Endometrioid Endometrial RNA Index Predicts Recurrence in Stage I Patients.

PURPOSE: Risk prediction with genomic and transcriptomic data has the potential to improve patient outcomes by enabling clinicians to identify patients requiring adjuvant treatment approaches, while sparing low-risk patients from unnecessary interventions. Endometrioid endometrial carcinoma (EEC) is the most common cancer in women in developed countries, and rates of endometrial cancer are increasing. EXPERIMENTAL DESIGN: We collected a 105-patient case-control cohort of stage I EEC comprised of 45 patients who experienced recurrence less than 6 years after excision, and 60 FIGO grade matched controls without recurrence. We first utilized two RNA based, previously validated machine learning approaches, namely EcoTyper and Complexity Index in Sarcoma (CINSARC). We developed Endometrioid Endometrial RNA Index (EERI) which uses RNA expression data from 46 genes to generate a personalized risk score for each patient. EERI was trained on our 105-patient cohort and tested on a publicly available cohort of 263 stage I EEC patients. RESULTS: EERI was able to predict recurrences with 94% accuracy in the training set and 81% accuracy in the test set. In the test set, patients assigned as EERI high-risk were significantly more likely to experience recurrence (30%) than the EERI low-risk group (1%) with a hazard ratio of 9.9 (95% CI 4.1-23.8, P <0.001). CONCLUSIONS: Tumors with high-risk genetic features may require additional treatment or closer monitoring and are not readily identified using traditional clinicopathologic and molecular features. EERI performs with high sensitivity and modest specificity, which may benefit from further optimization and validation in larger independent cohorts.

Less than whole uterus irradiation for patients with locally advanced cervical cancer.

INTRODUCTION: Current consensus guidelines for definitive cervical cancer intensity modulated radiation therapy (IMRT) recommend inclusion of the entire uterus within the clinical target volume, however this is debated. We aimed to evaluate outcomes of patients with cervical cancer who were treated with less than whole uterus irradiation. METHODS: We identified 109 patients with FIGO Stage IB-IVA cervical cancer treated definitively with concurrent chemoradiation, including IMRT and brachytherapy, from 2010 to 2022 at a single institution where the practice was to include the gross cervix tumor with an internal target volume with differences in bladder filing accounted for, plus additional 5 mm planning target volume (PTV) margin. Local, regional, and distant recurrences were analyzed using competing risk methods, and a Wilcoxon rank sum test was performed to assess differences in dose to organs at risk based on the proportion of the uterus included in the PTV, with the median proportion of the uterus included (75 %) used as the cut-point. RESULTS: The median follow-up time was 65 months (range 3-352 months). The 2-year cumulative incidence of LR for the entire cohort was 4.2 % (95 % confidence interval [CI] 1.3-9.7). Compared with patients who had ≥ 75 % of the uterus included in the PTV, patients who had < 75 % of the uterus included in the PTV had significantly lower bowel D200cc (p = 0.02). The cumulative incidence of local failure (LR) was not significantly different between the two groups. CONCLUSIONS: Including less than the whole uterus for definitive cervix cancer IMRT does not seem to compromise local control. Less than whole uterus irradiation could be considered for carefully selected cervix cancer patients to decrease bowel dose and possible treatment-related toxicity.

Design approach and benefits of the 3D-printed vaginal individualized applicator (VIA).

