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AbstractBackgroundPrior longitudinal studies among older adults have documented associations between hearing loss and changes in brain morphology. Whether interventions involving hearing aids can reduce age‐related atrophy is unknown. A substudy within the Aging and Cognitive Health Evaluation in Elders (ACHIEVE, Clinicaltrials.gov Identifier: NCT03243422) randomized controlled trial tested the effect of a best‐practices hearing intervention versus health education control on three‐year change in cortical thickness among older adults with hearing loss.MethodThe ACHIEVE study enrolled 977 community‐dwelling adults aged 70‐84 years at baseline (2018‐2019) with untreated hearing loss (better ear pure tone average [0.5‐4 kHz] ≥30 and <70 dB HL) and without substantial cognitive impairment from four sites across the U.S. (Jackson, MS, Forsyth County, NC, Minneapolis, MN, Washington County, MD). Participants were randomized to a hearing intervention (provision of hearing aids and related technologies, counseling, and education) or a health education control (individual sessions with a health educator covering topics relevant to chronic disease and disability prevention). Three‐dimensional magnetic resonance imaging was performed on 3 Tesla Siemens scanners in a subsample of 445 participants at the ACHIEVE baseline and three‐year follow‐up. Linear mixed effects models were used in intention‐to‐treat analyses to estimate three‐year change in cortical thickness. All models adjusted for baseline measures of hearing loss, recruitment source, site, age, sex, and education. Missing outcome and covariate data was imputed to mitigate bias caused by informative attrition.ResultAt baseline, 224 participants were women (50.3%), 52 participants were Black (11.7%), and the mean (SD) age was 76.4 (4.0) years old (Table 1). Compared to the health education control, the hearing intervention exhibited a nominally protective effect on three‐year change in average cortical thickness (Figure 1). The greatest effect size for cortical thickness was observed in the occipital lobe, while the smallest effect size was detected in the temporal lobe. Statistically significant effects were detected in the pars orbitalis, rostral anterior cingulate, posterior cingulate, and isthmus cingulate (Figure 2).ConclusionHearing aid use may reduce decline in cortical thickness among older adults. The effects of hearing aids may be greatest in regions other than those associated with the auditory cortex.

Aims . To identify the most common reasons for consultation to a large specialty breast pathology service at a major institution. To provide insight into the overall challenges in practicing breast pathology. Methods . The anatomic pathology database at one institution was searched for all breast consultations received in 2021, excluding in-house patients and patients who were transferring care. Results . A total of 553 patients met the criteria ( n = 553) from a variety of academic and private practices. For each patient, the paperwork from the submitting institution was reviewed to identify the specific question, and subsequently classified into 14 categories. The reason for the consultation request was not provided for 78 (14%) patients, and a review of the outside diagnoses, where applicable, was performed. In summary, the top 5 reasons for consultation were: (1) assistance with classification of atypical intraductal epithelial proliferations (32%); (2) evaluation for the presence of (micro-)invasive carcinoma (14%); (3) evaluation of fibroepithelial (12%), (4) papillary (11%), and (5) spindle cell lesions (7%). Conclusion . We show an ongoing educational and practice gap for pathologists who most commonly struggle with classifying atypical precursor lesions, specifically when these are small and focal, or bordering on intraductal carcinoma (32%, 177/553). The second most common reason for consultation was classifying invasive carcinomas as microinvasive and subtypes (total of 20.4%, 113/553). As such, our data supports the continued need for rigid and clear criteria for diagnosing threshold lesions (namely atypical hyperplasias) and intraductal carcinoma of the breast.

