Developing an educational "hub": impact of a distance-learning curriculum in a multinational cohort.

PURPOSE: To address a gap in radiation oncology education in low- and middle-income countries (LMICs), we sought to evaluate the effectiveness and generalizability of a refined curriculum on intensity modulated radiotherapy (IMRT) offered to existing radiation therapy (RT) clinics across Africa and Latin America (LATAM) at no cost. METHODS: A curriculum was created based on prior needs assessments and adapted for participating medical physicists, radiation oncologists, radiation therapists, and trainees in LMICs. English-speaking and Spanish-speaking teams of volunteer educators delivered 27 hour-long sessions 1-2 times weekly for 4 months using video conferencing to African and LATAM cohorts, respectively. Pre- and post-course multiple-choice examinations were administered to LATAM participants, and pre- and post-course self-confidence (1-5 Likert-scale) and open-ended feedback were collected from all participants. RESULTS: Twenty-five centers across Africa (13) and LATAM (12) participated, yielding a total of 332 enrolled participants (128 African, 204 LATAM). Sessions were delivered with a mean of 44 (22.5) and 85 (25.4) participants in the African and LATAM programs, respectively. Paired pre and post-course data demonstrated significant (p < 0.001) improvement in knowledge from 47.9 to 89.6% and self-confidence across four domains including foundations (+ 1.1), commissioning (+ 1.3), contouring (+ 1.7), and treatment planning (+ 1.0). Attendance was a significant predictor of change in self-confidence in "high attendance" participants only, suggesting a threshold effect. Qualitative data demonstrates that participants look forward to applying their knowledge in the clinical setting. CONCLUSION: A specialized radiation oncology curriculum adapted for LMIC audiences was effective for both African and LATAM participants. Participant feedback suggests that the refined IMRT course empowered clinics with knowledge and confidence to help train others. This feasible "Hub and Spokes" approach in which a distance-learning course establishes a hub to be leveraged by spokes (learners) may be generalizable to others aiming to reduce global health care disparities through training efforts.

Development of a Musculoskeletal Ultrasound Protocol to Evaluate Hand Pain in Systemic Sclerosis Patients.

Hand impairment is a frequently reported complaint in systemic sclerosis (SSc) patients and a leading cause of disability and diminished quality of life. Managing hand pain can be particularly challenging due to the coexistence of non-inflammatory arthralgias, inflammatory arthritis, acro-osteolysis, tenosynovitis, joint contractures, tendon friction rubs, nerve entrapment, Raynaud's phenomenon (RP), digital ulcers (DU), sclerodactyly, calcinosis, and chronic pain. While physical examination and radiographs are the first line methods for evaluating hand pain, they are limited in scope and miss many underlying etiologies of hand impairment. We propose a joint ultrasound (US) hand protocol to differentiate between various articular, periarticular, ischemic, skin, and nerve pathologies and to assist in targeted treatment strategies.

Giant cell arteritis associated with intravenous zoledronic acid administration.

Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association between aminobisphosphonates, such as alendronate and zoledronic acid, and rheumatologic and/or immune-mediated syndromes (RIMS) has been described. Herein we report 2 patients, one with a prior history of rheumatic disease and one without, who developed giant cell arteritis meeting the American College of Rheumatology 2022 criteria following zoledronic acid infusion. We subsequently review existing mechanistic and clinical literature supporting this link. The duration of symptoms and elevation of inflammatory markers may serve as indicators for differentiating between the more common ACR and less frequent but potentially morbid RIMS. Although the benefit of bisphosphonates will outweigh the risk of RIMS for most patients with high fracture risk, clinicians should be aware of this phenomenon to assist earlier diagnosis and treatment in affected individuals.

Feasibility and Tolerability of Adjuvant Capecitabine-Based Chemoradiation in Patients With Breast Cancer and Residual Disease After Neoadjuvant Chemotherapy: A Prospective Clinical Trial.

