Now showing items 21-40 of 13626

    • Interior design: a new perspective in supportive care of patients with acute onset of debilitating diseases

      Mauri, D.; Kampletsas, E.; Smyris, G.; Tsali, L.; Tsekeris, P.; Harissis, H.; Kamposioras, Konstantinos; Tolia, M.; Hyphantis, T.; Ntellas, P.; et al. (2021)
      Background: Upon the onset of a debilitating rapidly evolving condition (such as cancer or a rapidly progressing myopathy, neuropathy, respiratory disease, or a severe traumatic injury), individuals have limited time to find a new home or make radical structural modifications in their residence. How the affected patients can continue sharing the same house with their families, while meeting their own special requirements, is thus rising as a critical issue. Household and daily routine rearrangements, either temporary or permanent, may be necessary, to ameliorate the life of patients with impairments, lasting for months or even years. Objectives: Interior design may provide a highly efficient "living" palliation for debilitating medical conditions directly at patients' home-site. Methods: Research of relevant literature, using keywords "debilitating conditions," "home care," "end of life care," "care of advanced cancer patients," "care of patients with mental disorders," "home care of covid-19 affected patients," and "care of patients with degenerative illnesses." Results: We found that patients and their relatives may not be aware of the probable interior design solutions to their daily life challenges, imposed by a disease-related impairment. In parallel, interior design experts may equally be unaware of these issues, as well as of who needs the available solutions.Similarly, medical and architectural sciences are not connected, eventually failing to meet patients' everyday needs. Conclusions: Interior architecture and health scientists are called to cooperate, aiming to provide a highly efficient and meaningful support to patients and families affected by unforeseen debilitating medical conditions.
    • Activity of cabazitaxel in metastatic or inoperable locally advanced dedifferentiated liposarcoma: A phase 2 study of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG)

      Sanfilippo, R.; Hayward, R. L.; Musoro, J.; Benson, C.; Leahy, Michael G; Brunello, A.; Blay, J. Y.; Steeghs, N.; Desar, I. M. E.; Ali, N.; et al. (2022)
      Importance: Treatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. New drugs are required. Objective: To assess whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DDLPS to justify further investigation in a phase 3 setting. Design, setting, and participants: This international multicenter, open-label single-arm phase 2 trial was conducted at 10 institutions in 4 European countries from March 2015 to March 2019. Eligible patients had to have metastatic or locally advanced histologically proven DDLPS with evidence of disease progression within the past 6 months and had to have received no more than 1 previous line of chemotherapy. Interventions: After mandatory central review of tumor blocks, if the DDLPS diagnosis was confirmed, patients started treatment within 72 hours after registration. Cabazitaxel was administered at a dose of 25 mg/m2 IV infusion over 1 hour every 21 days until intolerance, progression, or withdrawal of consent. Main outcomes and measures: The primary end point was progression-free survival (PFS) rate at 12 weeks per RECIST 1.1. Based on a Simon 2-stage design, at least 4 of 17 (stage 1) and 11 of 37 (stage 2) eligible and evaluable patients who were progression free at 12 weeks were needed. The final analysis report was completed on November 17, 2021. Results: Forty patients were registered, with 2 patients being ineligible. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Progression-free survival at 12 weeks was 55%, achieving the primary study end point. At a median follow-up of 21.6 months, median PFS was 6 months and median OS 21 months. Response rate (RR) was 8% with 1 clinical response (CR) and 2 partial responses (PR). Twenty-three (60.5%) patients had a stable disease (SD). Disease control (PR+SD) was achieved in 26 patients (68%). Conclusions and relevance: This nonrandomized phase 2 clinical trial met its primary end point, with 21 of 38 patients (55%) being progression free at 12 weeks. These results suggest important activity of cabazitaxel in patients with metastatic or inoperable locally advanced DDLPS. The drug is worth being further studied in these tumors in a phase 3 setting.
    • Programmed death-ligand 1 (PD-L1) expression predicts response to neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis

      Azim, H. A.; Shohdy, Kyrillus S; Elghazawy, H.; Salib, M. M.; Almeldin, D.; Kassem, L.; Clinical Oncology Department, Cairo University, Cairo, Egypt (2022)
      Background: In patients with metastatic triple-negative breast cancer (TNBC), programmed death-ligand 1 (PD-L1) expression has been demonstrated to predict response to immunotherapy. It is unclear whether PD-L1 expression measured with currently available validated assays can predict chemotherapy response in patients with non-metastatic TNBC. Methods: We conducted a systematic review and meta-analysis of clinical studies to assess the PD-L1 expression as a predictor of response to chemotherapy in non-metastatic TNBC using validated assays. The primary endpoint was pathological complete response (pCR) rate to neoadjuvant chemotherapy. Secondary endpoints included the prevalence of PD-L1 expression in non-metastatic TNBC and its impact on disease-free survival (DFS) and overall survival (OS). Moreover, RNA sequence data from the TCGA breast cancer cohort was used to define the relationship between PDCD1 expression and response to chemotherapy and prognosis. Results: Nineteen studies were eligible for the meta-analysis with a total of 2403 patients with non-metastatic TNBC disease. The PD-L1-positive cohort had a significantly higher likelihood of achieving pCR with neoadjuvant chemotherapy (pooled odds ratio = 1.95; 95% CI = 1.39-2.73, p < 0.0001). In studies which reported long-term outcomes, PD-L1 positivity was associated with significantly better DFS and OS compared to PD-L1 negative patients (pooled hazard ratio = 0.51; 95% CI = 0.35-0.74, p < 0.0001 and 0.51; 95% CI = 0.27-0.94, p = 0.031, respectively). Transcriptomic data suggested that PD-L1 expression is a surrogate marker for the upregulation of key immune-related genes that mediate response to chemotherapy in TNBC. Conclusion: This analysis clearly shows that patients with PD-L1 positive TNBC respond better to neoadjuvant chemotherapy and are associated with better survival outcomes compared to patients with PD-L1 negative tumours. The newly distinct quadruple negative breast cancer (QNBC) subtype should be defined as the BC subtype with the poorest outcome in the non-metastatic setting, highlighting the need for more aggressive therapy approaches.
    • Changes in body weight and serum cholesterol after heart transplant in relation to ventricular assist device implantation

      Miura, K.; Yu, R.; Entwistle, T. R.; McKenzie, S. C.; Green, Adèle C; Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia (2022)
      Weight gain is common after implantation of a ventricular assist device (VAD) prior to heart transplantation, but post-transplant changes in weight and also in blood lipids in those with VAD is virtually unknown. This study aimed to determine the influence of pre-transplant VAD implantation on body weight, blood cholesterol and triglyceride levels in Australian adult heart transplant recipients (HTRs), 1990-2017, from time of transplantation to 36 months post-transplantation. Information on VAD implantation, weight and blood lipids was collected for HTRs from medical records. Changes in weight and blood lipids from post-transplant to 12-, 24 and 36 months later, were assessed by VAD status using linear mixed-effects models. Of 236 heart transplant recipients, 48 (20%) had VAD implants. HTRs irrespective of VAD status, tended to increase their mean weight (p < 0.001) over 36 months (VAD implant: 76.9-84.4 kg; no VAD: 81.3-88.2 kg). Patients with VAD tended to have lower mean blood lipids but experienced increases similar to those with no VAD, from baseline to 36 months (cholesterol: VAD: 4.24-4.66 mmol/l; no VAD: 4.73-4.88 mmol/l; p = 0.05; triglycerides: VAD 1.59-1.63 mmol/l; no VAD 1.85-2.22 mmol/l; p = 0.09). We conclude that HTRs in general experience weight gain and lipid increases in the first 36 months after transplantation, regardless of prior VAD implantation.
    • Low-cost and clinically applicable copy number profiling using repeat DNA

