Citations

Introduction Maintaining fluid intake sufficient to reduce arginine vasopressin (AVP) secretion has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, evidence to support this as a clinical practice recommendation is of poor quality. The aim of the present study is to determine the long-term efficacy and safety of prescribed water intake to prevent the progression of height-adjusted total kidney volume (ht-TKV) in patients with chronic kidney disease (stages 1–3) due to ADPKD. Methods and analysis A multicentre, prospective, parallel-group, open-label, randomised controlled trial will be conducted. Patients with ADPKD (n=180; age ≤65 years, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 ) will be randomised (1:1) to either the control (standard treatment+usual fluid intake) or intervention (standard treatment+prescribed fluid intake) group. Participants in the intervention arm will be prescribed an individualised daily fluid intake to reduce urine osmolality to ≤270 mOsmol/kg, and supported with structured clinic and telephonic dietetic review, self-monitoring of urine-specific gravity, short message service text reminders and internet-based tools. All participants will have 6-monthly follow-up visits, and ht-TKV will be measured by MRI at 0, 18 and 36 months. The primary end point is the annual rate of change in ht-TKV as determined by serial renal MRI in control vs intervention groups, from baseline to 3 years. The secondary end points are differences between the two groups in systemic AVP activity, renal disease (eGFR, blood pressure, renal pain), patient adherence, acceptability and safety. Ethics and dissemination The trial was approved by the Human Research Ethics Committee, Western Sydney Local Health District. The results will inform clinicians, patients and policy-makers regarding the long-term safety, efficacy and feasibility of prescribed fluid intake as an approach to reduce kidney cyst growth in patients with ADPKD. Trial registration number ANZCTR12614001216606.

Conditions related to cardiometabolic disease, including metabolic syndrome and type 2 diabetes, are common among men with Klinefelter syndrome (KS). The molecular mechanisms underlying this aberrant metabolism in KS are largely unknown, although there is an assumption that chronic testosterone deficiency plays a role. This cross-sectional study compared plasma metabolites in 31 pubertal adolescent males with KS to 32 controls of similar age (14 ± 2 years), pubertal stage, and body mass index z -score of 0.1 ± 1.2 and then between testosterone-treated ( n = 16) and untreated males with KS. The plasma metabolome in males with KS was distinctly different from that in controls, with 22% of measured metabolites having a differential abundance and seven metabolites nearly completely separating KS from controls (area under the curve > 0.9, P < 0.0001). Multiple saturated free fatty acids were higher in KS, while mono- and polyunsaturated fatty acids were lower, and the top significantly enriched pathway was mitochondrial β-oxidation of long-chain saturated fatty acids (enrichment ratio 16, P < 0.0001). In contrast, there were no observed differences in metabolite concentrations between testosterone-treated and untreated individuals with KS. In conclusion, the plasma metabolome profile in adolescent males with KS is distinctly different from that in males without KS independent of age, obesity, pubertal development, or testosterone treatment status and is suggestive of differences in mitochondrial β-oxidation.

AbstractBackgroundCommunity-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce.MethodsWe evaluated children and adolescents aged &lt;19 years admitted to a pediatric intensive care or high-acuity unit for COVID-19 between March and December 2020. Based on qualifying microbiology results from the first 3 days of admission, we adjudicated whether patients had community-onset bacterial coinfection. We compared demographic and clinical characteristics of those who did and did not (1) receive antibiotics and (2) have bacterial coinfection early in admission. Using Poisson regression models, we assessed factors associated with these outcomes.ResultsOf the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01–1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05–1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36–2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15–4.62]) was associated with bacterial coinfection.ConclusionsCommunity-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely.

AbstractIntroductionIn October 2021, the American Society of Transplantation (AST) hosted a virtual consensus conference aimed at identifying and addressing barriers to the broader, safe expansion of living donor liver transplantation (LDLT) throughout the United States (US).MethodsA multidisciplinary group of LDLT experts convened to address issues related to financial implications on the donor, transplant center crisis management, regulatory and oversight policies, and ethical considerations by assessing the relative significance of issues in preventing LDLT growth, with proposed strategies to overcome barriers.ResultsLiving liver donors endure multiple obstacles including financial instability, loss of job security, and potential morbidity. These concerns, along with other center, state, and federal specific policies can be perceived as significant barriers to expanding LDLT. Donor safety is of paramount importance to the transplant community; however, regulatory and oversight policies aimed at ensuring donor safety can be viewed as ambiguous and complicated leading to time‐consuming evaluations that may deter donor motivation and program expansion.ConclusionTransplant programs need to establish appropriate crisis management plans to mitigate potential negative donor outcomes and ensure program viability and stability. Finally, ethical aspects, including informed consent for high‐risk recipients and use of non‐directed donors, can be perceived as additional barriers to expanding LDLT.

