Social determinants of health inequalities in early phase clinical trials in Northern England.

BACKGROUND: Early phase clinical trials in Oncology represent a subspecialised area where UK patient selection is influenced by access to Experimental Cancer Medicine Centres (ECMCs). Equity of access with respect to social determinants of health (SDoH) were explored for two major ECMCs. METHODS: A retrospective cohort study including all referrals to Newcastle and Manchester ECMCs in 2021 was completed. Consent to screening or pre-screening was stratified against SDoH characteristics, including: Index of Multiple Deprivation (IMD) decile, ethnicity and distance to centre. RESULTS: 1243 patients were referred for trials. IMD quintile 1 (most deprived) patients had reduced likelihood of referral compared to expected population models (OR, 0.67; 95% CI: 0.55 to 0.80, p = <0.0001). IMD quintile 5 (least deprived) had increased likelihood of referral (OR, 1.46; 95% CI: 1.17 to 1.82, p = 0.0007). Living beyond median distance from Manchester reduced the likelihood of consenting to trials (OR, 0.72; 95% CI: 0.55 to 0.94, p = 0.015). Ethnicity data represented a White British propensity. CONCLUSIONS: Inequalities in socioeconomic and geographic factors influence referral and enrolment to early phase clinical trials in Northern England. This has implications for equity of access and generalisability of trial results internationally and warrants further study.

Efficacy and safety of high-dose chemotherapy as the first or subsequent salvage treatment line in patients with relapsed or refractory germ cell cancer: an international multicentric analysis.

BACKGROUND: In relapsed or refractory (RR) metastatic germ cell cancer (GCC), high-dose (HD) chemotherapy (CTX) plus autologous stem cell transplantation is considered the standard of care. Limited data exist regarding the efficacy of HD-CTX following conventionally dosed salvage regimens (CDRs). This analysis explores and contrasts the efficacy of HD-CTX as the first or subsequent salvage regimen. PATIENTS AND METHODS: Data were retrospectively collected to explore the efficacy of HD-CTX administered as the first (group A) or subsequent salvage CTX (group B) after a CDR. The primary endpoint was OS from the time of HD-CTX. Associations of survival, overall response rate (ORR), and toxicity with clinical characteristics were explored using stratified Kaplan-Meier and Cox regression models. RESULTS: Overall, 283 patients with GCC were included from 11 international centers, with 159 patients (56%) in group A and 124 patients (44%) in group B. The first salvage treatment was administered between 1998 and 2022, with a median follow-up of 27.0 [standard deviation (SD) 46.2] months for group A and 17.0 (SD 48.5) months for group B. The median OS from HD-CTX treatment initiation was not reached in group A, compared with 25 months in group B (P = 0.00027), associated with 2- and 5-year OS rates of 74% and 63% (group A) versus 53% and 37% (group B), respectively. When administered as the first salvage treatment, HD-CTX was associated with a higher ORR (79% versus 60%; P = 0.013) and lower nonhematologic grade ≥3 toxicity rate (78% versus 97%; P < 0.001). Concerning risk factor analysis for the total cohort, the International Prognostic Factors Study Group score was the only independent predictor of OS in multivariable analysis (P = 0.006). CONCLUSIONS: When administered as the initial salvage treatment or after CDR, HD-CTX exhibits curative potential for patients with RR GCC. The efficacy and safety outcomes were more favorable when HD-CTX was conducted as the first salvage treatment line.

The impact of COVID-19 on oncology professionals-one year on: lessons learned from the ESMO Resilience Task Force survey series.

