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Background: Uterine clear cell and serous carcinomas have a high propensity for locoregional and distant spread, tend to be more advanced at presentation, and carry a higher risk of recurrence and death than endometrioid cancers. Limited prospective data exist to guide evidence-based management of these rare malignancies., Objective: The American Radium Society sought to summarize evidence-based guidelines developed by a multidisciplinary expert panel that help to guide the management of uterine clear cell and serous carcinomas., Methods: The American Radium Society Appropriate Use Criteria presented in this manuscript were developed by a multidisciplinary expert panel using an extensive analysis of current published literature from peer-reviewed journals. A well-established methodology (modified Delphi) was used to rate the appropriate use of diagnostic and therapeutic procedures for the management of uterine clear cell and serous carcinomas., Results: The primary treatment for non-metastatic uterine clear cell and serous carcinomas is complete surgical staging, with total hysterectomy, salpingo-oophorectomy, omentectomy, and lymph node staging. Even in early-stage disease, patients with uterine clear cell and serous carcinomas have a worse prognosis than those with type I endometrial cancers, warranting consideration for adjuvant therapy regardless of the stage. Given the aggressive nature of these malignancies, and until further research determines the most appropriate adjuvant therapy, it may be reasonable to counsel patients about combined-modality treatment with systemic chemotherapy and radiotherapy., Conclusion: Patients diagnosed with uterine clear cell and serous carcinomas should undergo complete surgical staging. Multimodal adjuvant therapies should be considered in the treatment of both early-stage and advanced-stage disease. Further prospective studies or multi-institutional retrospective studies are warranted to determine optimal sequencing of therapy and appropriate management of patients based on their unique risk factors. Long-term surveillance is indicated due to the high risk of locoregional and distant recurrence., Competing Interests: Competing interests: All panelists were required to declare all conflicts of interest for the previous 36 months prior to initiating work on this document. These complete disclosure forms are retained by the American Radium Society (ARS) in perpetuity. The ARS Appropriate Use Criteria Steering Committee reviewed these disclosures with the chair and co-chair of this document and approved participation of the panelists prior to starting development of this work. Disclosures potentially relevant to the content of this guideline are provided. List of any potentially relevant conflicts of interest for the past 3 years for guideline chair, guideline co-chair, all voting and non-voting panelists: MB: consulting fee/honoraria (Elekta, Inc.). DG: consulting fee/honoraria (AstraZeneca, Merck). RLC: grants for clinical trials (NIH, Gateway Foundation, V-Foundation, Judy Rees/Albert Pisani MD Ovarian Cancer Research Fund, AstraZeneca, Merck, Clovis, Genmab, Roche/Genentech, Janssen); consulting fee/honoraria (AstraZeneca, Tesaro, Medivation, Clovis, Gamamab, Genmab, Roche/Genentech, Janssen, Agenus, Regeneron, OncoQuest). MH: consulting fee/Honoraria (Varian Brachytherapy; AstraZeneca). SJ: consulting fee/honoraria (AstraZeneca, Varian). WS, Jr: consulting fee/honoraria (Merck, Carl Zeiss, Varian)., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

ECOG-ACRIN EA5181 is a current prospective, randomized trial that is investigating whether the addition of concomitant durvalumab to standard chemo/radiation followed by 1 year of consolidative durvalumab results in an overall survival benefit over standard chemo/radiation alone followed by 1 year of consolidative durvalumab in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC). Because multiple phase I/II trials have shown the relative safety of adding immunotherapy to chemo/radiation and due to the known synergism between chemotherapy and immunotherapy, it is hoped that concomitant durvalumab can reduce the relatively high incidence of local failure (38%-46%) as seen in recent prospective, randomized trials of standard chemo/radiation in this patient population. We will review the history of radiation for LA-NSCLC and discuss the role of induction, concurrent and consolidative chemotherapy as well as the concerns for late cardiac and pulmonary toxicities associated with treatment. Furthermore, we will review the potential role of next generation sequencing, PD-L1, ctDNA and tumor mutation burden and their possible impact on this trial., Competing Interests: Disclosure None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Radiation pneumonitis (RP) is a local inflammatory response, and we hypothesize that RP serves as an immune stimulator and is a protective factor against disease progression.  