PURPOSE: Interstitial gynecologic brachytherapy necessitates precise needle placement, requiring time and expertise. We aimed to simplify interstitial procedures and facilitate optimal needle distribution with individualized vaginal templates to guide interstitial needles. MATERIALS/METHODS: We developed the 3D-printed vaginal individualized applicator (VIA), a cylindrical template containing individualized internal channels that guide interstitial needles to cover the tumor extent. Eight patients underwent VIA only interstitial implants (VIA only), and five intact cervical cases were treated using tandem and customized VIA (VIA + T). Procedure length, number of needles utilized and dosimetric measures were evaluated. RESULTS: VIA was successfully designed and used clinically for 24 procedures (8 VIA only, 16 VIA + T). Average procedure needle insertion time reduced from 80.9 min for traditional interstitial to 42.9 min for VIA only, approximately 47% shorter with a similar mean high risk CTV volume (28.3 cc VIA only vs. 32.4 cc) and excellent dosimetry with average CTV V100% (94.3% and 94.4%). VIA + T was particularly useful in patients with small vaginal canals and large tumor size. For the five VIA + T patients average tumor size was 68.0cc (range 26.6-143.5 cc). VIA + T procedures were approximately 20% shorter than hybrid procedures with other applicators with mean length of 20.1 min and an average of 6.8 needles (range 3-12). CONCLUSION: Our novel 3D-printed VIA facilitates gynecologic interstitial brachytherapy by simplifying needle placement, reducing procedure time, and maintaining excellent dosimetry. VIA can be customized for various clinical scenarios, particularly beneficial for large tumors or small vaginal canals.

Prognostic Effect of Mismatch Repair Status in Early-Stage Endometrial Cancer Treated With Adjuvant Radiation: A Multi-institutional Analysis.

PURPOSE: The aim of this work was to report the effect of mismatch repair (MMR) status on outcomes of patients with stage I-II endometrioid endometrial adenocarcinoma (EEC) who receive adjuvant radiation therapy. METHODS AND MATERIALS: This is a multi-institutional retrospective cohort study across 11 institutions in North America. Patients with known MMR status and stage I-II EEC status postsurgical staging were included. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated via the Kaplan-Meier method. Univariable and multivariable analyses were performed via Cox proportional hazard models for RFS and OS. Statistical analyses were conducted using SPSS version 27. RESULTS: In total, 744 patients with a median age at diagnosis of 65 years (IQR, 58-71) were included. Most patients were White (69.4%) and had Federation of Obstetrics and Gynecology 2009 stage I (84%) and Federation of Obstetrics and Gynecology grade 1 to 2 (73%). MMR deficiency was reported in 234 patients (31.5%), whereas 510 patients (68.5%) had preserved MMR. External beam radiation therapy with or without vaginal brachytherapy was delivered to 186 patients (25%), whereas 558 patients (75%) received vaginal brachytherapy alone. At a median follow-up of 43.5 months, the estimated crude OS and RFS rates for the entire cohort were 92.5% and 84%, respectively. MMR status was significantly correlated with RFS. RFS was inferior for MMR deficiency compared with preserved MMR (74.3% vs 88.6%, P < .001). However, no difference in OS was seen (90.8% vs 93.2%, P = .5). On multivariable analysis, MMR deficiency status was associated with worse RFS (hazard ratio, 1.86; P = .001) but not OS. CONCLUSIONS: MMR status was independently associated with RFS but not OS in patients with early-stage EEC who were treated with adjuvant radiation therapy. These findings suggest that differential approaches to surveillance and/or treatment based on MMR status could be warranted.

Development and clinical implementation of simple needle attachment post placement interstitial template (SNAPP-IT) enabling a shorter, more direct needle path while preserving tumor visualization.