BACKGROUND: COVID-19 has had a significant impact on the well-being and job performance of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration set out to investigate and monitor well-being since COVID-19 in relation to work, lifestyle and support factors in oncology professionals 1 year on since the start of the pandemic. METHODS: An online, anonymous survey was conducted in February/March 2021 (Survey III). Key outcome variables included risk of poor well-being or distress (expanded Well-Being Index), feeling burnout (single item from expanded Well-Being Index), and job performance since COVID-19. Longitudinal analysis of responses to the series of three surveys since COVID-19 was carried out, and responses to job demands and resources questions were interrogated. SPSS V.26.0/V.27.0 and GraphPad Prism V9.0 were used for statistical analyses. RESULTS: Responses from 1269 participants from 104 countries were analysed in Survey III: 55% (n = 699/1269) female, 54% (n = 686/1269) >40 years, and 69% (n = 852/1230) of white ethnicity. There continues to be an increased risk of poor well-being or distress (n = 464/1169, 40%) and feeling burnout (n = 660/1169, 57%) compared with Survey I (25% and 38% respectively, P < 0.0001), despite improved job performance. Compared with the initial period of the pandemic, more participants report feeling overwhelmed with workload (45% versus 29%, P < 0.0001). There remain concerns about the negative impact of the pandemic on career development/training (43%), job security (37%). and international fellowship opportunities (76%). Alarmingly, 25% (n = 266/1086) are considering changing their future career with 38% (n = 100/266) contemplating leaving the profession. CONCLUSION: Oncology professionals continue to face increased job demands. There is now significant concern regarding potential attrition in the oncology workforce. National and international stakeholders must act immediately and work closely with oncology professionals to draw up future-proof recovery plans.

Proteomic profiling of cisplatin-resistant and cisplatin-sensitive germ cell tumour cell lines using quantitative mass spectrometry.

PURPOSE: Advanced testicular germ cell tumours (GCT) generally have a good prognosis owing to their unique sensitivity towards cisplatin-based chemotherapies. However, cisplatin-resistant GCT have a poor outcome. Further studies are mandatory to better understand resistance mechanisms and develop therapeutic strategies for refractory GCTs. METHODS: Protein levels in cisplatin-resistant GCT cell lines of NTERA-2, NCCIT and 2102EP were analyzed by quantitative proteomic mass spectrometry (MS) in combination with stable isotope labelling by amino acids in cell culture (SILAC). Differentially abundant protein markers of acquired cisplatin resistance were validated by Western blotting. Comprehensive bioinformatical annotation using gene set enrichment analyses (GSEA) and STRING interaction analysis were performed to identify commonly affected pathways in cisplatin resistance and the data were compared to the GCT cohort of the 'The Cancer Genome Atlas'. RESULTS: A total of 4375 proteins were quantified by MS, 144 of which were found to be differentially abundant between isogenic resistant and sensitive cell line pairs (24 proteins for NTERA-2, 60 proteins for NCCIT, 75 proteins for 2102EP). Western blotting confirmed regulation of key resistance-associated proteins (CBS, ANXA1, LDHA, CTH, FDXR). GSEA revealed a statistically significant enrichment of DNA repair-associated proteins in all three resistant cell lines and specific additional processes for individual cell lines. CONCLUSION: High resolution MS combined with SILAC is a powerful tool and 144 significantly deregulated proteins were found in cisplatin-resistant GCT cell lines. Our study provides the largest proteomic in vitro library for cisplatin resistance in GCT, yet, enabling further studies to develop new treatment options for patients with refractory GCT.

The concerns of oncology professionals during the COVID-19 pandemic: results from the ESMO Resilience Task Force survey II.

BACKGROUND: The COVID-19 pandemic has resulted in significant changes to professional and personal lives of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration aimed to provide contemporaneous reports on the impact of COVID-19 on the lived experiences and well-being in oncology. METHODS: This online anonymous survey (July-August 2020) is the second of a series of global surveys launched during the course of the pandemic. Longitudinal key outcome measures including well-being/distress (expanded Well-being Index-9 items), burnout (1 item from expanded Well-being Index), and job performance since COVID-19 were tracked. RESULTS: A total of 942 participants from 99 countries were included for final analysis: 58% (n = 544) from Europe, 52% (n = 485) female, 43% (n = 409) ≤40 years old, and 36% (n = 343) of non-white ethnicity. In July/August 2020, 60% (n = 525) continued to report a change in professional duties compared with the pre-COVID-19 era. The proportion of participants at risk of poor well-being (33%, n = 310) and who reported feeling burnout (49%, n = 460) had increased significantly compared with April/May 2020 (25% and 38%, respectively; P < 0.001), despite improved job performance since COVID-19 (34% versus 51%; P < 0.001). Of those who had been tested for COVID-19, 8% (n = 39/484) tested positive; 18% (n = 7/39) felt they had not been given adequate time to recover before return to work. Since the pandemic, 39% (n = 353/908) had expressed concerns that COVID-19 would have a negative impact on their career development or training and 40% (n = 366/917) felt that their job security had been compromised. More than two-thirds (n = 608/879) revealed that COVID-19 has changed their outlook on their work-personal life balance. CONCLUSION: The COVID-19 pandemic continues to impact the well-being of oncology professionals globally, with significantly more in distress and feeling burnout compared with the first wave. Collective efforts from both national and international communities addressing support and coping strategies will be crucial as we recover from the COVID-19 crisis. In particular, an action plan should also be devised to tackle concerns raised regarding the negative impact of COVID-19 on career development, training, and job security.