      Abujudeh, S.; Zeki, S. S.; van Lanschot, M. C. J.; Pusung, M.; Weaver, Jamie M; Li, X.; Noorani, A.; Metz, A. J.; Bornschein, J.; Bower, L.; et al. (2022)
      Background: Somatic copy number alterations (SCNAs) are an important class of genomic alteration in cancer. They are frequently observed in cancer samples, with studies showing that, on average, SCNAs affect 34% of a cancer cell's genome. Furthermore, SCNAs have been shown to be major drivers of tumour development and have been associated with response to therapy and prognosis. Large-scale cancer genome studies suggest that tumours are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Despite the frequency of SCNAs and their clinical relevance, the use of genomics assays in the clinic is biased towards targeted gene panels, which identify SNVs but provide limited scope to detect SCNAs throughout the genome. There is a need for a comparably low-cost and simple method for high-resolution SCNA profiling. Results: We present conliga, a fully probabilistic method that infers SCNA profiles from a low-cost, simple, and clinically-relevant assay (FAST-SeqS). When applied to 11 high-purity oesophageal adenocarcinoma samples, we obtain good agreement (Spearman's rank correlation coefficient, rs=0.94) between conliga's inferred SCNA profiles using FAST-SeqS data (approximately £14 per sample) and those inferred by ASCAT using high-coverage WGS (gold-standard). We find that conliga outperforms CNVkit (rs=0.89), also applied to FAST-SeqS data, and is comparable to QDNAseq (rs=0.96) applied to low-coverage WGS, which is approximately four-fold more expensive, more laborious and less clinically-relevant. By performing an in silico dilution series experiment, we find that conliga is particularly suited to detecting SCNAs in low tumour purity samples. At two million reads per sample, conliga is able to detect SCNAs in all nine samples at 3% tumour purity and as low as 0.5% purity in one sample. Crucially, we show that conliga's hidden state information can be used to decide when a sample is abnormal or normal, whereas CNVkit and QDNAseq cannot provide this critical information. Conclusions: We show that conliga provides high-resolution SCNA profiles using a convenient, low-cost assay. We believe conliga makes FAST-SeqS a more clinically valuable assay as well as a useful research tool, enabling inexpensive and fast copy number profiling of pre-malignant and cancer samples.
    • Triplet therapy with androgen deprivation, docetaxel, and androgen receptor signalling inhibitors in metastatic castration-sensitive prostate cancer: A meta-analysis

      Ciccarese, C.; Iacovelli, R.; Sternberg, C. N.; Gillessen, Silke; Tortora, G.; Fizazi, K.; Medical Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy (2022)
      Background: The addition of either docetaxel or an androgen receptor signalling pathway inhibitor (ARSi) to androgen-deprivation therapy (ADT) has become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC) patients. Recent phase III data support even greater survival impact of a triplet regimen with ADT plus docetaxel plus an ARSi (abiraterone or darolutamide) compared to ADT plus docetaxel. Objective: To evaluate whether the addition of an ARSi to ADT improves outcomes of mCSPC patients treated with docetaxel. Methods: We searched MEDLINE/PubMed, the Cochrane Library, and ASCO Meeting abstracts for randomised clinical trials (RCTs) testing the combination of ARSi + ADT in mCSPC men who received docetaxel. Data extraction was conducted according to the PRISMA statement. Summary hazard ratio (HR) was calculated using random- or fixed-effects models. The statistical analyses were performed with RevMan software (v.5.2.3). Results: Five RCTs were selected. Triplet therapy improved overall survival (OS) compared to ADT + docetaxel in mCSPC patients (HR = 0.73; p < 0.00001). This intensified strategy maintained the OS benefit when the ARSi was administered concomitant to chemotherapy (HR = 0.72; p < 0.00001), but no statistical effect was detected if the ARSi was sequential to docetaxel (p = 0.44). Moreover, in the subgroup of men with de novo mCSPC, triplets significantly improved OS (HR = 0.72, p < 0.0001). The lack of access to raw data was the main limit of our analysis. Conclusion: Our results support a clear survival advantage of adding an ARSi to ADT in mCSPC patients treated with docetaxel, mainly when the ARSi was administered concomitantly to chemotherapy and in the subgroup of de novo mCSPC.
    • Checkpoint inhibitor associated bullous cutaneous immune related adverse events: a multi-centre observational study