Abstract PURPOSE: Treatment options for patients (pts) with HER2+ BCBM remain limited. We previously reported that neratinib monotherapy is associated with a volumetric central nervous system objective response rate (CNS ORR) of 8%, whereas the combination of neratinib and capecitabine resulted in a volumetric CNS ORR of 49% (in lapatinib-naïve pts). Preclinical data suggest that neratinib may overcome resistance to trastuzumab-emtansine (T-DM1) and that the combination has potential CNS efficacy. Here, we report results of neratinib plus T-DM1 in pts with HER2+ BCBM. PATIENTS AND METHODS: In this prospective, multicenter, phase II study, pts with measurable HER2+ BCBM received neratinib 160 mg orally once daily plus T-DM1 3.6 mg/kg IV every 21 days in three parallel-enrolling cohorts. Cohort 4A enrolled pts with previously untreated brain metastases. Cohort 4B enrolled pts with BCBM progressing after prior local CNS-directed therapy without prior exposure to T-DM1. Cohort 4C enrolled pts with BCBM progressing after prior local CNS-directed therapy who had previous exposure to T-DM1. Diarrhea prophylaxis with colestipol and loperamide was required during cycle 1. Cohorts 4A and 4B were single-stage with a planned enrollment of 20 patients; cohort 4C had a two-stage design, with a requirement for at least 1 of the first 9 pts to achieve a response in order to enroll a total of 24 patients. The primary endpoint was Response Assessment in Neuro-Oncology-Brain Metastases (RANO BM) in each cohort separately. Correlative studies included patient-reported outcomes (PROs) for gastrointestinal toxicity. RESULTS: We enrolled 6, 17, and 21 patients to cohorts 4A, 4B, and 4C, during 11/07/2018 – 11/01/2021. Enrollment was stopped prematurely due to slow accrual. Across Cohorts 4A-4C, the median number of prior lines of chemotherapy prior to enrollment was 2 (range 1-10); 25% received prior lapatinib and no patients received prior tucatinib. In cohorts 4B and 4C (prior CNS-treated cohorts), 33% had prior CNS surgery and &gt;94% had prior CNS radiation. Among evaluable patients, CNS ORR in cohorts 4A (n=6), 4B (n=16), and 4C (n=21) was 50.0% (95% CI 18.8- 81.2%), 25.0% (95% CI 8.3-52.6%), and 38.1% (95% CI 19.0-61.3%), respectively. Median (range) number of cycles completed for 4A, 4B, and 4C was 4.5 (1-15), 4 (range 0-49+), and 6 (0-23); three patients on Cohort 4B remain on protocol therapy (cycles 14, 45, and 49). The overall survival at 12-months for cohorts 4A, 4B, and 4C was 83.3% (95% CI, 58.3-100%), 86.2% (95% CI 70-100%), and 83.3% (95% CI 67.6-100%). Diarrhea was the most common grade 3 toxicity (19.0–33.3% across cohorts); one grade 4 liver function event occurred in cohort 4B. Updated efficacy results will be reported at the meeting; PRO analyses are ongoing. CONCLUSION: Intracranial activity was observed for the combination of neratinib plus T-DM1 across all three enrolled cohorts, including those with prior T-DM1 exposure, suggesting synergistic effects of this treatment combination. Our data provide additional evidence for consideration of neratinib-based combinations in pts with HER2+ BCBM. Citation Format: Rachel Freedman, Siyang Ren, Nabihah Tayob, Rebecca Gelman, Karen L. Smith, Raechel Davis, Alyssa Pereslete, Victoria Attaya, Christine Cotter, Wendy Y. Chen, Cesar Augusto Santa-Maria, Catherine Van Poznak, Beverly Moy, Adam M. Brufsky, Michelle Melisko, Ciara C. O’Sullivan, Nadia Ashai, Yasmeen Rauf, Julie Nangia, Dario Trapani, Jennifer Savoie, Robyn Burns, Antonio C. Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy U. Lin. Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-03.