Methods: We analyzed patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiation therapy (SBRT) at two institutions. Radiographic RP (RRP) was evaluated and maximal axial dimensions were measured at three-, six-, and twelve-month timepoints with surveillance CT. RRP was measured using radiographic markers such as ground-glass opacities and airspace consolidation. Disease recurrence was evaluated and categorized as local, regional, and distant.  Results: Seventy-seven unique patient records were randomly selected from the database, 72 patients (93.5%) had RRP and five patients (6.5%) did not. The median follow-up was 24.3 months (IQR: 12.0 - 41.9). Disease failure occurred in 28.6% of patients with 6.5% local only, 2.6% regional only, 7.8% distant only, and 11.7% with multiple recurrences. Patients with RRP demonstrated a lower rate of disease failure with 25.0% of those with RRP experiencing disease failure and 80% of those without RRP experiencing disease failure (p=0.02). Patients with RRP had a 71% reduced risk of disease recurrence, compared to patients with no RRP, after adjusting for maximum tumor dimension (HR 0.29, p = 0.05). Among patients with RRP, there was no significant difference in recurrence based on extent of RRP (maximal area of RRP on CT). RRP did not correlate with overall survival.  Discussion: Most patients who received SBRT had RRP, and this study suggests that it may be protective of cancer recurrence. These results are hypothesis-generating and will need to be validated in larger and independent datasets., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Wolf et al.)

In the modern era, cervical cancer treatment has become more multidisciplinary in nature. Accurate and precise staging based on clinical and radiographic findings, as well as identification of pathologic and molecular risk factors, may alter treatment recommendations. Additionally, the body of evidence guiding optimal treatment recommendations continues to grow. Multiple specialists including gynecologic oncologists, radiation oncologists, medical oncologists, radiologists, pathologists, and other ancillary staff, often with subspecialty experience in gynecology or cancer care, now staff multidisciplinary gynecologic oncology teams. This review highlights the basis of multidisciplinary treatment of early-stage cervical cancer, with a focus on surgical interventions, the role of adjuvant therapy, and indications for definitive chemoradiation. We specifically focus on the treatment of cervical cancer from stage IA1 (microinvasive disease) to stage IIB (parametrial involvement without involvement of pelvic sidewall). The staging manuals referenced in this review include the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging as well as the updated American Joint Committee on Cancer (AJCC) 9th edition (2021)., Competing Interests: Competing interests: WS reports personal fees from Carl Zeiss and other support from NRG Oncology. RLC reports grants and personal fees from AstraZeneca, grants from Merck, personal fees from GSK, grants and personal fees from Clovis, grants and personal fees from Genmab, grants and personal fees from Roche/Genentech, grants and personal fees from Janssen, personal fees from Agenus, personal fees from Regeneron, personal fees from OncoQuest, outside the submitted work., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite the modern advances in treatment techniques, the survival of locally advanced lung cancer patients continues to remain poor. Circulating lymphocytes have an important role to play in local immune response to RT as well as immune checkpoint inhibitors, and radiation related lymphopenia has been associated with inferior survival in various tumors., Methods: We undertook this systematic review and meta-analysis to evaluate the literature on risk and impact of lymphopenia in thoracic tumors. A systematic methodology search of the PubMed, Embase and Cochrane library was performed and eligible studies selected based on pre-defined inclusion and