      Kawsar, A.; Edwards, C.; Patel, P.; Heywood, Richard; Gupta, A.; Mann, J.; Harland, C.; Heelan, K.; Larkin, J.; Lorigan, Paul C; et al. (2022)
      Background: Checkpoint inhibitor therapy (CPI) has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune-related adverse events (irAEs) secondary to CPI are commonly observed, however autoimmune blistering disorders such as bullous pemphigoid (BP) are rare. Objectives: To review the prevalence, incidence risk, clinicopathological features and management of bullous cutaneous irAEs toxicity associated to CPI therapy. Methods: A multicentre, retrospective, observational study of CPI associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006-2019. Results: 7391 patients were identified. CPI associated bullous irAEs including BP (n=16) occurred in 0.3% (n=22). Median age of onset was 76 years old with male preponderance. Most patients had cutaneous melanoma (73%, n=16) of which 81% (13/16) were BRAF wildtype. Grade 1,2,3,4 skin toxicity occurred in 9% ,45%, 41%,4% respectively. The mucosae were involved in 27% and 25% of confirmed BP cases did not present with bullae. Median time to onset of bullous irAEs was 12 months, with median total symptom duration of 6 months. Single PD-1/PD-L1 agents had a longer time to onset of symptoms compared with combination therapy (median 12 months versus 7 months, respectively). 91%, 64%, 9% of patients required one, two or three lines of treatment respectively. Two cases occurred after completion of CPI (1 and 3 months). Of the 20 cases which presented whilst on CPI this was permanently discontinued in 55% (11/20) and temporarily held in 20% (4/20). In the four held CPI cases, bullous eruption re-flared in 50%. Conclusions: CPI associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0.3% over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared to other cutaneous irAEs, with a median time of 12 months and it can occur after cessation of therapy. Discontinuation of CPI's may be required. Recognising bullous irAEs promptly and referral to dermatology is essential to optimise management and improve patient outcomes and tumour responses.
    • Palliative radiotherapy in cancers of female genital tract: Outcomes and prognostic factors

      Harsha Kombathula, Sri; Cree, Anthea; Joshi, P. V.; Akturk, Nesrin; Barraclough, Lisa H; Haslett, Kate; Choudhury, Ananya; Hoskin, Peter J; The Christie NHS Foundation Trust, Clinical Oncology, Manchester, United Kingdom (2022)
      Background and purpose: Metastatic and incurable cancers of the gynaecological tract (FGTC) represent a major global health burden. Systemic treatment has modest efficacy and radiotherapy is often used for local symptoms. This study combines experience from two large UK centres in palliative radiotherapy for gynaecological cancers. Materials and methods: Pooled data from two major centres was analysed. Advanced FGTC patients who received at least one fraction of palliative radiotherapy to the pelvis between 2013 and 2018 were included. Data collected included demographic and tumour details, radiotherapy dose fractionation and details of previous and subsequent treatment. Response was defined in terms of toxicity, symptomatic response and survival. Comorbidities were recorded using a modified ACE 27 score which is adjusted for the presence of uncontrolled FGTC in all the patients. Results: A total of 184 patients were included for treatment response and toxicity; survival data was available for 165 patients. Subjective response in pre-radiotherapy symptoms was documented in 80.4%. Grade 3 or worse gastrointestinal, urinary and other (vomiting, fatigue, pain) toxicity incidence was 2.2%, 3.8%, and 2.7% respectively. No statistically significant correlation between the prescribed EQD210 and symptom control or toxicity was seen. 1 year overall survival was 25.1% (median 5.9 months). Absent distant metastases, completion of the intended course of radiotherapy, response to radiotherapy, and receipt of further lines of treatment were independent prognostic factors. Conclusion: Palliative radiotherapy is effective for symptoms of advanced FGTC with low toxicity. The absence of a dose response argues for short low dose palliative radiotherapy schedules to be used.
    • Treatment planning considerations for the development of FLASH proton therapy