PURPOSE: Historical gynecologic interstitial brachytherapy templates block direct tumor visualization during needle placement, presenting an opportunity for clinical innovation to develop a novel interstitial template allowing direct tumor visualization during needle insertion. METHODS AND MATERIALS: We designed and implemented a novel interstitial template, simple needle attachment post placement interstitial template (SNAPP-IT), that allowed direct visualization of the target vaginal tumor during interstitial needle placement while maintaining the ability to individually secure needles to the template, allow a vaginal cylinder, suture holes for securing to the perineum, MRI compatibility and sterilizable for repeat use. Procedure outcomes including procedure time, needle path lengths, and plan dosimetry were prospectively captured in a patient database. RESULTS: Forty gynecologic interstitial brachytherapy cases were recorded (20 SNAPP-IT, 20 traditional templates). Needle insertion depth was reduced using the SNAPP-IT in comparison with traditional interstitial templates (11.8 cm vs. 3.6 cm, p < 0.0001). The average CTV volume was 25.6 cc for SNAPP-IT and 20.7 cc for traditional; both methods averaged a similar number of needles (15.8, 15.6). Dosimetric constraints were similarly met in both treatment groups. Procedures performed using the SNAPP-IT were shorter compared with those performed with traditional interstitial devices (83.4 minutes vs. 100.7 minutes) and there were no post-operative infections in the SNAPP-IT group. CONCLUSIONS: Implementation of a novel gynecologic interstitial brachytherapy template (SNAPP-IT) reduced procedure times, allowed direct tumor visualization, and decreased needle insertion depth. SNAPP-IT provides a useful alternative approach for vaginal interstitial brachytherapy, may increase brachytherapist efficiency with complex procedures and potentially expands access to interstitial brachytherapy.

Does lymph node assessment change the prognostic significance of substantial LVSI and p53 status in endometrial endometrioid carcinoma?

OBJECTIVE: The PORTEC-2 update suggested that substantial lymphovascular space invasion (LVSI) and abnormal p53 expression (p53abnl) predict for poorer outcomes and that these patients should be treated with external beam radiation therapy (EBRT). We aim to determine if patients with these risk factors who undergo a lymph node (LN) assessment show similar outcomes. METHODS: We retrospectively reviewed 126 patients with FIGO 2009 stage IA grade 3, stage IB grade 1-2, and stage IIIC (positive LN but no other stage II/III risk factors) endometrioid endometrial cancer who underwent LN assessment. Local (LR), regional recurrences (RR), and distant metastases were analyzed using competing risk methods, and overall survival (OS) was analyzed using Kaplan-Meier. RESULTS: Median follow-up time was 37.2 months. OS was significantly different between patients with and without p53abnl expression (16.7% versus 3.1% deceased), and between patients with and without LVSI (11.1% versus 1.5% deceased; p < 0.01 for both). The 2-year cumulative incidence of LR for patients with p53abnl versus wild type p53 and LVSI versus no LVSI was 11.1% (95% CI 0-25.6) versus 2.2% (95% CI 0-5.25; p = 0.04), and 11.4% (95% CI 2.0-20.9) versus 0%, respectively (p < 0.01). The 2-year cumulative RR in patients with LVSI versus no LVSI was 6.9% (95% CI 0-14.4) versus 0% (p = 0.05). No patients who completed pelvic RT experienced an in-field recurrence. CONCLUSIONS: Despite LN assessment, patients with high-intermediate risk early-stage or stage IIIC (with positive lymph nodes only but no other stage II or III risk factors) endometrial cancer with p53abnl expression and/or LVSI have worse outcomes. These patients may derive benefit from intensification with EBRT to improve local and pelvic control.

Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial.

Importance: Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy. Objective: To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control. Design, Setting, and Participants: This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3). Intervention: Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3. Main outcome: Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up. Results: In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects). Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials. Trial Registration: ClinicalTrials.gov Identifier: NCT01463423.

Adjuvant radiation therapy in early-stage endometrial cancer with abnormal beta-catenin expression is associated with improved local control.