Abstract Purpose: To determine the rate of rib fracture in a cohort of patients with breast cancer treated with proton therapy and enrolled on a prospective registry. In series investigating photon therapy for breast cancer, the rib fracture rate ranges from 0.3-13% Methods: From a prospective database, we identified patients treated with proton therapy for breast cancer at our institution between January 1, 2012 and December 31, 2020. Clinical and dosimetric data was extracted from the electronic medical record. The cumulative incidence method assessed rib fracture rate; the Fine-Gray test statistic assessed prognostic significance select variables. Results: 225 patients were identified, 223 women and 2 men. Median age at the time of radiation was 57.8 years (range, 25 – 87). 26% of patients were black, 69% white and 5% were other races or race not disclosed. 5% were Hispanic. 74% of patients had left-sided breast cancer, 5% bilateral, and 21% right-sided. DEXA scan was normal in 20%, showed osteopenia in 34%, osteoporosis in 6%, and not performed in 40%. 57% of patients received antiendocrine therapy with an aromatase inhibitor. For 16% of patients, the breast +/- internal mammary nodes (IMN) were treated, while 32% underwent proton therapy to treat the breast and comprehensive regional lymphatics. 1% of patients had chest wall +/- IMN treated, while 51% underwent proton therapy to treat the chest wall and comprehensive regional lymphatics. 41% of patients were treated with passive scatter proton therapy (n=92); 52% of these had mastectomy. 58% of patients received treatment with pencil beam scanning (PBS) proton therapy (n=131); 53% of these had mastectomy. A combination of passive scatter and PBS was used for 2 patients (1%). 85% of patients received a boost. Median follow-up was 3.1 years (range, 0.2 – 9.1). 97% of patients had &gt; 12 months of follow-up. The 3 year cumulative incidence of in-field rib fracture was 3.7% (95%CI: 1.6%-7.1%). In total, 8 patients developed in-field rib fractures, one symptomatic and 7 identified incidentally on surveillance imaging, for a 0.4% rate of symptomatic rib fracture. Median time from completion of radiation to identification of rib fracture was 1.8 years (range, 0.4-7.4 years). Rib fractures occurred within 2.2 years from radiotherapy completion for seven of the eight patients who experienced this side effect. Three patients developed rib fractures outside of the radiation field, for a cumulative incidence of out-of-field rib fracture of 0.9% (95%CI: 0.2-3.0%). No variables were associated with rib fracture on univariate analysis. Of those with in-field rib fractures, 3 had low and 3 had normal bone density while 2 had not undergone testing; of those with out-of-field rib fractures, 2 had osteopenia and 1 did not have testing. Conclusions: Although a proton beam has higher biological dose deposition at end-of-range than the assumed constant RBE=1.1, the 3 year rate of any in-field rib fractures in our series remains low at 3.7%, with a 0.4% rate of symptomatic rib fracture. Contouring ribs as an OAR and establishing a dose constraint warrants further investigation as a means to maintaining a low rate of rib fracture with proton therapy. Citation Format: Julie Bradley, Xiaoying Liang, Raymond Mailhot Vega, Chunbo Liu, Eric Brooks, Teena Burchianti, Emma Viviers, Roi Dagan, Oluwadamilola Oladeru, Christopher Morris, Nancy Mendenhall. Incidence of rib fracture following treatment with proton therapy for breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-08.

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p&lt; 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was &gt;20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was &lt; 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.