      Rothwell, Bethany; Lowe, Matthew; Traneus, E.; Krieger, M.; Schuemann, J.; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, (2022)
      With increasing focus on the translation of the observed FLASH effect into clinical practice, this paper presents treatment planning considerations for its development using proton therapy. Potential requirements to induce a FLASH effect are discussed along with the properties of existing proton therapy delivery systems and the changes in planning and delivery approaches required to satisfy these prerequisites. For the exploration of treatment planning approaches for FLASH, developments in treatment planning systems are needed. Flexibility in adapting to new information will be important in such an evolving area. Variations in definitions, threshold values and assumptions can make it difficult to compare different published studies and to interpret previous studies in the context of new information. Together with the fact that much is left to be understood about the underlying mechanism behind the FLASH effect, a systematic and comprehensive approach to information storage is encouraged. Collecting and retaining more detailed information on planned and realised dose delivery as well as reporting the assumptions made in planning studies creates the potential for research to be revisited and re-evaluated in the light of future improvements in understanding. Forward thinking at the time of study development can help facilitate retrospective analysis. This, we hope, will increase the available evidence and accelerate the translation of the FLASH effect into clinical benefit.
    • Cancer patient care during different war times; is the response too slow?

      Tolia, M.; Kamposioras, Konstantinos; Symvoulakis, E. K.; Mauri, D.; Skouras, P.; Schizas, D.; Charalampakis, N.; Kokakis, I.; Matthaios, D.; Gazouli, I.; et al. (2022)
    • Durvalumab after sequential chemoradiotherapy in stage III, unresectable NSCLC: the phase 2 PACIFIC-6 trial

      Garassino, M. C.; Mazieres, J.; Reck, M.; Chouaid, C.; Bischoff, H.; Reinmuth, N.; Cove-Smith, Laura; Mansy, T.; Cortinovis, D.; Migliorino, M. R.; et al. (2022)
      Background: Based on the findings of the phase 3 PACIFIC trial (NCT02125461), durvalumab is standard of care for patients with stage III, unresectable NSCLC and no disease progression following concurrent chemoradiotherapy (cCRT). Many patients are considered unsuitable for cCRT due to concerns with tolerability. The phase 2 PACIFIC-6 trial (NCT03693300) evaluates the safety and tolerability of durvalumab following sequential CRT (sCRT). Methods: Patients with stage III, unresectable NSCLC and no progression following platinum-based, sCRT were enrolled to receive durvalumab (1500 mg intravenously) every 4 weeks for up to 24 months. The primary endpoint was the incidence of grade 3/4 adverse events possibly related to treatment (PRAEs) occurring within 6 months. Secondary endpoints included investigator-assessed progression-free survival (PFS; RECIST v1.1) and overall survival (OS). Results: Overall, 117 patients were enrolled (59.8% with PS >0, 65.8% aged ≥65 years, and 37.6% with stage IIIA disease). Median treatment duration was 32.0 weeks; 37.6% of patients remained on treatment at data cut-off (July 15, 2021). Grade 3/4 AEs occurred in 18.8% of patients. Five patients had grade 3/4 PRAEs within 6 months (incidence: 4.3%; 95% CI: 1.4-9.7), including two pneumonitis cases. Two patients (1.7%) had grade 5 AEs of any cause. Survival data maturity was limited. Median PFS was 10.9 months (95% CI: 7.3-15.6) and 12-month PFS and OS rates were 49.6% and 84.1%, respectively. Conclusions: Durvalumab following sCRT had a comparable safety profile to that observed with durvalumab following cCRT in PACIFIC and showed encouraging preliminary efficacy in a frailer population.
    • European Association of Neuro-Oncology (EANO) guidelines for treatment of primary central nervous system lymphoma (PCNSL)

