used marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weights to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During follow-up of 148,781 women (1991-2016, mean 14.3 years), 653 women were diagnosed with cSCC. The effect on cSCC risk of SPF≥15+ versus SPF<15+ sunscreens was close to the null when used at any latitudes (HR=1.02, 95% CI: 0.82, 1.27) and when used in lower latitude settings (HR=1.05, 95% CI: 0.84, 1.32). In conclusion, we found no indication that SPF≥15+ sunscreens reduced Norwegian women's cSCC risk more than SPF<15+ sunscreens, suggesting that either there is no difference in their effects long-term, or the difference is diluted by incorrect application.
    • Saphenous sparing ascending video-endoscopic inguinal lymph node dissection (VEILND-AS plus ) using a leg approach: Surgical technique, perioperative and pathological outcomes

      Fankhauser, Christian D; Lee, Esther; Issa, Allaudin; Oliveira, Pedro.; Lau, Maurice W; Sangar, Vijay K; Parnham, Arie S; The Christie NHS Foundation Trust, Dept. of Urology, Manchester (2021)
      Introduction & Objectives: Open inguinal lymph node dissection (oILND) has a high morbidity. Video-endoscopic inguinal lymph node dissection (VEILND) represents a minimally invasive alternative with potential benefits. The aim of this study was to describe our saphenous sparing ascending video-endoscopic inguinal lymph node dissection (VEILND-AS+) using a leg approach and to compare the outcomes to our oILND experience. Materials & Methods: Retrospective cohort study of penile cancer patients undergoing either oILND or VEILND comparing perioperative and pathological outcomes. Results: In 206 men we performed 40 VEILND and 251 oILND. VEILND compared to oILND had a longer operation time (185 vs 120 minutes) but shorter hospital stay (2 vs 4 days). A median of 8 resected lymph nodes with a median of 1 affected node per groin was observed in both groups with extra nodal extension in 30% after VEILND and 35% after oILND. Both groups had a median of 13 days of drainage. Wound infections were observed in 38% after VEILND and 27% after oILND. Skin necrosis or wound break down occurred in 0% and 6% after VEILND and oILND, whilst lymphoceles were drained in 18% and 7% respectively. Following VEILND and oILND 20% and 14% were referred to lymph oedema clinic. Conclusions: In this video we describe our VEILND-AS+ technique and our data suggests that VEILND-AS+ is a safe procedure. Compared to oILND, VEILND-AS+ may offer a shorter hospital stay and possibly a lower risk of skin necrosis or wound break down. Further improvement of this and other VEILND techniques are required to decrease complications associated with dead space and injury to lymphatic vessels. This study is limited by its retrospective nature.
    • Subcutaneous (SC) epcoritamab induces complete responses across R/R B-cell NHL subtypes: Updated dose-escalation data

      Hutchings, M.; Mous, R.; Clausen, M. R.; Johnson, P.; Linton, Kim M; Chamuleau, M. E. D.; Lewis, D. J.; Balari, A. S.; Cunningham, D.; Oliveri, R. S.; et al. (2021)
      Background: Epcoritamab is a CD3CD20 bispecific antibody with a favorable safety profile and encouraging preliminary antitumor activity in both aggressive and indolent B-NHL in a phase I/II trial (NCT03625037). Updated dose-escalation data are reported here. Methods: Adults with R/R CD20+ B-NHL receive a SC 1 mL injection of flat-dose epcoritamab in 28-day cycles (q1w: cycles 1-2; q2w: cycles 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Objectives include safety and antitumor activity. Results: As of 6 July 2020, 67 patients (pts) were enrolled (DLBCL, 67%; FL, 18%; MCL, 6%). Pts were heavily pretreated, with a median (range) of 3.0 (1-6) prior lines of therapy for DLBCL and 4.5 (1-18) for FL. A total of 6 pts received prior CAR-T therapy. At median follow-up of 8.3 months, treatment is ongoing in 25 pts (37%). Epcoritamab was generally well tolerated, with no discontinuations due to treatment-emergent adverse events (TEAEs). The most common TEAEs were pyrexia (70%), local injection-site reactions (48%), and fatigue (45%). Observed TEAEs of special interest were cytokine release syndrome (CRS; all events were Gr 1/2 [58%], no Gr 3/4) and limited neurotoxicities (Gr 1, 3%; Gr 3, 3%; all transient). There were no DLTs, febrile neutropenia events, or deaths due to TEAEs. In pts with DLBCL treated with epcoritamab 12 mg (n¼18), ORR was 66.7% (6 CR). For pts who received higher doses (48 mg [RP2D], n¼4; 60 mg, n¼3) ORR was 100% (2 CR, 5 PR). All 4 DLBCL pts with prior CAR-T therapy achieved a response (2 CR, 2 PR). In FL (epcoritamab 0.76 mg, n¼8), ORR was 100% (2 CR). Responses (1 CR,1 PR) were observed in 2/4 pts with blastoid variant MCL. Conclusions: Epcoritamab demonstrates a consistent, favorable safety profile, with no Gr 3 CRS events and limited neurotoxicity, in support of future outpatient administration. Emerging data are encouraging, including CR in heavily y pretreated pts with DLBCL, FL, and MCL.
    • Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial

      Eggermont, A. M. M.; Blank, C. U.; Mandala, M.; Long, G. V.; Atkinson, V. G.; Dalle, S.; Haydon, A. M.; Meshcheryakov, A.; Khattak, A.; Carlino, M. S.; et al. (2021)
      Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results. Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]). Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.
    • Central venous access devices for the delivery of systemic anticancer therapy (CAVA): a randomised controlled trial

      Moss, J. G.; Wu, O.; Bodenham, A. R.; Agarwal, R.; Menne, T. F.; Jones, B. L.; Heggie, R.; Hill, Steve; Dixon-Hughes, J.; Soulis, E.; et al. (2021)
      Background: Hickman-type tunnelled catheters (Hickman), peripherally inserted central catheters (PICCs), and totally implanted ports (PORTs) are used to deliver systemic anticancer treatment (SACT) via a central vein. We aimed to compare complication rates and costs of the three devices to establish acceptability, clinical effectiveness, and cost-effectiveness of the devices for patients receiving SACT. Methods: We did an open-label, multicentre, randomised controlled trial (Cancer and Venous Access [CAVA]) of three central venous access devices: PICCs versus Hickman (non-inferiority; 10% margin); PORTs versus Hickman (superiority; 15% margin); and PORTs versus PICCs (superiority; 15% margin). Adults (aged ≥18 years) receiving SACT (≥12 weeks) for solid or haematological malignancy from 18 oncology units in the UK were included. Four randomisation options were available: Hickman versus PICCs versus PORTs (2:2:1), PICCs versus Hickman (1:1), PORTs versus Hickman (1:1), and PORTs versus PICCs (1:1). Randomisation was done using a minimisation algorithm stratifying by centre, body-mass index, type of cancer, device history, and treatment mode. The primary outcome was complication rate (composite of infection, venous thrombosis, pulmonary embolus, inability to aspirate blood, mechanical failure, and other) assessed until device removal, withdrawal from study, or 1-year follow-up. This study is registered with ISRCTN, ISRCTN44504648. Findings: Between Nov 8, 2013, and Feb 28, 2018, of 2714 individuals screened for eligibility, 1061 were enrolled and randomly assigned, contributing to the relevant comparison or comparisons (PICC vs Hickman n=424, 212 [50%] on PICC and 212 [50%] on Hickman; PORT vs Hickman n=556, 253 [46%] on PORT and 303 [54%] on Hickman; and PORT vs PICC n=346, 147 [42%] on PORT and 199 [58%] on PICC). Similar complication rates were observed for PICCs (110 [52%] of 212) and Hickman (103 [49%] of 212). Although the observed difference was less than 10%, non-inferiority of PICCs was not confirmed (odds ratio [OR] 1·15 [95% CI 0·78-1·71]) potentially due to inadequate power. PORTs were superior to Hickman with a complication rate of 29% (73 of 253) versus 43% (131 of 303; OR 0·54 [95% CI 0·37-0·77]). PORTs were superior to PICCs with a complication rate of 32% (47 of 147) versus 47% (93 of 199; OR 0·52 [0·33-0·83]). Interpretation: For most patients receiving SACT, PORTs are more effective and safer than both Hickman and PICCs. Our findings suggest that most patients receiving SACT for solid tumours should receive a PORT within the UK National Health Service.
    • Sequencing therapies in Hodgkin lymphoma

      Phillips, Elizabeth H; Collins, G. P; Cwynarski, K.; University of Manchester, The Christie Hospital and National Institutes of Health Research Manchester Biomedical Research Centre, Manchester M20 4BX, (2021)
    • Radical hemiscrotectomy and en-bloc orchidectomy: Surgical technique, perioperative and oncologic outcomes of a supra-regional UK referral centre