ImportanceRetrieval strategies for children, adolescents, and young adults with relapsed classic Hodgkin lymphoma (cHL) aim to maintain efficacy while minimizing long-term toxic effects. Children, adolescents, and young adults with low-risk, relapsed cHL may benefit from replacing high-dose chemotherapy and autologous stem cell transplant with less intensive involved-site radiotherapy (ISRT).ObjectiveTo evaluate a risk-stratified, response-adapted, transplant-free approach for treatment of children, adolescents, and young adults with low-risk relapsed cHL with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response and ISRT (30.0 to 30.6 Gy).Design, Setting, and ParticipantsCheckMate 744 (R1 cohort) was a phase 2, nonrandomized, single-arm study enrolling children, adolescents, and young adults aged 5 to 30 years with low-risk cHL between September 25, 2017, and December 16, 2020, across the US, Canada, and Europe. Data were analyzed from September 2017 to November 2022.ExposuresPatients received 4 cycles of nivolumab plus BV induction; patients with complete metabolic response (CMR) received an additional 2 cycles of nivolumab plus BV while patients with suboptimal response received 2 cycles of BV plus bendamustine intensification. Patients with CMR after induction or intensification received ISRT consolidation.Main Outcomes and MeasuresPrespecified coprimary end points were CMR rate (Lugano 2014 classification) any time before ISRT and 3-year event-free survival (EFS) rate, per blinded independent central review (BICR).ResultsOf 28 included patients treated in the low-risk cohort, 18 (64%) were female, and the median (range) age was 17 (6-27) years. At a median (range) follow-up of 31.9 (2.2-55.3) months, CMR per BICR any time before ISRT was 93% (26 of 28; 90% CI, 79.2-98.7; objective response rate [ORR], 100%), and 23 of 28 (82%) achieved CMR per BICR after 4 cycles of nivolumab plus BV (ORR, 96.4%). Kaplan-Meier estimates of EFS and progression-free survival rates at 3 years were 87% (3 of 18; 90% CI, 69.5-94.7) and 95% (1 of 18; 90% CI, 76.7-99.0), respectively. During induction, 22 patients (79%) had treatment-related adverse events, including 7 with grade 3 or 4 adverse events, 2 with anemia, 1 with neutropenia, and 6 with immune-mediated adverse events. Serious adverse events leading to discontinuation occurred in 2 patients.Conclusions and RelevanceThis nonrandomized clinical trial found that for children, adolescents, and young adults with low-risk, relapsed cHL, a transplant-free, risk-adapted, response-based approach with nivolumab plus BV and ISRT offered high CMR rates and high 3-year EFS rate, with a safety profile consistent with that of each agent used.Trial RegistrationClinicalTrials.gov Identifier: NCT02927769

Abstract Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management. Experimental Design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168–246], within the Wing2 region of FKH (class 1B: AA 247–269), or outside FKH (class 1C: AA 1–167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1–269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims. Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P &lt; 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P &lt; 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P &lt; 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P &lt; 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations. Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Trends in diagnostic biopsy sample collection approaches for primary bone sarcomas have shifted in the past 2 decades. Although open/incisional biopsies used to be the predominant approach to obtain diagnostic material for Ewing sarcoma and osteosarcoma, image-guided core needle biopsies have increased in frequency and are safe for patients. These procedures are less invasive and reduce recovery times but have potential limitations. The quantity and quality of tissue obtained through these procedures vary between institutions. Acquired viable tissue volumes can be low, limiting the conduct of downstream expanded clinical workup, molecular analyses, and research. Patients with advanced Ewing sarcoma and osteosarcoma continue to have overall poor outcomes despite dose-intensive cytotoxic chemotherapy. The biology of treatment resistance is not currently well understood, partly due to limited availability of relevant tissue to study. There is a need for access to quality tumor specimens for molecular and other analyses to identify high-risk tumor subsets and drive discovery to improve patient outcomes. Given broad variability in bone tumor tissue procurement and processing across member institutions, the Children’s Oncology Group Bone Tumor Committee convened a multidisciplinary group of experts to outline the current and near-future tissue needs for optimal clinical care and access to research platforms. The goal of this working group was to provide high-level guidance on biopsy practices that safely meet these evolving needs. Harmonizing tissue collection practices is paramount to improving the care of children, adolescents, and young adults diagnosed with Ewing sarcoma and osteosarcoma.