      Hoang-Xuan, K.; Deckert, M.; Ferreri, A. J. M.; Furtner, J.; Gallego Perez-Larraya, J.; Henriksson, R.; Hottinger, A. F.; Kasenda, B.; Lefranc, F.; Lossos, A.; et al. (2022)
      The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and publication of practice-changing randomised trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for treatment of PCNSL, including intraocular manifestations and specific management of elderly . The main changes from the previous guideline include strenghtened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.
    • Interplay of developmental hippo-notch signaling pathways with the DNA damage response in prostate cancer

      Mourkioti, I.; Angelopoulou, A.; Belogiannis, K.; Lagopati, N.; Potamianos, S.; Kyrodimos, E.; Gorgoulis, Vassilis G; Papaspyropoulos, A.; Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National Kapodistrian University of Athens (NKUA), 11527 Athens, Greece (2022)
      Prostate cancer belongs in the class of hormone-dependent cancers, representing a major cause of cancer incidence in men worldwide. Since upon disease onset almost all prostate cancers are androgen-dependent and require active androgen receptor (AR) signaling for their survival, the primary treatment approach has for decades relied on inhibition of the AR pathway via androgen deprivation therapy (ADT). However, following this line of treatment, cancer cell pools often become resistant to therapy, contributing to disease progression towards the significantly more aggressive castration-resistant prostate cancer (CRPC) form, characterized by poor prognosis. It is, therefore, of critical importance to elucidate the molecular mechanisms and signaling pathways underlying the progression of early-stage prostate cancer towards CRPC. In this review, we aim to shed light on the role of major signaling pathways including the DNA damage response (DDR) and the developmental Hippo and Notch pathways in prostate tumorigenesis. We recapitulate key evidence demonstrating the crosstalk of those pathways as well as with pivotal prostate cancer-related 'hubs' such as AR signaling, and evaluate the clinical impact of those interactions. Moreover, we attempt to identify molecules of the complex DDR-Hippo-Notch interplay comprising potentially novel therapeutic targets in the battle against prostate tumorigenesis.
    • A randomized, double-blind, biomarker-selected, phase II clinical trial of maintenance poly ADP-ribose polymerase inhibition with rucaparib following chemotherapy for metastatic urothelial carcinoma

      Crabb, S. J.; Hussain, S.; Soulis, E.; Hinsley, S.; Dempsey, L.; Trevethan, A.; Song, Yeepei; Barber, J.; Frew, J.; Gale, J.; et al. (2022)
      Purpose: A DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker-positive mUC. Methods: DRD biomarker-positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model. Results: Out of 248 patients, 74 (29.8%) were DRD biomarker-positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib. Conclusion: Maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.
    • Brief communication on the impact of β-blockers on outcomes in patients receiving cancer immunotherapy

