Faculty Bibliography

Sexual and gender minorities (SGM) include persons identifying as lesbian, gay, bisexual, transgender/non-binary, and queer experience a greater cancer burden than their heterosexual or cisgender counterparts. Access to cancer care includes prevention and early detection, however despite known increased risk for various malignancies among SGM individuals, cancer screening rates remain low. This commentary outlines disparities in cancer screening for SGM individuals and provides the current evidence-based screening guidelines for these patients.

BACKGROUND:Cancer-associated fibroblasts (CAFs) are a major component of the cancer stroma, and their response to therapeutic treatments likely impacts the outcome. We tested the hypothesis that CAFs develop unique characteristics that enhance their resistance to ionizing radiation. METHODS:CAFs were generated through intimate coculture of normal human fibroblasts of skin or lung origin with various human cancer cell types using permeable microporous membrane inserts. Fibroblasts and cancer cells are grown intimately, yet separately, on either side of the insert's membrane for extended times to generate activated fibroblast populations highly enriched in CAFs. RESULTS:Cs γ rays compared to naïve fibroblasts. Addition of repair inhibitors of single- or double-stranded DNA breaks attenuated the resistance of CAFs to the clastogenic effects of γ rays, supporting a role for increased ability to repair DNA damage in CAF radioresistance. CONCLUSIONS:This study reveals that CAFs are radioresistant and experience significant changes in indices of oxidative metabolism. The CAFs that survive radiation treatment likely modulate the fate of the associated cancer cells. Identifying them together with their mode of communication with cancer cells, and eradicating them, particularly when they may exist at the margin of the radiotherapy planning target volume, may improve the efficacy of cancer treatments. Video Abstract.

Transgender, non-binary, and gender non-conforming people, also referred to as gender minorities, have unique cancer prevention, treatment, and care needs and experience cancer health disparities compared to the cisgender population. We present four composite cases of the cancer care challenges experienced by gender minorities.

INTRODUCTION:The Institute of Medicine's 2011 report on lesbian, gay, bisexual, and transgender (LGBT) health and the legalization of same-sex marriage are just two of the numerous milestones that have hastened medical schools' efforts to prepare trainees to address the needs of LGBT community members. Early awareness of sexual diversity through self- and peer introspection and video-based education can help trainees build a foundation towards providing affirming care to LGBT patients. METHODS:The Kern model was used to develop, implement, and evaluate an interactive multimodal workshop to provide first-year medical students with a formative introduction to LGBT health. Learning objectives focused on comprehending the spectrum of human sexuality, health issues for LGBT patients, and better practices for promoting affirming care. The module consisted of a PowerPoint presentation, sexuality survey, videos of provider-patient encounters, and community-based resources. RESULTS:The workshop was implemented among 178 first-year medical students in September 2018, with 93% completing the pre-/postworkshop evaluations. Comparison of evaluations showed an increase in confidence in addressing each of the three learning objectives. Over 85% rated the PowerPoint and videos as very good or excellent. DISCUSSION:This workshop was effective in helping first-year medical students appreciate the spectrum of sexual diversity, health issues facing LGBT individuals, and better practices to promote affirming care. The real-time sexuality survey helped trainees appreciate sexual diversity through self-reflection and near-peer sharing. The videos and accompanying discussion provided real-life encounters, along with common pitfalls in and pearls for communicating with LGBT patients.

The treatment of cancer using targeted radionuclide therapy is of interest to nuclear medicine and radiation oncology because of its potential for killing tumor cells while minimizing dose-limiting toxicities to normal tissue. The ionizing radiations emitted by radiopharmaceuticals deliver radiation absorbed doses over protracted periods of time with continuously varying dose rates. As targeted radionuclide therapy becomes a more prominent part of cancer therapy, accurate models for estimating the biologically effective dose (BED) or equieffective dose (EQD2_α/β) will become essential for treatment planning. This study examines the radiobiological impact of the dose rate increase half-time during the uptake phase of the radiopharmaceutical. MDA-MB-231 human breast cancer cells and V79 Chinese hamster lung fibroblasts were irradiated chronically with 662 keV γ rays delivered with time-varying dose rates that are clinically relevant. The temporal dose-rate patterns were: 1. acute, 2. exponential decrease with a half-time of 64 h (T_d = 64 h), 3. initial exponential increase to a maximum (half time T_i = 2, 8 or 24 h) followed by exponential decrease (T_d = 64 h). Cell survival assays were conducted and surviving fractions were determined. There was a marked reduction in biological effect when T_i was increased. Cell survival data were tested against existing dose-response models to assess their capacity to predict response. Currently accepted models that are used in radiation oncology overestimated BED and EQD2_α/β at low-dose rates and underestimated them at high-dose rates. This appears to be caused by an adaptive response arising as a consequence of the initial low-dose-rate phase of exposure. An adaptive response function was derived that yields more accurate BED and EQD2_α/β values over the spectrum of dose rates and absorbed doses delivered. Our experimental data demonstrate a marked increase in cell survival when the dose-rate-increase half-time is increased, thereby suggesting an adaptive response arising as a consequence of this phase of exposure. We have modified conventional radiobiological models used in the clinic for brachytherapy and external beams of radiation to account for this phenomenon and facilitate their use for treatment planning in targeted radionuclide therapy.

The health risks to humans and non-human biota exposed to low dose ionizing radiation remain ambiguous and are the subject of intense debate. The need to establish risk assessment standards based on the mechanisms underlying low-level radiation exposure has been recognized by regulatory agencies as critical to adequately protect people and to make the most effective use of national resources. Here, the authors briefly review evidence showing that the molecular and biochemical changes induced by low doses of radiation differ from those induced by high doses. In particular, an array of redundant and inter-related mechanisms act in both prokaryotes and eukaryotes to restore DNA integrity following exposures to relatively low doses of sparsely ionizing radiation. Furthermore, the radiation-induced protective mechanisms often overcompensate and minimize the mutagenic potential of the byproducts of normal oxidative metabolism. In contrast to adaptive protection observed at low doses of sparsely ionizing radiation, there is evidence that even a single nuclear traversal by a densely ionizing particle track can trigger harmful effects that spread beyond the traversed cell and induce damaging effects in the nearby bystander cells. In vivo studies examining whether exposure to low dose radiation at younger age modulates the latency of expression of age-related diseases such as cancer, together with studies on the role of genetic susceptibility, will further illuminate the magnitude of risk of exposure to low dose radiation.