exclusion criteria. Review Manager Version 5.4.1 was used for the meta-analysis., Results: Fourteen studies were included in the final systematic review and 10 in the quantitative analysis. Overall mean incidence of severe lymphopenia (absolute lymphocyte count < 500) was 64.24%. The patients with severe lymphopenia were at increased risk of death with a pooled HR of 1.59 (95% CI: 1.40, 1.81, I 2  = 17%, P < 0.001) and progression with a pooled HR of 2.1 (95% CI: 1.57, 2.81, I 2  = 59%, P < 0.001) compared to patients with no severe lymphopenia. Dosimetric parameters including gross tumor volume, lung V5 and heart V5 were predictive of lymphopenia, while advanced age, lower baseline lymphocyte counts, higher stage and large tumor size were other risk factors. Models predicting estimated radiation dose to lymphocytes were a good surrogate for treatment outcomes., Conclusion: Radiation related lymphopenia is associated with increased hazard of progression and death in lung cancer. Minimizing the lung and heart dose, especially in patients with concurrent other risk factors can reduce lymphopenia and potentially improve treatment outcomes in these patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction Recent data suggest synergy of chemoradiotherapy and metformin in locally-advanced non-small cell lung cancer (NSCLC). It remains unclear if similar synergy exists with stereotactic lung body radiation therapy (SBRT) and metformin. We analyzed the role of metformin on progression-free survival (PFS) and toxicity in the setting of lung SBRT. Methods We identified 31 patients on metformin-treated with SBRT for early-stage NSCLC. Eighty-nine similarly treated patients were chosen as controls. Kaplan-Meier method was used to estimate cumulative PFS probabilities. Results Median follow-up was 30.7 months. Forty-two patients had diabetes, 31 (74%) of which were taking metformin concurrent with SBRT. Median PFS for metformin-users vs. metformin non-users was 36.4 months vs 48.9 months, respectively (p = 0.29). Among diabetic patients, median PFS for metformin users was 36.4 months and was unobserved for non-users (p= 0.40). On univariable analysis, male sex (p = 0.03) and tumor size (p = 0.01) were associated with the risk of progression or death; use of metformin was not significant (p = 0.34). There was no difference in grade ≥2 radiation pneumonitis between metformin users vs non-users (p = 0.51) Conclusion In this retrospective sample of lung SBRT patients, we did not detect a meaningful effect of concurrent metformin use on PFS. Since SBRT and conventional RT may have different cell kill mechanisms, the previously described beneficial effects of metformin may not apply in a hypofractionated setting. These results should be validated in an independent dataset, and we await the results of ongoing clinical trials., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Stang et al.)

Objective Radiation pneumonitis (RP) is a dose-limiting toxicity that affects the treatment of lung cancer. Data on factors predictive of developing symptomatic RP after stereotactic body radiation therapy (SBRT) are limited. We reviewed data to identify pretreatment factors predictive of the development of symptomatic RP in patients' lung cancer treated with SBRT. Methods Data were collected on 296 patients treated with SBRT for lung cancer. Factors available at time of consultation were analyzed for the development of symptomatic RP, defined as CTCAE v. 4.0 ≥ Grade 2. The factors analyzed included patient demographic, tumor-specific, and pretreatment pulmonary function data. Univariate and multivariate analyses were performed to assess for predictive factors. Results Median follow-up was 22 months. The rate of symptomatic RP was 16%. Univariate analysis showed an increased rate of symptomatic RP with treatments to the right lung (22% vs. 9%, p = 0.007), driven primarily by an increased rate of symptomatic RP when treating the right lower lobe (RLL) vs. other lobes (31 vs. 13%, p = 0.03). Patients with a history of prior lung directed therapy were also more likely to develop symptomatic RP (12% vs. 24%, p = 0.008). These statistical differences were retained on multivariate analysis. Conclusion SBRT to the right lung, especially the RLL, and to patients with a history of prior lung-directed therapy increases the risk of developing symptomatic RP after SBRT. Further studies on ways to predict and prevent symptomatic RP are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Harris et al.)