OBJECTIVES: Emerging data suggests that abnormal (nuclear) ß-catenin expression in some settings is associated with poorer outcomes. Our study aimed to verify the significance of abnormal ß-catenin expression in early-stage endometrial cancer patients and determine if adjuvant radiation therapy (RT) improves local control. METHODS: We identified 213 patients with FIGO 2018 stage I-II endometrioid endometrial cancer who underwent surgery from 2009 to 2021 with ß-catenin expression assessed. Vaginal, regional, and distant recurrences were analyzed using competing risk methods, and overall survival was analyzed using Kaplan-Meier. RESULTS: Median follow up was 53.2 months; 6.9% experienced vaginal, 8.2% regional, and 7.4% distant recurrence. For the entire cohort, abnormal ß-catenin expression was significantly associated with vaginal recurrence and remained significant on multivariate analysis (p = 0.03). There were 114 patients in the no specific molecular profile (NSMP) subgroup, and abnormal ß-catenin expression was present in 46.5%. In the NSMP subgroup, abnormal ß-catenin expression was associated with increased rates of vaginal recurrence (p = 0.06). Abnormal ß-catenin expression in the NSMP subgroup was significant on multivariate analysis for vaginal recurrence (p = 0.04). RT significantly decreased vaginal recurrences in the entire cohort in patients with abnormal ß-catenin expression (0%) versus wild type expression (17.5%; p = 0.03). In the NSMP subgroup 0% of patients who received RT versus 20.9% of patients who did not receive RT experienced a vaginal recurrence (p = 0.03). CONCLUSION: Use of adjuvant RT for stage I-II NSMP endometrial cancer with abnormal ß-catenin expression improved local control. RT should be considered in these patients to decrease risk of vaginal recurrences.

Racial Disparities in Brachytherapy Treatment among Women with Cervical and Endometrial Cancer in the United States.

Brachytherapy improves clinical outcomes among women diagnosed with cervical and endometrial cancers. Recent evidence demonstrates that declining brachytherapy boosts for women with cervical cancer were associated with higher mortality. In this retrospective cohort study, women diagnosed with endometrial or cervical cancer in the United States between 2004 and 2017 were selected from the National Cancer Database for evaluation. Women ≥18 years of age were included for high intermediate risk (PORTEC-2 and GOG-99 definition) or FIGO Stage II-IVA endometrial cancers and FIGO Stage IA-IVA-non-surgically treated cervical cancers. The aims were to (1) evaluate brachytherapy treatment practice patterns for cervical and endometrial cancers in the United States; (2) calculate rates of brachytherapy treatment by race; and (3) determine factors associated with not receiving brachytherapy. Treatment practice patterns were evaluated over time and by race. Multivariable logistic regression assessed predictors of brachytherapy. The data show increasing rates of brachytherapy for endometrial cancers. Compared to non-Hispanic White women; Native Hawaiian and other Pacific Islander (NHPI) women with endometrial cancer and Black women with cervical cancer were significantly less likely to receive brachytherapy. For both NHPI and Black women, treatment at community cancer centers was associated with a decreased likelihood of brachytherapy. The data suggest racial disparities among Black women with cervical cancer and NHPI women with endometrial cancer and emphasize an unmet need for brachytherapy access within community hospitals.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol.

PURPOSE: The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. METHODS AND MATERIALS: SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy × 2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy × 3 fx to 5 mm, 5 to 5.5 Gy × 4 fx to 5 mm, and 6 Gy × 5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD23). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. RESULTS: The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy × 3 and 5 to 5.5 Gy × 4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy × 5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD23 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy × 3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. CONCLUSIONS: Experimental short-course VCB of 11 Gy × 2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD23 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects.

Developing Next-Generation 3-Dimensional Printing for Cervical Cancer Hybrid Brachytherapy: A Guided Interstitial Technique Enabling Improved Flexibility, Dosimetry, and Efficiency.

