Tetrafluoroethylene (TFE), a compound used for the production of fluorinated polymers including polytetrafluoroethylene, increases the incidence of liver and kidney cancers and leukemia in rats and mice. This is the first time the cancer risk in humans has been explored comprehensively in a cohort mortality study (1950-2008) that included all polytetrafluoroethylene production sites in Europe and North America at the time it was initiated. A job-exposure matrix (1950-2002) was developed for TFE and ammonium perfluoro-octanoate, a chemical used in the polymerization process. National reference rates were used to calculate standardized mortality ratios (SMRs) and 95% confidence intervals. Among 4,773 workers ever exposed to TFE, we found a lower rate of death from most causes, as well as increased risks for cancer of the liver (SMR = 1.27; 95% confidence interval: 0.55, 2.51; 8 deaths) and kidney (SMR = 1.44; 95% confidence interval: 0.69, 2.65; 10 deaths) and for leukemia (SMR = 1.48; 95% confidence interval: 0.77, 2.59; 12 deaths). A nonsignificant upward trend (P = 0.24) by cumulative exposure to TFE was observed for liver cancer. TFE and ammonium perfluoro-octanoate exposures were highly correlated, and therefore their separate effects could not be disentangled. This pattern of findings narrows the range of uncertainty on potential TFE carcinogenicity but cannot conclusively confirm or refute the hypothesis that TFE is carcinogenic to humans.

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The DNA damage response (DDR) is a well-coordinated cellular network activated by DNA damage. The unravelling of the key players in DDR, their specific inactivation in different tumor types and the synthesis of specific chemical inhibitors of DDR represent a new hot topic in cancer therapy. In this article, we will review the importance of DDR in lymphoma development and how this can be exploited therapeutically. Specifically, we will focus on CHK1, WEE1, ATR, DNA-PK and PARP inhibitors, for which preclinical data as single agents or in combination has been accumulating, fostering their clinical development. The few available clinical data on these inhibitors will also be discussed.

BackgroundImmune checkpoint inhibitors (ICIs) demonstrate unprecedented efficacy in multiple malignancies; however, the mechanisms of sensitivity and resistance are poorly understood and predictive biomarkers are scarce. INSPIRE is a phase 2 basket study to evaluate the genomic and immune landscapes of peripheral blood and tumors following pembrolizumab treatment.MethodsPatients with incurable, locally advanced or metastatic solid tumors that have progressed on standard therapy, or for whom no standard therapy exists or standard therapy was not deemed appropriate, received 200 mg pembrolizumab intravenously every three weeks. Blood and tissue samples were collected at baseline, during treatment, and at progression. One core biopsy was used for immunohistochemistry and the remaining cores were pooled and divided for genomic and immune analyses. Univariable analysis of clinical, genomic, and immunophenotyping parameters was conducted to evaluate associations with treatment response in this exploratory analysis.ResultsEighty patients were enrolled from March 21, 2016 to June 1, 2017, and 129 tumor and 382 blood samples were collected. Immune biomarkers were significantly different between the blood and tissue. T cell PD-1 was blocked (≥98%) in the blood of all patients by the third week of treatment. In the tumor, 5/11 (45%) and 11/14 (79%) patients had T cell surface PD-1 occupance at weeks six and nine, respectively. The proportion of genome copy number alterations and abundance of intratumoral 4-1BB+ PD-1+ CD8 T cells at baseline (P < 0.05), and fold-expansion of intratumoral CD8 T cells from baseline to cycle 2–3 (P < 0.05) were associated with treatment response.ConclusionThis study provides technical feasibility data for correlative studies. Tissue biopsies provide distinct data from the blood and may predict response to pembrolizumab.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0541-0) contains supplementary material, which is available to authorized users.