      Fankhauser, Christian D; Issa, Allaudin; Lee, Esther; Oing, Christoph; Oliveira, Pedro; Parnham, Arie S; Oates, Jeremy E; Sangar, Vijay K; Gulamhusein, Aziz; Clarke, Noel W; et al. (2021)
      Introduction & Objectives: Several rare urogenital cancers arising from tissues of the spermatic cord, epididymis, testis or scrotal skin have a high risk of local recurrence. A radical resection by a hemiscrotectomy with or without en-bloc orchidectomy is therefore recommended to try to reduce this complication. Given the limited literature describing this surgery, we summarized our surgical technique, perioperative and oncological outcomes. Materials & Methods: Retrospective cohort study of 16 men treated at a supra-regional referral centre between 2010 and 2020. Results: Radical hemiscrotectomy and en-bloc orchidectomy was performed in 16 patients with a mean age of 56 years (range 20 to 80). Four men had a primary resection, 9 underwent completion surgery with the remaining 3 undergoing salvage surgery. In men with primary surgery 2 patients had well differentiated liposarcoma (WDLS), 1 rhabdomyosarcoma and 1 mammary type myofibroblastoma. Completion surgery was performed within a mean of 3 months (range 1-4 months) after initial diagnosis of dedifferentiated liposarcoma (DLS) in 4, WDLS in 2, leiomyosarcoma in 2 and mesothelioma in 1 patient. In the subsequent hemiscrotectomy specimens, 6 out of 9 (67%) showed no evidence of tumour whereas 3 patients had residual disease including LDS, WDLS and mesothelioma (Figure 3). Salvage surgery was performed in two patients 31 and 50 months after inguinal excision of a lipomatous mass which was incorrectly diagnosed as lipoma and reclassified on review as WDLS. The third patient with salvage surgery was operated 72 months after orchiectomy as the patient initially refused completion orchiectomy and failed to re-attend thereafter. The median hospital stay was 2 days (IQR 2–4). Four patients (25%) had 90-day postoperative complications. Two (12%) had wound infections requiring oral antibiotics (Clavien-Dindo II), with the remaining 2 (12%) developing a haematoma (Clavien-Dindo I) which was managed conservatively. During a median follow-up of 18 months (IQR 2-66), one patient (6%) initially presenting with locally advanced dedifferentiated liposarcoma measuring 130x50x48mm had recurrence. Metastatic disease in the pelvic and retroperitoneal lymph nodes was diagnosed 2 months after hemiscrotectomy with rapid clinical deterioration. He died 4 months after initial diagnosis despite palliative chemotherapy with Doxorubicin and Olaratumab. Conclusions: If careful dissection is performed, radical hemiscrotectomy and en-bloc orchidectomy is a radical but safe procedure with a short hospital stay. Haematoma and infection represent the main complications and within limited follow-up most men appear to be cured
    • Magnetic resonance guided adaptive Radiotherapy (MRgRT) for localised prostate cancer: The first result from a prospective international registry for the evidence-based Introduction of MRgRT

      Teunissen, F. R.; Willigenburg, T.; Tree, A. C.; Hall, W. A.; Choi, S. L.; Choudhury, Ananya; Christodouleas, J. P.; De Boer, J. C. J.; De Groot-Van Breugel, E. N.; Kerkmeijer, L. G. W.; et al. (2021)
      Introduction & Objectives: Magnetic Resonance (MR) guided adaptive radiotherapy (MRgRT) is a new technique for treatment of localised Prostate Cancer (PCa). MR-guided linear accelerator (MR-Linac) systems have been implemented in radiotherapy departments around the world. However, the theoretical benefits of MRgRT still need to be confirmed in clinical practice. We report the short-term outcomes for the first PCa patients treated within an international consortium on a 1.5T MR-Linac system with ultrahypofractionated radiotherapy. Materials & Methods: Patients treated with 5x7.25 Gray were identified within the registry. Prostate Specific Antigen (PSA), Common Terminology Criteria for Adverse Events (CTCAE) and Patient Reported Outcome (PRO) using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-PR25, EORTC QLQ-C30 and the EuroQol EQ5D-5L were prospectively recorded at baseline and at 3 and 6 months follow-up (FU). Descriptive and pairwise comparative statistics were conducted. Results: One-hundred-and-fifty-six consecutive patients with localised PCa (13.2% low-, 77.2% intermediate-, and 9.6% high-risk [National Comprehensive Cancer Network risk groups]) were included. Thirty-one patients (19.9%) received neoadjuvant Androgen Deprivation Therapy (ADT). A significant decline of PSA in non-ADT patients was observed between baseline (median: 7.8 ng/mL), 3 months FU (median: 2.7 ng/ mL) and 6 months FU (median: 1.7 ng/mL) (p<0.001). No grade ≥3 Genitourinary (GU) and Gastrointestinal (GI) toxicity was reported (table). No significant deterioration of PRO scores were observed. The percentage of men reporting no difficulty getting or maintaining an erection remained constant throughout FU (44.4% at baseline, 40.0% at 3 months FU, and 42.9% at 6 months FU). Conclusions: Ultrahypofractionated 1.5T MR-Linac treatment of localised PCa is effective and safe (no grade ≥3 GU and GI toxicity). In the first 6 months following treatment, patients reported stable erectile function. No significant deterioration of PROs at 3- and 6-months FU was observed.