MRI-Guided Adaptive Radiation Therapy.

Magnetic resonance imaging-guided radiation therapy (MRIgRT) has improved soft tissue contrast over computed tomography (CT) based image-guided RT. Superior visualization of the target and surrounding radiosensitive structures has the potential to improve oncological outcomes partly due to safer dose-escalation and adaptive planning. In this review, we highlight the workflow of adaptive MRIgRT planning, which includes simulation imaging, daily MRI, identifying isocenter shifts, contouring, plan optimization, quality control, and delivery. Increased utilization of MRIgRT will depend on addressing technical limitations of this technology, while addressing treatment efficacy, cost-effectiveness, and workflow training.

MRI-Guided Radiation Therapy for Prostate Cancer: The Next Frontier in Ultrahypofractionation.

Technological advances in MRI-guided radiation therapy (MRIgRT) have improved real-time visualization of the prostate and its surrounding structures over CT-guided radiation therapy. Seminal studies have demonstrated safe dose escalation achieved through ultrahypofractionation with MRIgRT due to planning target volume (PTV) margin reduction and treatment gating. On-table adaptation with MRI-based technologies can also incorporate real-time changes in target shape and volume and can reduce high doses of radiation to sensitive surrounding structures that may move into the treatment field. Ongoing clinical trials seek to refine ultrahypofractionated radiotherapy treatments for prostate cancer using MRIgRT. Though these studies have the potential to demonstrate improved biochemical control and reduced side effects, limitations concerning patient treatment times and operational workflows may preclude wide adoption of this technology outside of centers of excellence. In this review, we discuss the advantages and limitations of MRIgRT for prostate cancer, as well as clinical trials testing the efficacy and toxicity of ultrafractionation in patients with localized or post-prostatectomy recurrent prostate cancer.

Single-cell transcriptome and accessible chromatin dynamics during endocrine pancreas development.

Delineating gene regulatory networks that orchestrate cell-type specification is a continuing challenge for developmental biologists. Single-cell analyses offer opportunities to address these challenges and accelerate discovery of rare cell lineage relationships and mechanisms underlying hierarchical lineage decisions. Here, we describe the molecular analysis of mouse pancreatic endocrine cell differentiation using single-cell transcriptomics, chromatin accessibility assays coupled to genetic labeling, and cytometry-based cell purification. We uncover transcription factor networks that delineate ß-, α-, and δ-cell lineages. Through genomic footprint analysis, we identify transcription factor-regulatory DNA interactions governing pancreatic cell development at unprecedented resolution. Our analysis suggests that the transcription factor Neurog3 may act as a pioneer transcription factor to specify the pancreatic endocrine lineage. These findings could improve protocols to generate replacement endocrine cells from renewable sources, like stem cells, for diabetes therapy.

NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Delays in Care Associated With Non-English-Speaking Patients With Breast Cancer.

BACKGROUND: Breast cancer care requires coordination between multiple diagnostic and treatment modalities. Disparities such as age, race/ethnicity, and socioeconomic status are associated with delays in care. This study investigates whether primary language is associated with delays in breast cancer diagnosis and treatment before and through radiotherapy (RT). PATIENTS AND METHODS: This study was an institutional retrospective matched-cohort analysis of women treated with breast RT over 2 years. A total of 65 non-English-speaking (NES) patients were matched with 195 English-speaking (ES) patients according to stage, age, and chemotherapy delivery. Key time intervals along the breast cancer care path from initial findings through RT were recorded. Data were analyzed in a mixed model with matching as the random effect. The impact of race and insurance status was analyzed in addition to language. RESULTS: Significant delays were found for NES patients, which varied by race. NES Latina patients experienced the longest delay, with a mean total care-path time of 13.53 months (from initial findings to end of RT) versus 8.18 months for all ES patients (P<.0001). Specifically, their mean total care-path time was 5.97 months longer than that of ES Latina patients (P=.001) and 5.80 months longer than that of ES White patients (P<.0001). In addition, NES Latina patients had a significantly longer total care-path time than NES patients of other races/ethnicities (P=.001). Delays were specifically seen between initial clinical or radiographic findings and diagnostic mammogram (P=.001) and between biopsy and resection (P=.044). Beyond language, race/ethnicity was itself associated with delays between resection and start of RT (P=.032) and between start and end of RT (P=.022). CONCLUSIONS: Language is associated with pre-RT delays in breast cancer care, especially for NES Latina patients. Delays are most pronounced before diagnostic mammograms, but they also exist before resection and RT. Future work should target NES patients to assist their progress along the care path.