PURPOSE: We developed a 3-dimensionally (3D) printed tandem anchored radially guiding interstitial template (TARGIT) to increase the simplicity of intracavitary/interstitial technique for tandem-and-ovoid (T&O) procedures in cervical cancer brachytherapy. This study compared dosimetry and procedure logistics between T&O implants using the original TARGIT versus the next-generation TARGIT-Flexible-eXtended (TARGIT-FX) 3D-printed template designed for practice-changing ease-of-use with further simplified needle insertion and increased flexibility in needle placement. METHODS AND MATERIALS: This single-institution retrospective cohort study included patients undergoing T&O brachytherapy as part of definitive cervical cancer treatment. Procedures used the original TARGIT from November 2019 through February 2022 and the TARGIT-FX from March 2022 through November 2022. The FX design features full extension to the vaginal introitus with 9 needle channels and allows for needle additions or depth adjustments intraprocedure and after computed tomography/magnetic resonance imaging. RESULTS: A total of 148 implants were performed, 68 (46%) with TARGIT and 80 (54%) with TARGIT-FX, across 41 patients. Across implants, the TARGIT-FX achieved higher mean V100% (+2.8%, P = .0019), and across patients, the TARGIT-FX achieved higher D90 (+2.0 Gy, P = .037) and higher D98 (+2.7 Gy, P = .016) compared with the original TARGIT. Doses to organs at risk were overall similar between templates. Procedure times for TARGIT-FX implants were 30% shorter on average than for those using the original TARGIT (P < .0001), and 28% shorter on average for the subset of implants with high-risk clinical target volume ≥30 cc (P = .013). All residents (100%, N = 6) surveyed regarding the TARGIT-FX indicated ease-of-use for needle insertion and interest in applying the technique in future practice. CONCLUSIONS: The TARGIT-FX achieved shorter procedure times with increased tumor coverage and similar normal tissue sparing compared with the previously applied TARGIT and illustrates the potential of 3D printing to enhance efficiency and shorten the learning curve for intracavitary/interstitial procedure technique in cervical cancer brachytherapy.

Cost-effectiveness of cognitive behavioural and personalized exercise interventions for reducing fatigue in inflammatory rheumatic diseases.

OBJECTIVES: To estimate the cost-effectiveness of a cognitive behavioural approach (CBA) or a personalized exercise programme (PEP), alongside usual care (UC), in patients with inflammatory rheumatic diseases who report chronic, moderate to severe fatigue. METHODS: A within-trial cost-utility analysis was conducted using individual patient data collected within a multicentre, three-arm randomized controlled trial over a 56-week period. The primary economic analysis was conducted from the UK National Health Service (NHS) perspective. Uncertainty was explored using cost-effectiveness acceptability curves and sensitivity analysis. RESULTS: Complete-case analysis showed that, compared with UC, both PEP and CBA were more expensive [adjusted mean cost difference: PEP £569 (95% CI: £464, £665); CBA £845 (95% CI: £717, £993)] and, in the case of PEP, significantly more effective [adjusted mean quality-adjusted life year (QALY) difference: PEP 0.043 (95% CI: 0.019, 0.068); CBA 0.001 (95% CI: -0.022, 0.022)]. These led to an incremental cost-effectiveness ratio (ICER) of £13 159 for PEP vs UC, and £793 777 for CBA vs UC. Non-parametric bootstrapping showed that, at a threshold value of £20 000 per QALY gained, PEP had a probability of 88% of being cost-effective. In multiple imputation analysis, PEP was associated with significant incremental costs of £428 (95% CI: £324, £511) and a non-significant QALY gain of 0.016 (95% CI: -0.003, 0.035), leading to an ICER of £26 822 vs UC. The estimates from sensitivity analyses were consistent with these results. CONCLUSION: The addition of a PEP alongside UC is likely to provide a cost-effective use of health care resources.

The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma: A Pooled Data Analysis.

OBJECTIVE: To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma. MATERIALS AND METHODS: A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27. RESULTS: The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively ( P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 ( P value=0.045) for OS and 1.487 ( P value=0.116) for RFS. After PSM, black patients were more likely to receive the "Sandwich" approach and concurrent chemoradiotherapy compared with non-black ( P =0.013) patients. CONCLUSIONS: Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the "Sandwich" approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities.

Executive summary of the American Radium Society appropriate use criteria for management of uterine clear cell and serous carcinomas.

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.

Remotely delivered cognitive behavioural and personalised exercise interventions for fatigue severity and impact in inflammatory rheumatic diseases (LIFT): a multicentre, randomised, controlled, open-label, parallel-group trial.