      Kennedy, Oliver J; Neary, M. T.; Christie NHS Foundation Trust (2022)
      Preclinical studies show that β-adrenergic activation suppresses the immune system and reduces the effectiveness of cancer immunotherapy. As a result, there is considerable interest in using β-blockers (BBs), a cheap and safe class of medication, in combination with immunotherapy to improve outcomes in cancer. This study is a systematic review and meta-analysis of clinical studies. A comprehensive literature search was performed up to May 2022. Studies were included if they reported hazard ratios (HRs) of overall survival (OS), all-cause mortality or progression-free survival (PFS) associated with BBs in patients with solid organ cancer treated with immunotherapy. Study-specific HRs and 95% confidence intervals were pooled in random effects meta-analyses. Nine studies involving over 6350 patients with melanoma, lung, renal, urothelial, or other solid cancers treated with a range of immunotherapies met the inclusion criteria. Across all studies combined, there was no association between concomitant BB use and OS (HR 0.99, 0.83-1.18) or PFS (HR 0.97, 0.89-1.05). In subgroup analyses, BB use made no difference to OS or PFS in melanoma (OS HR 0.66, 0.33-1.34; PFS HR 0.81, 0.62-1.05) or to OS in lung cancer (OS HR 1.00, 0.49-2.07). In summary, this study found no evidence that BBs enhance immunotherapy effectiveness.
    • Untangling the tumorigenic role of homotrimeric collagen I

      Jørgensen, Claus; Systems Oncology, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK. (2022)
      Pancreatic ductal adenocarcinoma is characterized by a complex microenvironment. In this issue of Cancer Cell, Chen and colleagues define an oncogenic role of tumor-cell-produced collagen I homotrimers, wherein tumor development is promoted by integrin α3/β1-dependent activation of tumor cell signaling and modulation of tumor microbiome and immunity.
    • Clonal diversification and histogenesis of malignant germ cell tumours

      Oliver, T. R. W.; Chappell, L.; Sanghvi, R.; Deighton, L.; Ansari-Pour, N.; Dentro, S. C.; Young, M. D.; Coorens, T. H. H.; Jung, H.; Butler, T.; et al. (2022)
      Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we study the relationship of histogenesis and clonal diversification in GCTs by analysing the genomes and transcriptomes of 547 microdissected histological units. We find no correlation between genomic and histological heterogeneity. However, we identify unifying features including the retention of fetal developmental transcripts across tissues, expression changes on chromosome 12p, and a conserved somatic evolutionary sequence of whole genome duplication followed by clonal diversification. While this pattern is preserved across all GCTs, the developmental timing of the duplication varies between prepubertal and postpubertal cases. In addition, tumours of younger children exhibit distinct substitution signatures which may lend themselves as potential biomarkers for risk stratification. Our findings portray the extensive diversification of GCT tissues and genetic subclones as randomly distributed, while identifying overarching transcriptional and genomic features.
    • A randomised, pragmatic clinical trial of ACUpuncture plus standard care versus standard care alone FOr Chemotherapy Induced peripheral Neuropathy (ACUFOCIN)

      Stringer, Jacqui; Ryder, W. D.; Mackereth, Peter A; Misra, Vivek; Wardley, Andrew M; The Christie NHS Foundation Trust, Wilmslow Rd, Manchester, M20 4BX, UK (2022)
      Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose limiting toxicity posing a major clinical challenge for managing patients receiving specific chemotherapy regimens (e.g., Taxanes). There is a growing body of literature suggesting acupuncture can improve CIPN symptoms. The purpose of the ACUFOCIN trial was to collect preliminary data on the safety, feasibility, acceptability and initial effectiveness of acupuncture as a treatment for CIPN, comparing use of acupuncture plus standard care (Acupuncture) against standard care alone (Control). Method: At a tertiary cancer centre, a pragmatic, randomised, parallel group design study was used to investigate the effectiveness of a 10-week course of acupuncture. Participants experiencing CIPN of ≥ Grade II, recording a 'Most Troublesome' CIPN symptom score of ≥3 using the "Measure Yourself Medical Outcome Profile" (MYMOP 2), were randomised to 'Acupuncture' or 'Control' arms. Clinicians were blinded to allocated groups, however as it was not possible to blind participants, it cannot be guaranteed they did not disclose study allocation within their clinic assessments. The primary outcome measure was the number of patients reporting a ≥ 2-point improvement (success) in their MYMOP2 score at week 10. 100 participants (120 to allow for attrition) were required for a hypothesised improvement in success proportions from 30% to 55% using a primary analysis model with logistic regression adjusted for stratification factors and baseline MYMOP2 scores. Feasibility and acceptability of study design was addressed through percentage return of primary outcome, retention rate and a nested qualitative study. Results: Primary MYMOP2 outcome data at week 10 was available for 108/120 randomised participants; this is greater than the 100 participants required to adequately power the study. There were 36/53 (68%) successes in 'Acupuncture' compared to 18/55 (33%) in 'Control'. Beneficial effects were seen in the secondary outcome data, including clinicians' grading of neuropathy, EORTC, QLQ-CIPN20, QLQ-C30 summary scores and patient reported pain scores. There were no serious adverse events reported within the study and only 16 acupuncture associated events, none of which required intervention. Conclusion: A 10-week course of acupuncture resulted in measurable improvement in participants symptoms of CIPN. The results warrant further investigation.
    • Clinical disease course and survival outcomes following disease recurrence in adenoid cystic carcinoma with and without NOTCH signaling pathway activation