The impact of COVID-19 on oncology professionals: results of the ESMO Resilience Task Force survey collaboration.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on well-being has the potential for serious negative consequences on work, home life, and patient care. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration set out to investigate well-being in oncology over time since COVID-19. METHODS: Two online anonymous surveys were conducted (survey I: April/May 2020; survey II: July/August 2020). Statistical analyses were performed to examine group differences, associations, and predictors of key outcomes: (i) well-being/distress [expanded Well-being Index (eWBI; 9 items)]; (ii) burnout (1 item from eWBI); (iii) job performance since COVID-19 (JP-CV; 2 items). RESULTS: Responses from survey I (1520 participants from 101 countries) indicate that COVID-19 is impacting oncology professionals; in particular, 25% of participants indicated being at risk of distress (poor well-being, eWBI ≥ 4), 38% reported feeling burnout, and 66% reported not being able to perform their job compared with the pre-COVID-19 period. Higher JP-CV was associated with better well-being and not feeling burnout (P < 0.01). Differences were seen in well-being and JP-CV between countries (P < 0.001) and were related to country COVID-19 crude mortality rate (P < 0.05). Consistent predictors of well-being, burnout, and JP-CV were psychological resilience and changes to work hours. In survey II, among 272 participants who completed both surveys, while JP-CV improved (38% versus 54%, P < 0.001), eWBI scores ≥4 and burnout rates were significantly higher compared with survey I (22% versus 31%, P = 0.01; and 35% versus 49%, P = 0.001, respectively), suggesting well-being and burnout have worsened over a 3-month period during the COVID-19 pandemic. CONCLUSION: In the first and largest global survey series, COVID-19 is impacting well-being and job performance of oncology professionals. JP-CV has improved but risk of distress and burnout has increased over time. Urgent measures to address well-being and improve resilience are essential.

Expression of miRNA-371a-3p in seminal plasma and ejaculate is associated with sperm concentration.

BACKGROUND: The microRNAs of the miR-371-3 cluster are novel serum markers for testicular germ cell tumors. Sporadic reports suggested the expression of this miRNA in semen. OBJECTIVES: To verify the expression of miR-371a-3p in seminal plasma and unprocessed ejaculate; to compare seminal plasma miRNA levels in germ cell tumors patients with those of controls; to look for an association of miRNA levels with semen quality. MATERIALS AND METHODS: The miR-371a-3p expression was analyzed with qPCR. The study population consisted of 100 participants: seminal plasma samples from 20 germ cell tumors patients and 30 controls, serum samples from 12 healthy men, ejaculate samples from 38 men undergoing fertility testing. RESULTS: The seminal plasma miR-371a-3p levels of germ cell tumors patients were not different from controls. The miRNA expression was very low in serum but much higher in seminal plasma. In ejaculate samples, the miRNA expression significantly correlated with sperm concentration and the total sperm count. DISCUSSION: miR-371-a-3p is present in sperm-containing fluids. Seminal plasma levels cannot be used to distinguish germ cell tumors from controls. The correlation with sperm concentration in ejaculate samples suggests the spermatozoa as possible source of miR-371a-3p production. CONCLUSION: The miR-371a-3p levels in ejaculate could represent a novel biomarker for the non-invasive evaluation of male infertility.