Background: Chronic fatigue is a poorly managed problem in people with inflammatory rheumatic diseases. Cognitive behavioural approaches (CBA) and personalised exercise programmes (PEP) can be effective, but they are not often implemented because their effectivenesses across the different inflammatory rheumatic diseases are unknown and regular face-to-face sessions are often undesirable, especially during a pandemic. We hypothesised that remotely delivered CBA and PEP would effectively alleviate fatigue severity and life impact across inflammatory rheumatic diseases. Methods: LIFT is a multicentre, randomised, controlled, open-label, parallel-group trial to assess usual care alongside telephone-delivered CBA or PEP against usual care alone in UK hospitals. Patients with any stable inflammatory rheumatic disease were eligible if they reported clinically significant, persistent fatigue. Treatment allocation was assigned by a web-based randomisation system. CBA and PEP sessions were delivered over 6 months by trained health professionals in rheumatology. Coprimary outcomes were fatigue severity (Chalder Fatigue Scale) and impact (Fatigue Severity Scale) at 56 weeks. The primary analysis was by full analysis set. This study was registered at ClinicalTrials.gov (NCT03248518). Findings: From Sept 4, 2017, to Sept 30, 2019, we randomly assigned and treated 367 participants to PEP (n=124; one participant withdrew after being randomly assinged), CBA (n=121), or usual care alone (n=122), of whom 274 (75%) were women and 92 (25%) were men with an overall mean age of 57·5 (SD 12·7) years. Analyses for Chalder Fatigue Scale included 101 participants in the PEP group, 107 in the CBA group, and 107 in the usual care group and for Fatigue Severity Scale included 101 in PEP, 106 in CBA, and 107 in usual care groups. PEP and CBA significantly improved fatigue severity (Chalder Fatigue Scale; PEP: adjusted mean difference -3·03 [97·5% CI -5·05 to -1·02], p=0·0007; CBA: -2·36 [-4·28 to -0·44], p=0·0058) and fatigue impact (Fatigue Severity Scale; PEP: -0·64 [-0·95 to -0·33], p<0·0001; CBA: -0·58 [-0·87 to -0·28], p<0·0001); compared with usual care alone at 56 weeks. No trial-related serious adverse events were reported. Interpretation: Telephone-delivered CBA and PEP produced and maintained statistically and clinically significant reductions in the severity and impact of fatigue in a variety of inflammatory rheumatic diseases. These interventions should be considered as a key component of inflammatory rheumatic disease management in routine clinical practice. Funding: Versus Arthritis.

Applying 3D-Printed Templates in High-Dose-Rate Brachytherapy for Cervix Cancer: Simplified Needle Insertion for Optimized Dosimetry.

PURPOSE: In cervical cancer brachytherapy, adding interstitial needles to intracavitary applicators can enhance dosimetry by improving target coverage while limiting normal tissue dose. However, its use is limited to a subset of practitioners with appropriate technical skill. We designed tandem anchored radially guiding interstitial templates (TARGITs) with a 3-dimensional (3D) printing workflow to optimize needle placement and facilitate greater ease-of-use of intracavitary/interstitial (IC/IS) technique. This study compared dosimetry and procedure characteristics between tandem and ovoid (T&O) implants using TARGIT technique versus non-TARGIT technique. METHODS AND MATERIALS: This single-institution retrospective cohort study included patients undergoing T&O brachytherapy as part of definitive radiation treatment for cervical cancer between February 2017 and January 2021. TARGIT technique was implemented from November 2019 onwards; all prior procedures involved non-TARGIT technique using a no needle or freehand needle approach. Target coverage, dose to organs at risk, and procedure times were evaluated and compared between TARGIT technique and non-TARGIT technique. RESULTS: The cohort included 70 patients with cervical cancer who underwent 302 T&O procedures: 68 (23%) with TARGIT technique and 234 (77%) with non-TARGIT technique, which included 133 no needle and 101 freehand needle implants. TARGIT implants involved longer average procedure times (+6.3 minutes, P < .0001). TARGIT implants achieved a higher mean high-risk clinical target volume V100% than non-TARGIT implants (+4.4%, P = .001), including for large tumors 30 cm3 or greater (+8.1%, P = .002). Average D90 was 4.6 Gy higher and average D98 was 3.2 Gy higher for TARGIT technique compared with non-TARGIT technique (P = .006 and P = .02). Total treatment doses to rectum, bowel, and bladder were not significantly different for TARGIT versus non-TARGIT technique. CONCLUSIONS: The 3D-printed TARGIT approach to T&O brachytherapy achieved greater tumor coverage while sparing normal tissues, particularly for large tumor volumes, with only a slight increase in average procedure time. TARGIT represents a creative technological solution for increasing accessibility of advanced IC/IS brachytherapy technique for cervical cancer definitive radiation treatment.