Background: Randomized trials describe differing sets of high-intermediate risk criteria., Objective: To use the National Cancer Database to compare the impact of radiation therapy in patients with stage I endometrial cancer meeting different criteria, and define a classification of "unfavorable risk.", Methods: Patients with stage I endometrial cancer between January 2010 and December 2014 were identified in the National Cancer Database and stratified into two cohorts: (1) patients meeting Gynecologic Oncology Group (GOG)-99 criteria only for high-intermediate risk, but not Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 criteria and (2) those meeting PORTEC-1 criteria only. High-risk stage I patients with both FIGO stage IB (under FIGO 2009 staging) and grade 3 disease were excluded. In each cohort, propensity score-matched survival analyses were performed. Based on these analyses, we propose a new classification of unfavorable risk. We then analyzed the association of adjuvant radiation with survival, stratified by this classification., Results: We identified 117,272 patients with stage I endometrial cancer. Of these, 11,207 patients met GOG-99 criteria only and 5,920 patients met PORTEC-1 criteria only. After propensity score matching, adjuvant radiation therapy improved survival (HR=0.73; 95% CI 0.60 to 0.89; p=0.002) in the GOG-99 only cohort. However, there was no benefit of adjuvant radiation (HR=0.89; 95% CI 0.69 to 1.14; p=0.355) in the PORTEC-1 only cohort. We, therefore, defined unfavorable risk stage I endometrial cancer as two or more of the following risk factors: lymphovascular invasion, age ≥70, grade 2-3 disease, and FIGO stage IB. Adjuvant radiation improved survival in stage I patients with adverse risk factors (HR=0.74; 95% CI 0.68 to 0.80; p<0.001), but not in other stage I patients (HR=1.02; 95% CI 0.91 to 1.15; p=0.710; p interaction <0.001)., Conclusion: Our study showed that adjuvant radiation was associated with an overall survival benefit in patients meeting GOG-99 criteria only; however, no survival benefit was seen in patients meeting PORTEC-1 criteria only. We propose a definition of unfavorable risk stage I endometrial cancer: ≥2 risk factors from among lymphovascular invasion, age ≥70, grade 2-3 disease, and FIGO stage IB disease., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: While Ir-192 remains the mainstay isotope for gynecologic high-dose-rate (HDR) brachytherapy in the U.S., Co-60 is used abroad. Co-60 has a longer half-life than Ir-192, which may lead to long-term cost savings; however, its higher energy requires greater shielding. This study analyzes Co-60 acceptability based on a one-time expense of additional shielding and reports the financial experience of Co-60 in Peru's National Cancer Institute, which uses both isotopes., Material and Methods: A nationwide survey was undertaken assessing physician knowledge of Co-60 and willingness-to-pay (WTP) for additional shielding, assuming a source more cost-effective than Ir-192 was available. With 440 respondents, 280 clinicians were decision-makers and provided WTPs, with results previously reported. After completing a shielding report, we estimated costs for shielding expansion, noting acceptability to decision makers' WTP. Using activity-based costing, we note the Peruvian fiscal experience., Results: Shielding estimates ranged from $173,000 to $418,000. The percentage of respondents accepting high-density modular or lead shielding (for union and non-union settings) were 17.5%, 11.4%, 3.9%, and 3.2%, respectively. Shielding acceptance was associated with greater number of radiation oncologists in a respondent's department but not time in practice or the American Brachytherapy Society membership. Peru's experience noted cost savings with Co-60 of $52,400 annually., Conclusions: By comparing the cost of additional shielding for a sample institution's HDR suite with radiation oncologists' WTP, this multi-institutional collaboration noted < 20% of clinicians would accept additional shielding. Despite low acceptability in the US, Co-60 demonstrates cost-favorability in Peru and may similarly in other locations., Competing Interests: Authors report no conflict of interest. Appendices are published as supplementary data in electronic form on the webpage www.jocb.eu.