History A 65-year-old male patient with a history of sarcomatoid renal cell carcinoma and prior right nephrectomy developed recurrent disease adjacent to the inferior vena cava. The patient underwent surveillance imaging 7 months after initiation of treatment with maximum-dose pazopanib and less than 1 month after completing a 2-month regimen of palliative stereotactic body radiation therapy to the right nephrectomy bed and site of recurrence. (Stereotactic body radiation therapy was initiated 5 months after pazopanib treatment was initiated.) One month after initiating treatment with pazopanib and 6 months before the surveillance imaging, the patient developed diarrhea and required ongoing treatment with loperamide to control symptoms. He denied any fatigue, mouth sores, or extremity pain, but described some abdominal pain and discomfort associated with the diarrhea. He was not experiencing any fevers, and vital signs were normal. White blood cell count was normal at 5100/μL (5.1 ×109/L) (reference range, 4200–10 200/μL [4.2–10.2 ×109/L]), with all components of the differential count also being normal. A normal serum albumin level of 3.9 g/dL (39 g/L) (reference range, 3.5–5.0 g/dL [35–50 g/L]) and low serum total protein level of 6.1 g/dL (61 g/L) (reference range, 6.3–7.9 g/dL [63–79 g/L]) were noted. A comprehensive metabolic panel was performed, indicating a serum chloride level of 98 mmol/L (reference range, 100–108 mmol/L) and an alkaline phosphatase level of 121 U/L (2.02 μkat/L) (reference range, 45–115 U/L [0.75–1.92 μkat/L]). The patient underwent surveillance imaging with contrast-enhanced CT of the abdomen and pelvis in the venous phase.

Abstract Background A passive dosimeter framework for the measurement of dose in carbon ion beams has yet to be characterized or implemented for regular use. Purpose This work determined the dose calculation correction factors for absorbed dose in thermoluminescent dosimeters (TLDs) in a therapeutic carbon ion beam. TLD could be a useful tool for remote audits, particularly in the context of clinical trials as new protocols are developed for carbon ion radiotherapy. Methods TLD‐100 were irradiated in a carbon ion beam at the Centro Nazionale di Adroterapia Oncologica (CNAO) in Pavia, Italy. The dose correction factors for linearity, fading, and beam quality were characterized. Fading was characterized from 5 to 100 days post‐irradiation. For linearity, the TLDs were irradiated to absorbed doses ranging from 1 to 15 Gy in both the entrance of a high‐energy pristine carbon ion peak and the center of a 2 cm spread‐out Bragg peak. For beam quality, the TLD was irradiated to the same absorbed dose (3 Gy) in several pristine carbon ion Bragg peaks, as well as in several spread‐out Bragg peaks. Each correction factor was calculated and compared to photon correction factors. The correction factors were also compared between high and low dose‐averaged linear energy transfer (LET D ) in the carbon ion beams. The absorbed dose was compared between ion chamber and TLD‐100 in the several tissue substitute phantom materials, applying the carbon ion TLD correction factors. Results There was no statistically significant difference in the TLD fading correction factor between photons, low LET D carbon ion beams, or high LET D carbon ion beams. The TLD linearity correction factor did differ between photons, low LET D carbon ions, and high LET D carbon ions. The beam quality correction factor was large and changed linearly with LET D . The overall uncertainty of the carbon ion absorbed dose calculation was 3.9% at the one‐sigma level, driven largely by a 3.5% uncertainty in the beam quality correction. TLD measurements were within 1.2% of ion chamber measurements in the phantom material for polyethylene, solid water (Gammex and Sun Nuclear), acrylic, blue water, and techtron HPV. TLD measurements in balsa wood were within 3.0% and cork was 6.6% low compared to ion chamber. Conclusion TLD‐100 can be used for passive dosimetry in a therapeutic carbon ion beam. Importantly, the linearity and beam quality correction factors are both different from photon therapy, and dependent on LET D of the carbon ion beam. This opens the possibility of TLD use for carbon ion output audits, phantom audits, and in vivo dose measurements, but may be subject to more complicated management and slightly larger uncertainties than are achieved in photon beams.

The NCCN Guidelines for Survivorship include recommendations for screening, evaluation, and treatment of psychosocial and physical problems resulting from adult-onset cancer and its treatment. They also include recommendations to promote healthy behaviors and immunizations in survivors and provide a framework for care coordination. These NCCN Guidelines Insights summarize the panel’s current recommendations regarding sexual health and fertility.