Abstract BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in breast cancer (BC) and are associated with endocrine resistance. Everolimus, an mTOR-inhibitor increased PFS when combined with endocrine therapy (ET) in the metastatic setting and is thought to revert endocrine resistance. S1207 is a phase III randomized, placebo-controlled trial evaluating the role of everolimus in combination with ET in the adjuvant setting among patients with high-risk hormone receptor-positive, HER2-negative BC (NCT01674140). METHODS: Eligible patients were &gt;18 years of age with histologically confirmed invasive hormone receptor-positive and HER2-negative high-risk BC. Four risk groups were defined as: 1) &gt; 2cm node-negative disease (or pN1mi), and either an Oncotype DX® Recurrence Score (RS) &gt; 25 or MammaPrint® high-risk category (MP high); 2) 1-3 positive nodes and either RS &gt;25, MP high or a pathological grade 3 tumor; 3) &gt;4 positive lymph nodes. Patients treated with neoadjuvant chemotherapy were eligible if: 4) after surgery had &gt;1 lymph node involvement. Patients were randomized 1:1 to physician’s choice adjuvant ET in combination with one year of everolimus (10 mg PO daily) or ET plus placebo stratified by risk group. The primary endpoint was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test. Secondary endpoints included overall survival (OS) and safety. The hazard ratio (HR) for treatment efficacy was estimated using Cox regression with stratification by risk groups. Subset analyses included preplanned evaluation within risk group and exploratory analyses of menopausal status and age. RESULTS: 1,939 patients were randomized between September 2013 and May 2019, of them 1,792 were eligible and included in the analysis (896 per arm). Primary reason for ineligibility was timing after chemotherapy/radiation or not high risk. Median age was 54 years (22-85) and 32% were premenopausal. With a median follow-up of 50.5 months, there were 389 IDFS events as of May 2022 (data cutoff). 5-year IDFS was 74.8% among patients treated with everolimus and 73.9% among patients treated with placebo, HR=0.93 (95% CI 0.76-1.14). However, the proportional hazards assumption was violated (p=0.02) suggesting differential treatment effect over time. The HR during the one year of treatment was 0.72 (95% CI 0.47-1.10) while after one year it was 1.00 (95% CI 0.80-1.26). The 5-year OS was 87.6% in the everolimus arm and 85.5% in the placebo arm, HR=0.98 (95% CI 0.75-1.28). Analysis by risk group did not show higher everolimus benefit as risk increased. No difference in IDFS or OS was seen among postmenopausal patients (IDFS HR=1.08 [95% CI 0.85-1.36], OS HR=1.19 [95% CI 0.87-1.61]). Among premenopausal patients, everolimus was associated with improved IDFS (HR=0.63 [95% CI 0.43-0.93]) and OS (HR=0.48 [95% CI 0.26-0.88]). Treatment completion of randomized therapy was lower in the everolimus arm compared to placebo (47.9% v 72.7%). Grade 3 and 4 toxicities were noted in 6.5% and 0.5% of patients in the placebo arm and in 31.2% and 3.7% in the everolimus arm respectively. CONCLUSIONS: Addition of one year of adjuvant everolimus to standard adjuvant ET did not improve IDFS or OS and was associated with low completion rate and increased AEs. Among premenopausal patients there was a benefit in IDFS and OS that is hypothesis generating. Future translational studies will evaluate potential predictors of everolimus benefit and drug toxicity. Citation Format: Marianna Chavez, Jieling Miao, Lajos Pusztai, Matthew P. Goetz, Priya Rastogi, Patricia A. Ganz, Eleftherios (Terry) Mamounas, Soonmyung Paik, Hanna Bandos, Wajeeha Razaq, Anne O’Dea, Virginia Kaklamani, Andrea L.M. Silber, Lisa E. Flaum, Eleni Andreopolu, Joseph Baar, Albert G. Wendt, Jennifer F. Carney, Priyanka Sharma, Julie R. Gralow, Danika L. Lew, William E. Barlow, Gabriel N. Hortobagyi. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-07.

Aims:Increased left ventricular (LV) wall thickness is frequently encountered in transthoracic echocardiography (TTE). While accurate and early diagnosis is clinically important, given the differences in available therapeutic options and prognosis, an extensive workup is often required to establish the diagnosis. We propose the first echo-based, automated deep learning model with a fusion architecture to facilitate the evaluation and diagnosis of increased left ventricular (LV) wall thickness. Methods and Results: Patients with an established diagnosis of increased LV wall thickness (hypertrophic cardiomyopathy (HCM), cardiac amyloidosis (CA), and hypertensive heart disease (HTN)/others) between 1/2015 and 11/2019 at Mayo Clinic Arizona were identified. The cohort was divided into 80%/10%/10% for training, validation, and testing sets, respectively. Six baseline TTE views were used to optimize a pre-trained InceptionResnetV2 model. Each model output was used to train a meta-learner under a fusion architecture. Model performance was assessed by multiclass area under the receiver operating characteristic curve (AUROC). A total of 586 patients were used for the final analysis (194 HCM, 201 CA, and 191 HTN/others). The mean age was 55.0 years, and 57.8% were male. Among the individual view-dependent models, the apical 4-chamber model had the best performance (AUROC: HCM: 0.94, CA: 0.73, and HTN/other: 0.87). The final fusion model outperformed all the view-dependent models (AUROC: HCM: 0.93, CA: 0.90, and HTN/other: 0.92). Conclusion: The echo-based InceptionResnetV2 fusion model can accurately classify the main etiologies of increased LV wall thickness and can facilitate the process of diagnosis and workup.