PURPOSE: Addition of adjuvant capecitabine improves overall survival for patients with breast cancer lacking pathologic complete response to standard-of-care neoadjuvant chemotherapy. Combining radiosensitizing capecitabine concurrent with radiation may further improve disease control, although the feasibility and tolerability of chemoradiation in this setting is unknown. This study aimed to determine the feasibility of this combination. Secondary objectives included the effect of chemoradiation on physician-reported toxicity, patient-reported skin dermatitis, and patient-reported quality of life compared with patients with breast cancer treated with adjuvant radiation. METHODS AND MATERIALS: Twenty patients with residual disease following standard neoadjuvant chemotherapy were enrolled in a prospective single-arm trial and treated with adjuvant capecitabine-based chemoradiation. Feasibility was defined as ≥75% of patients completing chemoradiation as planned. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 5.0 and the patient-reported radiation-induced skin reaction scale. Quality of life was measured using the RAND Short-Form 36-Item Health Survey. RESULTS: Eighteen patients (90%) completed chemoradiation without interruption or dose reduction. The incidence of grade ≥3 radiation dermatitis was 5% (1 of 20 patients). Patient-reported radiation dermatitis did not show a clinically meaningful difference following chemoradiation (mean increase, 55 points) compared with published reports of patients with breast cancer treated with adjuvant radiation alone (mean increase, 47 points). On the other hand, patient-reported quality of life demonstrated a clinically meaningful decline at the end of chemoradiation (mean, 46; SD, 7) compared with the reference population of patients treated with adjuvant radiation alone (mean, 50; SD, 6). CONCLUSIONS: Adjuvant chemoradiation with capecitabine is feasible and tolerable in patients with breast cancer. Although current studies using adjuvant capecitabine for residual disease following neoadjuvant chemotherapy have specified sequential treatment of capecitabine and radiation, these results support the conduct of randomized trials in this setting to investigate the efficacy of concurrent radiation with capecitabine and provide patient-reported toxicity estimates for trial design.

Update on Biomarkers for the Stratification of Indeterminate Pulmonary Nodules.

Lung cancer is the leading cause of cancer-related deaths. Early detection and diagnosis are critical, as survival decreases with advanced stages. Approximately 1.6 million nodules are incidentally detected every year on chest CT scan images in the United States. This number of nodules identified is likely much larger after accounting for screening-detected nodules. Most of these nodules, whether incidentally or screening detected, are benign. Despite this, many patients undergo unnecessary invasive procedures to rule out cancer because our current stratification approaches are suboptimal, particularly for intermediate probability nodules. Thus, noninvasive strategies are urgently needed. Biomarkers have been developed to assist through the continuum of lung cancer care and include blood protein-based biomarkers, liquid biopsies, quantitative imaging analysis (radiomics), exhaled volatile organic compounds, and bronchial or nasal epithelium genomic classifiers, among others. Although many biomarkers have been developed, few have been integrated into clinical practice as they lack clinical utility studies showing improved patient-centered outcomes. Rapid technologic advances and large network collaborative efforts will continue to drive the discovery and validation of many novel biomarkers. Ultimately, however, randomized clinical utility studies showing improved patient outcomes will be required to bring biomarkers into clinical practice.

Peripheral T-cell receptor repertoire dynamics in small cell lung cancer.

Background: Identifying a circulating biomarker predictive of immune checkpoint inhibitor (ICI) benefit in patients with small cell lung cancer (SCLC) remains an unmet need. Characteristics of peripheral and intratumoral T-cell receptor (TCR) repertoires have been shown to predict clinical outcomes in non-small cell lung cancer (NSCLC). Recognizing a knowledge gap, we sought to characterize circulating TCR repertoires and their relationship with clinical outcomes in SCLC. Methods: SCLC patients with limited (n=4) and extensive (n=10) stage disease were prospectively enrolled for blood collection and chart review. Targeted next-generation sequencing of TCR beta and alpha chains of peripheral blood samples was performed. Unique TCR clonotypes were defined by identical CDR3, V gene, and J gene nucleotide sequences of the beta chain and subsequently used to calculate TCR diversity indices. Results: Patients with stable versus progressive and limited versus extensive stage disease did not demonstrate significant differences in V gene usage. Kaplan-Meier curve and log-rank analysis did not identify a statistical difference in progression-free survival (PFS) (P=0.900) or overall survival (OS) (P=0.200) between high and low on-treatment TCR diversity groups, although the high diversity group exhibited a trend toward increased OS. Conclusions: We report the second study investigating peripheral TCR repertoire diversity in SCLC. With a limited sample size, no statistically significant associations between peripheral TCR diversity and clinical outcomes were observed, though further study is warranted.