Clinical records (n = 24) with an established diagnosis of 5α-reductase-2 deficiency were reviewed. A previous misdiagnosis was present in about 70% (period from first observation to definitive diagnosis: 9.1 ± 10.8 years), and in 8 children gonadal removal was performed before certain diagnosis. Initial sex assignment was female in 16/24 (67%) and male in 8/24 (33%) cases. After diagnosis, sex re-assignment was performed in 5 babies (4 girls to male sex; 1 boy to female sex). Baseline testosterone/DHT ratio was diagnostic in 6/12 subjects (first months of life n = 4; puberty n = 2), while post-hCG testosterone/DHT ratio was diagnostic in all tested individuals (choosing both the cut-off value 15 or 10). Eighteen different mutations in the steroid-5α-reductase-2 (SRD5A2) gene were identified, 5 of which have never been reported. In conclusion, a time lag exists before the diagnosis of 5α-reductase-2 deficiency is established; sex assignment and gonadal removal may be performed before certain diagnosis. Sex re-assignment is usually female to male, but the contrary may occur. A large variability in clinical phenotypes and genetic mutations was present in this cohort. Accurate endocrine evaluation is recommended in babies possibly affected by 5α-reductase-2 deficiency, since the use of appropriate cut-off values of testosterone/DHT ratio after hCG stimulation may permit to select individuals for SRD5A2 gene analysis. A genotype-phenotype correlation was not found in this study.

The rapid spread of severe acute respiratory syndrome coronavirus 2 infection and its related disease (COVID-19) has required an immediate and coordinate healthcare response to face the worldwide emergency and define strategies to maintain the continuum of care for the non-COVID-19 diseases while protecting patients and healthcare providers. The dimension of the COVID-19 pandemic poses an unprecedented risk especially for the more vulnerable populations. To manage patients with cancer adequately, maintaining the highest quality of care, a definition of value-based priorities is necessary to define which interventions can be safely postponed without affecting patients’ outcome. The European Society for Medical Oncology (ESMO) has endorsed a tiered approach across three different levels of priority (high, medium, low) incorporating information on the value-based prioritisation and clinical cogency of the interventions that can be applied for different disease sites. Patients with gynaecological cancer are at particular risk of COVID-19 complications because of their age and prevalence of comorbidities. The definition of priority level should be based on tumour stage and histology, cancer-related symptoms or complications, aim (curative vs palliative) and magnitude of benefit of the oncological intervention, patients’ general condition and preferences. The decision-making process always needs to consider the disease-specific national and international guidelines and the local healthcare system and social resources, and a changing situation in relation to COVID-19 infection. These recommendations aim to provide guidance for the definition of deferrable and undeferrable interventions during the COVID-19 pandemic for ovarian, endometrial and cervical cancers within the context of the ESMO Clinical Practice Guidelines.

PurposeTo assess the association between computed tomography (CT)-derived quantitative measures of body composition profiling and chemotherapy-related complications, in terms of dose reduction, premature discontinuation of chemotherapy, and cycle delays in patients with ovarian cancer. Secondary purposes were to evaluate associations between sarcopenia and survival, and to evaluate differences in body composition profiling at baseline and after neoadjuvant chemotherapy.Materials and MethodsThe study population was retrospectively selected from a database of patients with newly diagnosed ovarian cancer (any stage) referred to our Institution between Feb 2011 and Mar 2020. Clinical data were recorded, and CT images at the level of the 3rd lumbar vertebra were stored. By using specific software, skeletal muscle area (SMA), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were extracted. Skeletal muscle index (SMI) was then calculated. Statistical analysis was performed by logistic regression models to identify body composition features predictive of dose reduction, premature end of chemotherapy, and cycle delays. Kaplan-Meier analyses were performed to assess overall survival (OS) and progression-free survival (PFS). The log-rank test was used to determine differences in OS and PFS between sarcopenic and non-sarcopenic patients. Wilcoxon test was performed to compare body composition features before and after neoadjuvant chemotherapy (NACT).ResultsSixty-nine patients were included. A significant association was found between VAT and cycle delays (OR = 1.01, z = 2.01, 95% CI: 1.00–1.02, p &lt; 0.05), between SMA and early discontinuation of chemotherapy (OR = 1.03, z = 2.10, 95% CI: 1.00–1.05, p &lt; 0.05), and between mean SMD and cycle delays (OR = 0.92, z = −2.70, 95%CI: 0.87–0.98, p &lt; 0.01). No significant difference emerged for OS in sarcopenic and non-sarcopenic patients, nor in CT body composition features before and after NACT.ConclusionsIn ovarian cancer patients, CT-derived body composition profiling might predict the risk of chemotoxicity. In particular, VAT and SMD are associated with chemotherapy cycle delays, and SMA with early discontinuation of chemotherapy.

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