Purpose: The purpose of this study was to develop a radiation therapy (RT) contouring atlas and recommendations for women with postoperative and locally advanced vulvar carcinoma., Methods and Materials: An international committee of 35 expert gynecologic radiation oncologists completed a survey of the treatment of vulvar carcinoma. An initial set of recommendations for contouring was discussed and generated by consensus. Two cases, 1 locally advanced and 1 postoperative, were contoured by 14 physicians. Contours were compared and analyzed using an expectation-maximization algorithm for simultaneous truth and performance level estimation (STAPLE), and a 95% confidence interval contour was developed. The level of agreement among contours was assessed using a kappa statistic. STAPLE contours underwent full committee editing to generate the final atlas consensus contours., Results: Analysis of the 14 contours showed substantial agreement, with kappa statistics of 0.69 and 0.64 for cases 1 and 2, respectively. There was high specificity for both cases (≥99%) and only moderate sensitivity of 71.3% and 64.9% for cases 1 and 2, respectively. Expert review and discussion generated consensus recommendations for contouring target volumes and treatment for postoperative and locally advanced vulvar cancer., Conclusions: These consensus recommendations for contouring and treatment of vulvar cancer identified areas of complexity and controversy. Given the lack of clinical research evidence in vulvar cancer radiation therapy, the committee advocates a conservative and consistent approach using standardized recommendations., Competing Interests: All other authors report no conflicts of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to report on long-term effectiveness of involved field radiation therapy (IFRT) in the salvage of localized recurrent ovarian cancer (ROC)., Methods: A retrospective analysis of 27 patients with a diagnosis of epithelial ovarian cancer who received tumor volume-directed IFRT for localized extraperitoneal recurrences (either as consolidation after cytoreductive surgery (CRS) or as attempted salvage if unresectable) forms the basis of this report. All patients were heavily pretreated with multiple chemotherapy regimens. Involved field radiation therapy was primarily with external beam (median dose, 50.4 Gy). Local recurrence-free survival (LRFS) was defined as freedom from in-field recurrences and was considered as a measure of effectiveness of radiotherapy. Statistical analyses evaluated association between disease-free survival, overall survival, LRFS, and various prognostic factors. Comparison was also made with a similar but unmatched cohort with localized recurrences salvaged by additional chemotherapy instead of local therapies (NIFRT group)., Results: Of 27 patients, 17 had optimal CRS before RT. The actuarial survival at 5 and 10 years (in parenthesis) from date of radiation were LRFS (70% and 60%), overall survival (30% and 19%), and disease-free survival (33% and 20%). None of the NIFRT patients survived beyond 5 years from initiation of salvage chemotherapy., Conclusions: Long-term follow-up in this selected series confirmed the benefit of IFRT (±CRS) in localized ROC. Chemotherapy salvage in a similar NIFRT group was not equivalent, suggesting a role for locoregional therapies in selected patients with ROC.