      Feeney, Laura; Hapuarachi, Brindley; Adderley, Helen; Rack, Samuel; Morgan, D.; Walker, R.; Rauch, R.; Herz, E.; Kaye, J.; Harrington, K.; et al. (2022)
      Background: Adenoid cystic carcinoma (ACC) is a rare salivary cancer. The highest rates of disease recurrence are in patients with NOTCH pathway activation, reported in up to 20%. Novel drugs targeting NOTCH signaling are under investigation in the recurrent/metastatic (R/M) setting. To understand their clinical utility, there is an urgent need to better characterize the disease course and outcomes following current standard of care treatment. Methods: 120 patients with R/M ACC underwent clinical review at a single UK Cancer Centre. Patients were retrospectively assessed for tumor NOTCH pathway activation using next generation sequencing (NGS) targeting NOTCH1/2/3 genes and/or NOTCH1 intra-cellular domain (NICD1) immunohistochemistry. Demographic and treatment data were extracted from the clinical notes. Kaplan-Meier survival analysis was performed using log rank test. Results: NOTCH pathway activation was identified in 13/120 patients (11 %). In 12/101 patients analyzed by NGS, NOTCH1/3 activating somatic mutations were identified, and a further patient was identified with NICD1 diffuse nuclear staining in whom NGS testing was not possible. Patients with NOTCH pathway activation had shorter median RFS (1.1 vs 3.4 years, p = 0.2032) and significantly reduced median OS from diagnosis (4.0 vs 16.3 years, p < 0.0001). There was significantly reduced median OS from time of disease recurrence/metastasis (1.9 vs 9.6 years, p < 0.0001). Conclusion: This study clearly demonstrates a reduction in OS from time of first confirmed disease recurrence/metastasis for patients with NOTCH pathway activated ACC. This provides support for developing new drugs for this sub-group of patients, for whom clinical outcomes are significantly worse and effective treatments are lacking.
    • cfDNA methylome profiling for detection and subtyping of small cell lung cancers

      Chemi, Francesca; Pearce, Simon P; Clipson, Alexandra; Hill, Steven M; Conway, Alicia-Marie; Richardson, Sophie A; Kamieniecka, Katarzyna; Caeser, R.; White, Daniel J; Mohan, Sumitra; et al. (2022)
      Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential differential therapeutic vulnerabilities, with epigenetically distinct SCLC subtypes also described. The clinical relevance of these subtypes is unclear, due in part to challenges in obtaining tumor biopsies for reliable profiling. Here we describe a robust workflow for genome-wide DNA methylation profiling applied to both patient-derived models and to patients' circulating cell-free DNA (cfDNA). Tumor-specific methylation patterns were readily detected in cfDNA samples from patients with SCLC and were correlated with survival outcomes. cfDNA methylation also discriminated between the transcription factor SCLC subtypes, a precedent for a liquid biopsy cfDNA-methylation approach to molecularly subtype SCLC. Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring and molecular subtyping of patients with SCLC.