Stereotactic Radiotherapy for Recurrent Post-Transplant Primary Central Nervous System Lymphoma.

Post-transplant primary central nervous system lymphoma (PCNSL) is a rare complication of solid organ transplantation. The optimal therapy for post-transplant PCNSL is not well established and generally includes reduction of immunosuppression and chemotherapy. Progression after front-line chemotherapy is common, and whole-brain radiotherapy (WBRT) is a standard salvage treatment as there is a concern that localized treatment fields would not prevent out-of-field recurrences. However, WBRT is associated with neurotoxicity and morbidity in these patients with inherently poor prognoses. Here, we report a patient with local recurrence of post-transplant PCNSL who was treated with fractionated stereotactic radiotherapy (SRT). He had no clinical toxicity from treatment and maintained pre-treatment neurocognition and performance status. Local control was achieved for 20 months following SRT, at which point he developed an in-field recurrence. He restarted lymphoma therapy but died one month later from fungal pneumonia. For central nervous system (CNS) lymphoma, further data are needed to optimize tumor control and toxicity outcomes and identify patients in whom localized radiotherapy fields may be beneficial, avoiding the potential toxicity of WBRT.

Impact of Insurance on Stage of Breast Cancer Presentation for Different Races and Ethnicities.

PURPOSE: Survival in breast cancer is largely stage-dependent. Lack of insurance and Medicaid have been associated with later-stage breast cancer, but it is unknown to what degree this association varies by race or ethnicity. METHODS: We conducted a retrospective single-institution cohort analysis of women undergoing breast radiotherapy from 2012 to 2017 (n = 1,019). Patients were categorized as having private insurance (n = 540), Medicare (n = 332), Medicaid (n = 122), or self-pay (n = 25). Ordinal logistic regression analysis identified variables associated with later-stage presentation, including age, race or ethnicity, insurance, the interaction between insurance and race or ethnicity, body mass index, education, and language. RESULTS: The association between insurance and breast cancer stage varied on the basis of a patient's race or ethnicity (P = .0114). White and Asian patients with Medicaid had significantly higher odds of later-stage breast cancer than those with private insurance (White odds ratio [OR], 2.10; 95% CI, 1.02 to 4.34; Asian OR, 3.22; 95% CI, 1.56 to 6.67). However, the inverse was true for Hispanic patients who had lower odds of later-stage disease with Medicaid than private insurance (OR, 0.36; 95% CI, 0.16 to 0.90). Hispanic patients with Medicaid had lower odds than either White or Asian patients with Medicaid. These findings persisted across all ages. CONCLUSION: The association between insurance and later-stage presentation is significantly influenced by race or ethnicity. Medicaid was generally associated with later-stage breast cancer diagnosis, but this was not true across all races and ethnicities. Although White and Asian patients with Medicaid presented with later stage, Hispanic patients fared better with Medicaid than private insurance. Future work should investigate how Medicaid is successfully targeting Hispanic patients in breast cancer care.

Harnessing genome-wide association studies to minimize adverse radiation-induced side effects.

Radiotherapy is used as definitive treatment in approximately two-thirds of all cancers. However, like any treatment, radiation has significant acute and long-term side effects including secondary malignancies. Even when similar radiation parameters are used, 5%-10% of patients will experience adverse radiation side effects. Genomic susceptibility is thought to be responsible for approximately 40% of the clinical variability observed. In the era of precision medicine, the link between genetic susceptibility and radiation-induced side effects is further strengthening. Genome-wide association studies (GWAS) have begun to identify single-nucleotide polymorphisms (SNPs) attributed to overall and tissue-specific toxicity following radiation for treatment of breast cancer, prostate cancer, and other cancers. Here, we review the use of GWAS in identifying polymorphisms that are predictive of acute and long-term radiation-induced side effects with a focus on chest, pelvic, and head-and-neck irradiation. Integration of GWAS studies with "omic" data, patient characteristics, and clinical correlates into predictive models could decrease radiation-induced side effects while increasing therapeutic efficacy.

Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Policy Challenges and Opportunities to Address Changing Paradigms in Cancer Care Delivery.

Multiple factors are forcing the healthcare delivery system to change. A movement toward value-based payment models is shifting these systems to team-based integration and coordination of care for better efficiencies and outcomes. Workforce shortages are stressing access and quality of care for patients with cancer and survivors, and their families and caregivers. Innovative therapies are expensive, forcing payers and employers to prioritize resources. Patients are advocating for care models centered on their needs rather than those of providers. In response, payment policies have recently focused on the promotion of alternative payment models that incentivize coordinated, high-quality care with consideration for value and controlling the increasing overall costs associated with cancer and its treatment. Given the multitude of factors confounding cancer care, NCCN convened a multistakeholder working group to examine the challenges and opportunities presented by changing paradigms in cancer care delivery. The group identified key challenges and developed policy recommendations to address 4 high-visibility topics in cancer care delivery. The findings and recommendations were then presented at the NCCN Policy Summit: Policy Challenges and Opportunities to Address Changing Paradigms in Cancer Care Delivery in September 2018, and multistakeholder roundtable panel discussions explored these findings and recommendations along with additional items. This article encapsulates the discussion from the NCCN Working Group meetings and the NCCN Policy Summit, including multistakeholder policy recommendations on delivery issues in cancer care designed to help inform national policies moving forward.

Association between primary language, a lack of mammographic screening, and later stage breast cancer presentation.

BACKGROUND: Health determinants are known to influence the stage of breast cancer presentation, but it is unclear to what extent language affects stage. This study investigates whether non-English-speaking (NES) patients present at a later stage than their English-speaking (ES) counterparts and whether language is associated with mammographic screening. METHODS: This study was a retrospective, single-institution cohort analysis of women undergoing breast radiotherapy from 2012 to 2017 (n = 1057). Patients were categorized as ES (n = 904) or NES (n = 153). Ordinal logistic regression analysis identified variables associated with later stage presentation, including language, race/ethnicity, and age. A subcohort analysis investigated the influence of mammographic screening on stage for NES patients. RESULTS: NES patients had greater odds of later stage disease than ES patients (odds ratio, 1.47; 95% confidence, 1.001-2.150). This association persisted across all races/ethnicities. An additional analysis examined age categories associated with mammographic screening. For women eligible for screening (ie, those 40-50 years old or older than 50 years), there was a significant association between language and stage. NES patients older than 50 years were twice as likely to present at an advanced stage in comparison with ES patients (16.19% vs 8.11%; P = .0082). An additional subset analysis accounted for mammograms. NES patients who did not undergo screening had a higher probability of stage III disease (40.3% of NES patients vs 12.7% of ES patients). There was no difference in stage between NES and ES patients who did undergo screening. CONCLUSIONS: Language is independently associated with later stage breast cancer for NES patients, regardless of race/ethnicity. NES patients may have difficulty in accessing the health care system. Future interventions should seek to reduce language barriers for mammographic screening and diagnosis.

NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology.

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

Hodgkin lymphoma, version 2.2015.

Hodgkin lymphoma (HL) is an uncommon malignancy involving lymph nodes and the lymphatic system. Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma are the 2 main types of HL. CHL accounts for most HL diagnosed in the Western countries. Chemotherapy or combined modality therapy, followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale), is the standard initial treatment for patients with newly diagnosed CHL. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, has produced encouraging results in the treatment of relapsed or refractory disease. The potential long-term effects of treatment remain an important consideration, and long-term follow-up is essential after completion of treatment.

An integrated cell purification and genomics strategy reveals multiple regulators of pancreas development.

