The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

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EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals

Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. Prostate cancer may be asymptomatic at the early stage and often has an indolent course that may require only active surveillance. Based on GLOBOCAN 2018 estimates, 1,276,106 new cases of prostate cancer were reported worldwide in 2018, with higher prevalence in the developed countries. Differences in the incidence rates worldwide reflect differences in the use of diagnostic testing. Prostate cancer incidence and mortality rates are strongly related to the age with the highest incidence being seen in elderly men (> 65 years of age). African-American men have the highest incidence rates and more aggressive type of prostate cancer compared to White men. There is no evidence yet on how to prevent prostate cancer; however, it is possible to lower the risk by limiting high-fat foods, increasing the intake of vegetables and fruits and performing more exercise. Screening is highly recommended at age 45 for men with familial history and African-American men. Up-to-date statistics on prostate cancer occurrence and outcomes along with a better understanding of the etiology and causative risk factors are essential for the primary prevention of this disease.

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Epidemiology of Prostate Cancer

Trex1 is an exonuclease that degrades cytosolic DNA and has been associated with modulation of interferon responses in autoimmunity and viral infections. Here, the authors show that Trex1 attenuates the immunogenicity of cancer cells treated with high radiation doses by d…

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DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.

Helicobacter pylori are bacteria that have coevolved with humans to be transmitted from person to person and to persistently colonize the stomach. Their population structure is a model for the ecology of the indigenous microbiota. A well-choreographed equilibrium between bacterial effectors and host responses permits microbial persistence and health of the host but confers risk of serious diseases, including peptic ulceration and gastric neoplasia.

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Helicobacter pylori persistence: biology and disease

Summary Background Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. Methods We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov, number NCT01295827. Findings Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8–34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio [HR] 0·56 [95% CI 0·34–0·91], p=0·019; median progression-free survival 4·4 months [95% CI 2·1–8·6] vs 2·1 months [1·6–2·3]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 [0·30–0·84], p=0·0084; median progression-free survival 6·3 months [95% CI 2·1–10·4] vs 2·0 months [1·8–2·1]). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 [95% CI 0·36–0·94], p=0·026; median overall survival 10·7 months [95% CI 6·5–18·9] vs 5·3 months [2·7–7·7]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 [95% CI 0·36–0·96], p=0·034; median overall survival 11·6 months [95% CI 6·5–20·5] vs 5·3 months [3·0–8·5]). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group). Interpretation Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC. Funding US National Institutes of Health.

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Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial

Increasing evidence demonstrates that radiation acts as an immune stimulus, recruiting immune mediators that enable anti-tumor responses within and outside the radiation field. There has been a rapid expansion in the number of clinical trials harnessing radiation to enhance antitumor immunity. If positive, results of these trials will lead to a paradigm shift in the use of radiotherapy. In this review, we discuss the rationale for trials combining radiation with various immunotherapies, provide an update of recent clinical trial results and highlight trials currently in progress. We also address issues pertaining to the optimal incorporation of immunotherapy with radiation, including sequencing of treatment, radiation dosing and evaluation of clinical trial endpoints.

https://jitc.bmj.com/content/jitc/4/1/51.full.pdf

Current clinical trials testing the combination of immunotherapy with radiotherapy

Stereotactic Body Radiotherapy (SBRT) has excellent control rates for low- and intermediate-risk prostate carcinoma.The role of SBRT for high-risk disease remains less studied. We present long-term results on a cohort of patients with NCCN-defined high-risk disease treated with SBRT. We retrospectively studied 97 patients treated as part of prospective trial from 2006–2010 with SBRT alone (n = 52) to dose of 35–36.25 Gy in 5 fractions, or pelvic radiation to 45 Gy followed by SBRT boost of 19–21 Gy in 3 fractions (n = 45). 46 patients received Androgen Deprivation Therapy. Quality of life and bladder/bowel toxicity was assessed using the Expanded Prostate Index Composite (EPIC) and RTOG toxicity scale. Median followup was 60 months. 6-year biochemical disease-free survival (bDFS) was 69%. On multivariate analysis, only PSA remained significant (P < 0.01) for bDFS. Overall toxicity was mild, with 5% Grade 2–3 urinary and 7% Grade 2 bowel toxicity. Use of pelvic radiotherapy was associated with significantly higher bowel toxicity (P = .001). EPIC scores declined for the first six months and then returned towards baseline. SBRT appears to be a safe and effective treatment for high-risk prostate carcinoma. Our data suggests that SBRT alone may be the optimal approach. Further followup and additional studies is required to corroborate our results.

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Stereotactic body radiotherapy with or without external beam radiation as treatment for organ confined high-risk prostate carcinoma: a six year study.

Epithelial ovarian cancer is the leading cause of gynecologic cancer death and the fifth most common cause of cancer mortality among women in the United States (1). The majority of patients are diagnosed with advanced (ie, stages III and IV) disease, for which the standard treatment is aggressive surgical debulking followed by six to eight cycles of platinum-based chemotherapy, which is typically delivered concurrently with a taxane (2). Because of high toxicity, up to 42% of patients are unable to complete therapy as initially prescribed (3). To date, no good clinical measures for prediction of response exist; as a result, approximately 30% of patients undergo multiple cycles of therapy, with little or no benefit, before they are identified as being chemoresistant. The remaining 70% of patients initially achieve a complete response (CR), but more than 75%

https://www.medpagetoday.com/upload/2012/4/13/JNCI%20J%20Natl%20Cancer%20Inst-2012-Kang-jnci-djs177.pdf

A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy

Prokaryotic genomes are substantially diverse, even when from closely related species, with the resulting phenotypic diversity representing a repertoire of adaptations to specific constraints. Within the microbial population, genome content may not be fixed, as changing selective forces favor particular phenotypes; however, organisms well adapted to particular niches may have evolved mechanisms to facilitate such plasticity. The highly diverse Helicobacter pylori is a model for studying genome plasticity in the colonization of individual hosts. For H. pylori, neither point mutation, nor intergenic recombination requiring the presence of multiple colonizing strains, is sufficient to fully explain the observed diversity. Here we demonstrate that H. pylori has extensive, nonrandomly distributed repetitive chromosomal sequences, and that recombination between identical repeats contributes to the variation within individual hosts. That H. pylori is representative of prokaryotes, especially those with smaller (<2 megabases) genomes, that have similarly extensive direct repeats, suggests that recombination between such direct DNA repeats is a widely conserved mechanism to promote genome diversification.

Extensive repetitive DNA facilitates prokaryotic genome plasticity

Microorganisms that persist in single hosts face particular challenges. Helicobacter pylori, an obligate bacterial parasite of the human stomach, has evolved a lifestyle that features interstrain competition and intraspecies cooperation, both of which involve horizontal gene transfer. Microbial species must maintain genomic integrity, yet H. pylori has evolved a complex nonlinear system for diversification that exists in dynamic tension with the mechanisms for ensuring fidelity. Here, we review these tensions and propose that they create a dynamic pool of genetic variants that is sufficiently genetically diverse to allow H. pylori to occupy all of the potential niches in the stomach.

Josephine Kang

Papers

Current clinical trials testing the combination of immunotherapy with radiotherapy

Stereotactic body radiotherapy with or without external beam radiation as treatment for organ confined high-risk prostate carcinoma: a six year study.

A DNA Repair Pathway–Focused Score for Prediction of Outcomes in Ovarian Cancer Treated With Platinum-Based Chemotherapy

Extensive repetitive DNA facilitates prokaryotic genome plasticity

Bacterial populations as perfect gases: genomic integrity and diversification tensions in Helicobacter pylori