A Multicenter Retrospective Chart Review of Clinical Outcomes Among Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer.

BACKGROUND: On May 28, 2021, the United States Food and Drug Administration (FDA) granted accelerated approval to sotorasib for second-line or later treatment of patients with locally advanced or metastatic KRAS G12C mutant non-small cell lung cancer (NSCLC). This was the first FDA-approved targeted therapy for this patient population. Due to a paucity of real world data describing clinical outcomes in patients with locally advanced or metastatic KRAS G12C mutated NSCLC in the second-line or later, we sought to compile a large, academic medical center-based historical dataset to clarify clinical outcomes in this patient population. MATERIALS AND METHODS: The clinical outcomes of 396 patients with stage IV (n = 268, 68%) or recurrent, metastatic (n = 128, 32%) KRAS G12C mutant NSCLC were evaluated in this multicenter retrospective chart review conducted through the Academic Thoracic Oncology Medical Investigator's Consortium (ATOMIC). Patients treated at 13 sites in the United States and Canada and diagnosed between 2006 and 2020 (30% 2006-2015, 70% 2016-2020) were included. Primary outcomes included real-world PFS (rwPFS) and overall survival (OS) from time of stage IV or metastatic diagnosis, with particular interest in patients treated with second-line docetaxel-containing regimens, as well as clinical outcomes in the known presence or absence of STK11 or KEAP1 comutations. RESULTS: Among all patients with stage IV or recurrent, metastatic KRAS G12C mutant NSCLC (n = 201 with KRAS G12C confirmed prior to first line systemic therapy), the median first-line rwPFS was 9.3 months (95% CI, 7.3-11.8 months) and median OS was 16.8 months (95% CI, 12.7-22.3 months). In this historical dataset, first line systemic therapy among these 201 patients included platinum doublet alone (44%), PD-(L)1 inhibitor monotherapy (30%), platinum doublet chemotherapy plus PD-(L)1 inhibitor (18%), and other regimens (8%). Among patients with documented second-line systemic therapy (n = 123), the second-line median rwPFS was 8.3 months (95% CI, 6.1-11.9 months), with median rwPFS 4.6 months (95% CI, 1.4-NA) among 10 docetaxel-treated patients (9 received docetaxel and 1 received docetaxel plus ramucirumab). Within the total study population, 49 patients (12%) had a co-occurring STK11 mutation and 3 (1%) had a co-occurring KEAP1 mutation. Among the 49 patients with a co-occurring KRAS G12C and STK11 mutation, median rwPFS on first-line systemic therapy (n = 23) was 6.0 months (95% CI, 4.7-NA), and median OS was 14.0 months (95% CI, 10.8-35.3 months). CONCLUSION: In this large, multicenter retrospective chart review of patients with KRAS G12C mutant NSCLC we observed a relatively short median rwPFS of 4.6 months among 10 patients with KRAS G12C mutant NSCLC treated with docetaxel with or without ramucirumab in the second-line setting, which aligns with the recently reported CodeBreak 200 dataset.

De Novo KRAS G12C-Mutant SCLC: A Case Report.

The application of KRAS G12C inhibitors in the setting of NSCLC represents a major milestone for a previously "undruggable" target. Here, we present the second reported case of de novo KRAS G12C-mutant primary SCLC. Would our patient benefit from a KRAS G12C inhibitor?