The regulatory logic underlying global transcriptional programs controlling development of visceral organs like the pancreas remains undiscovered. Here, we profiled gene expression in 12 purified populations of fetal and adult pancreatic epithelial cells representing crucial progenitor cell subsets, and their endocrine or exocrine progeny. Using probabilistic models to decode the general programs organizing gene expression, we identified co-expressed gene sets in cell subsets that revealed patterns and processes governing progenitor cell development, lineage specification, and endocrine cell maturation. Purification of Neurog3 mutant cells and module network analysis linked established regulators such as Neurog3 to unrecognized gene targets and roles in pancreas development. Iterative module network analysis nominated and prioritized transcriptional regulators, including diabetes risk genes. Functional validation of a subset of candidate regulators with corresponding mutant mice revealed that the transcription factors Etv1, Prdm16, Runx1t1 and Bcl11a are essential for pancreas development. Our integrated approach provides a unique framework for identifying regulatory genes and functional gene sets underlying pancreas development and associated diseases such as diabetes mellitus.

Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation.

Developmental biology is challenged to reveal the function of numerous candidate genes implicated by recent genome-scale studies as regulators of organ development and diseases. Recapitulating organogenesis from purified progenitor cells that can be genetically manipulated would provide powerful opportunities to dissect such gene functions. Here we describe systems for reconstructing pancreas development, including islet ß-cell and α-cell differentiation, from single fetal progenitor cells. A strict requirement for native genetic regulators of in vivo pancreas development, such as Ngn3, Arx, and Pax4, revealed the authenticity of differentiation programs in vitro. Efficient genetic screens permitted by this system revealed that Prdm16 is required for pancreatic islet development in vivo. Discovering the function of genes regulating pancreas development with our system should enrich strategies for regenerating islets for treating diabetes mellitus.

Gene regulatory networks governing pancreas development.

Elucidation of cellular and gene regulatory networks (GRNs) governing organ development will accelerate progress toward tissue replacement. Here, we have compiled reference GRNs underlying pancreas development from data mining that integrates multiple approaches, including mutant analysis, lineage tracing, cell purification, gene expression and enhancer analysis, and biochemical studies of gene regulation. Using established computational tools, we integrated and represented these networks in frameworks that should enhance understanding of the surging output of genomic-scale genetic and epigenetic studies of pancreas development and diseases such as diabetes and pancreatic cancer. We envision similar approaches would be useful for understanding the development of other organs.

Deconstructing pancreas developmental biology.

The relentless nature and increasing prevalence of human pancreatic diseases, in particular, diabetes mellitus and adenocarcinoma, has motivated further understanding of pancreas organogenesis. The pancreas is a multifunctional organ whose epithelial cells govern a diversity of physiologically vital endocrine and exocrine functions. The mechanisms governing the birth, differentiation, morphogenesis, growth, maturation, and maintenance of the endocrine and exocrine components in the pancreas have been discovered recently with increasing tempo. This includes recent studies unveiling mechanisms permitting unexpected flexibility in the developmental potential of immature and mature pancreatic cell subsets, including the ability to interconvert fates. In this article, we describe how classical cell biology, genetic analysis, lineage tracing, and embryological investigations are being complemented by powerful modern methods including epigenetic analysis, time-lapse imaging, and flow cytometry-based cell purification to dissect fundamental processes of pancreas development.

Effects of telomere length in Drosophila melanogaster on life span, fecundity, and fertility.

Chromosome length in Drosophila is maintained by targeted transposition of three non-long terminal repeat retrotransposons, HeT-A, TART, and TAHRE, to the chromosome ends. The length and composition of these retrotransposon arrays can vary significantly between chromosome tips and between fly stocks, but the significance and consequences of these length differences are not understood. A dominant genetic factor, Tel, has been described, which causes a severalfold elongation of the retrotransposon arrays at all telomeres. We used this strain to assess possible affects of extended telomeres on the organism. While we found no effect on life span of the adults, we could demonstrate a correlation between long telomeres and reduced fertility and fecundity in individual females, which is also reflected in abnormal oocyte development.

The protein encoded by the gene proliferation disrupter (prod) is associated with the telomeric retrotransposon array in Drosophila melanogaster.

We report in this paper that the PROD protein, encoded by the gene proliferation disrupter (prod), is associated with the telomeric chromatin in Drosophila melanogaster. It binds to a region just upstream of the promoter of the telomere-specific retrotransposon HeT-A, which is located in the long 3'untranslated region of the element near its oligo(A) tail. Reduction of PROD in prod heterozygote flies results in elevated levels of HeT-A RNA in the ovaries, suggesting that PROD functions as a repressor of HeT-A transcriptional activity at the telomeres.