Epigenetic treatment combinations to effectively target cisplatin-resistant germ cell tumors: past, present, and future considerations.

BACKGROUND: Type II germ cell tumors represent the most common solid malignancy in men aged 15-45 years. Despite high cure rates of >90% over all stages, 10-15% of advanced patients develop treatment resistance and potentially succumb to their disease. Treatment of refractory germ cell tumors remains unsatisfactory, and new approaches are needed to further improve outcomes. OBJECTIVES: With this narrative review, we highlight epigenetic mechanisms related to resistance to standard systemic treatment, which may act as promising targets for novel combined epigenetic treatment approaches. MATERIALS AND METHODS: A comprehensive literature search of PubMed and MEDLINE was conducted to identify original and review articles on resistance mechanisms and/or epigenetic treatment of germ cell tumors in vitro and in vivo. Review articles were hand-searched to identify additional articles. RESULTS: Distinct epigenetic phenomena have been linked to chemotherapy resistance in germ cell tumors, among which DNA hypermethylation, histone acetylation, and bromodomain proteins appear as promising targets for therapeutic exploitation. Inhibitors of key regulators, for example DNA methyltransferases (e.g. decitabine, guadecitabine), histone deacetylases (e.g. romidepsin), and bromodomain proteins (e.g. JQ1) decreased cell viability, triggered apoptosis, and growth arrest. Additionally, these epigenetic drugs induced differentiation and led to loss of pluripotency and re-sensitization towards cisplatin in cell lines and animal models. DISCUSSION: Epigenetic treatments hold promise to (i) reduce the treatment burden of and (ii) overcome resistance to standard cisplatin-based chemotherapy. Combined approaches may enhance activity, while the ideal target and treatment combination of epigenetic drugs, either with another epigenetic agent or conventional cytotoxic agents need to be defined. CONCLUSION: Epigenetic (combination) treatment for germ cell tumors should be further explored in pre-clinical and clinical research for its potential to further improve germ cell tumor treatment.

[Positron emission tomography in germ cell tumors in men : Possibilities and limitations]. / Positronenemissionstomographie bei Keimzelltumoren des Mannes : Einsatzmöglichkeiten und Grenzen.

BACKGROUND: Conventional radiographic imaging may fail to safely distinguish clinical stage I from stage IIA germ cell cancer, to localize isolated tumor marker relapses, and to equivocally identify the viability of postchemotherapy residual masses. OBJECTIVES: To provide an overview of the diagnostic value and limitations of functional imaging by positron emission tomography with 2­deoxy-2-[fluorine-18]fluoro-D-glucose with computed tomography (18F-FDG-PET-CT) in male germ cell cancer. MATERIALS AND METHODS: A narrative review based on a literature search of PubMed/MEDLINE for original articles published from 1990-2018 and conference proceedings of ASCO (American Society of Clinical Oncology) and EAU (European Association of Urology) annual meetings 2014-2017 is presented. RESULTS: 18F-FDG-PET-CT does not improve diagnostic accuracy compared to conventional CT imaging clinical stage (CS) I disease. Particularly PET-negativity of postchemotherapy residual masses of seminomas >3 cm in size guide decision-making against further additional treatment. Even PET-positive residues must not result in relapse. For nonseminoma, the value of PET imaging is reduced by potential mature teratoma components, which are commonly PET negative. CONCLUSIONS: Current guidelines recommend 18F-FDG-PET-CT 6-8 weeks postchemotherapy for viability assessment of seminoma residues >3 cm in size. Exceptional circumstances, in which 18F-FDG-PET-CT may be helpful, include: (1) detection of active disease in CS IS, (2) viability assessment of residual masses >1 cm where complete secondary resection is impossible, (3) staging at marker relapse with unconspicuous conventional CT scan, (4) early response assessment during chemotherapy.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer.

Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either in-vitro or in-vivo in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although PTEN loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy.

Impact of primary metastatic bone disease in germ cell tumors: results of an International Global Germ Cell Tumor Collaborative Group G3 Registry Study.