Purpose: To evaluate dose-volume histograms (DVHs) and dose-surface histograms (DSHs) to analyze bladder distension during cervical brachytherapy., Methods: Twenty brachytherapy fractions from five cervical cancer patients were selected. For each fraction, empty and full (200cc of contrasted saline) bladder simulation CT scans existed, one of which was used to plan treatment. An alternative plan was then created with the unused scan. DVH for each fraction was generated for the bladder, rectum, sigmoid colon, and small bowel. Mean DVH dose, D0.1cc, and D2cc were calculated for each organ at risk. Plans were then exported to a MATLAB-based program to generate a DSH., Results: Full bladder plans showed no difference in bladder D2cc or D0.1cc compared with empty bladder plans; however, bladder mean DVH dose and DSH dose were both significantly reduced. Full bladder plans showed a significant reduction in small intestine D2cc from 2.81 Gy to 1.83 Gy and reduction in D0.1cc from 4.07 Gy to 2.57 Gy (p < 0.05); similarly, sigmoid D2cc was significantly reduced from 4.24 Gy to 3.87 Gy (p < 0.05) and D0.1cc was reduced from 6.12 Gy to 5.61 Gy (p < 0.05) in full bladder plans. Both small intestine and sigmoid also showed reduced mean DVH and DSH dose in full bladder plans. The rectum showed no significant difference in D2cc, D0.1cc, mean DVH, or DSH dose between plans., Conclusions: Bladder distension during cervical brachytherapy significantly reduced dose in all DVH and DSH parameters for sigmoid and small intestine with no change in bladder parameters. It reduces dose to organ at risk, but the correlation to toxicity requires further investigation., (Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Genetic variation can have important consequences for populations: high population genetic diversity is typically associated with ecological success. Some mechanisms that account for these benefits assume that local social groups with high genetic diversity are more successful than low-diversity groups. At the same time, active decision-making by individuals can influence group genetic diversity. Here, we examine how maternal decisions that determine group genetic diversity influence the viability of Drosophila melanogaster larvae. Our groups contained wild-type larvae, whose genetic diversity we manipulated, and genetically marked 'tester' larvae, whose genotype and frequency were identical in all trials. We measured wild-type and tester viability for each group. Surprisingly, the viability of wild-type larvae was neither augmented nor reduced when group genetic diversity was altered. However, the viability of the tester genotype was substantially depressed in large, high-diversity groups. Further, not all high-diversity groups produced this effect: certain combinations of wild-type genotypes were deleterious to tester viability, while other groups of the same diversity-but containing different wild-type genotypes-were not deleterious. These deleterious combinations of wild-type genotypes could not be predicted by observing the performance of the same tester and wild-type genotypes in low-diversity groups. Taken together, these results suggest that nonadditive interactions among genotypes, rather than genetic diversity per se, account for between-group differences in viability in D. melanogaster and that predicting the consequences of genetic diversity at the population level may not be straightforward., (© 2012 Blackwell Publishing Ltd.)

Purpose: To test the hypothesis that the robust expansion of bovine corneal endothelial cells (BCECs) in vitro is due to the presence of individual endothelial cells with various levels of proliferative potential., Methods: BCECs and bovine vascular endothelial cells (ECs) derived from aorta, coronary artery, and pulmonary artery were cultivated in optimized medium. These cell populations were confirmed by morphologic features, functional assays, and gene expression profiles. Moreover, ECs were plated in a single-cell clonogenic assay to evaluate colony-forming ability., Results: Both corneal and vascular ECs were confirmed to be pure populations of endothelium uncontaminated with hematopoietic cells. A complete hierarchy of endothelial colony-forming cells (ECFCs) was identified in BCECs by a single-cell clonogenic assay. The distribution of the various types of ECFCs was similar to the control ECs removed from the systemic vessels., Conclusions: Cultured BCECs display clonal proliferative properties similar to those of vascular ECs.

The standard of care for stage I non-small-cell lung carcinoma is generally accepted to be lobectomy. In patients who are deemed not to be candidates for lobectomy, various treatment strategies are available, including observation, sublobar resection, conventional fractionated radiotherapy, stereotactic body radiotherapy and radiofrequency ablation. However, there is no standardized, clearly established therapy to offer patients in this situation. While ongoing prospective trials will allow refinement of these techniques, the role of these treatment modalities warrants further investigation for this setting.

Brain metastasis occurs rarely in patients with testicular cancer in the modern era where cisplatin-based chemotherapy regimens are used. The occurrence of brain metastasis can be synchronous or metachronous (with or without concurrent systemic disease). Long-term survival can be achieved in some patients. The vast majority of testicular cancer cases with brain metastasis reported in the literature involve nonseminomatous germ cell tumor and this subtype will be the focus of this review. This article reviews the literature of the diagnosis and management of brain metastasis from nonseminomatous germ cell tumor of the testis.