Imaging to optimize gynecological radiation oncology.

Gynecological cancers have particularly benefited from the increasing use of imaging to guide radiation treatment planning for both external beam radiation and brachytherapy. While the different gynecological cancers have varying use of imaging, certain trends predominate. CT represents an economical choice for evaluating initial disease extent or potential metastasis at follow-up, particularly for endometrial and ovarian cancers. F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is particularly useful for assessing the initial disease extent and longer term treatment response of squamous predominant cancers, including cervical, vaginal, and vulvar cancers. With its excellent pelvic soft tissue discrimination, MRI provides the greatest assistance in evaluating the local extent of gynecological tumors, including initial evaluation for non-operative endometrial and vulvar cancer, and assessment before, after and during brachytherapy for cervix, locally recurrent endometrial, and primary vaginal cancers. With more limited availability of MRI, ultrasound can also help guide brachytherapy, particularly during procedures. The benefits of using imaging to better spare bone marrow or earlier assessment of treatment response are topics still being explored, in particular for cervical cancer. As imaging along with radiation oncology technologies continue to evolve and develop, such as with MRI-linacs and ultra high dose rate (FLASH) radiation, we may continue to see increasing use of imaging for advancing gynecological radiation oncology.

Evaluating dosimetric parameters predictive of hematologic toxicity in cervical cancer patients undergoing definitive pelvic chemoradiotherapy.

PURPOSE: We performed a retrospective study of cervical cancer pelvic radiotherapy plans to explore dosimetric parameters predictive of hematologic toxicity (HT), with specific interest in evaluating metabolic parameters and identifying the best predictive model. METHODS: Active marrow was retroactively contoured as pelvic bone with SUV > mean on 18F-FDG-PET. "Highly active" marrow was contoured as the hottest 10-14% volume of active marrow. Pelvic bone contour was segmented into lumbosacral, iliac crest, and lower pelvis. Predictors of HT were evaluated using logistic regression and repeated measures modeling. RESULTS: One hundred women were evaluated from 2009 to 2020. The plurality/majority had stage IIIC1 disease (38%) and underwent IMRT (88%) with pelvic field alone (72%). The majority received weekly cisplatin (78%), and 82% completed at least five cycles. The most common HT was leukopenia (grade 2+: 68%). Predictors of grade 2+ and 3+ HT were baseline WBC (p < 0.001), and 10- and 20-Gy dosimetric parameters to the active marrow, highly active marrow, and pelvic bone. The best predictive model of leukocyte trajectory included baseline WBC (p < 0.001), highly active marrow V20 (p < 0.001), and interactions of baseline WBC with time (p < 0.001) and highly active marrow V20 (p < 0.001), such that those with low baseline WBC experienced the greatest impact of highly active marrow V20. CONCLUSION: Baseline WBC was highly predictive of HT; dosimetric predictors included dose to the active marrow, highly active marrow, and pelvic bone, with the greatest impact from V20 to the highly active marrow, particularly in women with low baseline WBC. Future studies should consider incorporating baseline WBC and limiting dose to the most highly active marrow.