Background: Bone metastases (BM) are rare in germ cell tumor (GCT) patients. Systematic data on risk factors, treatment and outcome are largely lacking. Patients and methods: A database created by an international consortium including 123 GCT patients with BM at primary diagnosis was retrospectively analysed. Survival estimates were calculated by the method of Kaplan-Meier and compared by log-rank testing. Cox regression analysis was applied for risk factor analyses. Results: In our cohort of patients, BM at primary diagnosis more often affected multiple sites (61%) and BM as the only metastatic site were scarce (9%). Histology was non-seminoma in 77% and seminoma in 23% of patients. After a median follow-up of 18 months (range, 0-228), estimated median PFS and OS were 21 (range, 0-225) and 98 months (95%CI, 36-160), respective 2-year PFS and OS rates were 34% and 45%. Negative prognosticators in univariate analysis were a mediastinal primary (PFS; HR 1.92; 95%CI, 1.05-3.50; OS; HR 2.16; 95%CI, 1.14-4.09) and the presence of liver and/or brain metastases (PFS; HR 1.89; 95%CI, 1.13-3.17; OS; HR 1.91; 95%CI, 0.024) Seminomatous histology was the strongest predictor for favorable PFS (multivariate Cox regression; HR, 0.32; P=0.011) with respective 2-year PFS and OS rates of 68% and 75% compared with 24% and 36% for non-seminoma patients. Conclusions: Outcome of GCT patients with primary metastatic bone disease is particularly poor in non-seminoma patients, even worse than the expected outcomes of the general IGCCCG 'poor prognosis' group. This series does not indicate that mutlimodal treatment improves the prognosis over stage-adapted chemotherapy alone, however, the statistical power of these results is limited due to low patient numbers in each specific subgroup.

Anxiety and depression in long-term testicular germ cell tumor survivors.

OBJECTIVE: Despite a good prognosis, the typically young age at diagnosis and physical sequelae may cause psychological distress in germ cell tumor survivors. We aimed to determine the frequency of anxiety and depression and analyze the impact of demographic and disease-related factors. METHOD: We enrolled N=164 testicular germ cell tumor survivors receiving routine follow-up care at the University Cancer Center Hamburg and a specialized private practice (mean, 11.6 years after diagnosis). Patients completed the Generalized Anxiety Disorder Screener-7, the Patient Health Questionnaire-9 and the Memorial Symptom Assessment Scale-Short Form. RESULTS: We found clinically significant anxiety present in 6.1% and depression present in 7.9% of survivors. A higher number of physical symptoms and having children were significantly associated with higher levels of both anxiety and depression in multivariate regression analyses controlling for age at diagnosis, cohabitation, socioeconomic status, time since diagnosis, metastatic disease and relapse. Younger age at diagnosis and shorter time since diagnosis were significantly associated with higher anxiety. CONCLUSION: Although rates of clinically relevant anxiety and depression were comparably low, attention toward persisting physical symptoms and psychosocial needs related to a young age at diagnosis and having children will contribute to address potential long-term psychological distress in germ cell tumor survivors.

Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation.

Ataxia-telangiectasia mutated (ATM) is needed for the initiation of the double-strand break (DSB) repair by homologous recombination (HR). ATM triggers DSB end resection by stimulating the nucleolytic activity of CtIP and MRE11 to generate 3'-ssDNA overhangs, followed by RPA loading and RAD51 nucleofilament formation. Here we show for the first time that ATM is also needed for later steps in HR after RAD51 nucleofilament formation. Inhibition of ATM after completion of end resection did not affect RAD51 nucleofilament formation, but resulted in HR deficiency as evidenced by (i) an increase in the number of residual RAD51/γH2AX foci in both S and G2 cells, (ii) the decrease in HR efficiency as detected by HR repair substrate (pGC), (iii) a reduced SCE rate and (iv) the radiosensitization of cells by PARP inhibition. This newly described role for ATM was found to be dispensable in heterochromatin-associated DSB repair, as KAP1-depletion did not alleviate the HR-deficiency when ATM was inhibited after end resection. Moreover, we demonstrated that ATR can partly compensate for the deficiency in early, but not in later, steps of HR upon ATM inhibition. Taken together, we describe here for the first time that ATM is needed not only for the initiation but also for the completion of HR.