Evaluation of safety outcomes between nivolumab regimens with differing dosing patterns.

BACKGROUND: Real-world safety outcomes between the two flat-dose nivolumab regimens demonstrated to be similar in a study of adjuvant nivolumab recipients for melanoma. However, this study was limited by a single oncology patient population, a small sample size, and insufficient study power. The primary objective of this study was to evaluate the incidence of immunotherapy-related adverse effects (irAEs) between nivolumab regimens with differing dosing patterns in various solid tumor patient populations. METHODS: Single-center retrospective cohort study of adult patients with solid tumor malignancies who received nivolumab 240 mg Q2W or 480 mg Q4W, or who were transitioned from 240 mg Q2W to 480 mg Q4W from March 1, 2018 to March 31, 2022 were selected for analysis from an electronic health record generated report. The primary endpoint evaluated was the incidence of irAEs. Secondary endpoints included the incidence of significant irAEs and reasons for treatment discontinuation. These endpoints were compared by univariate analysis between all three cohorts. A multivariate analysis was then conducted for the primary endpoint. RESULTS: Nivolumab 240 mg Q2W was associated with a statistically significant increase in the incidence of colitis whereas the 480 mg Q4W regimen was associated with a statistically significant increase in the incidence of pruritis. The incidence of irAEs was not different between the three cohorts, while the incidence of significant irAEs was higher in the 240 mg Q2W and 240 mg Q2W to 480 mg Q4W cohorts. CONCLUSION: Clinicians ought to be aware of differences in the irAE profiles between nivolumab regimens with differing dosing patterns.

Indigenizing and Ruralizing NCI Screen to Save Program: Resources, Optimizing Outreach, Teaching, Science (ROOTS).

Colorectal cancer (CRC) is a complex health disparity in many Indigenous and rural populations. While it affects anyone regardless of race, age, gender, or other common differences among people, Indigenous and rural populations are at a higher risk of dying from colorectal cancer. An NCI Screen to Save (S2S) program was culturally tailored to promote awareness and knowledge of colorectal cancer and screening in both Indigenous and rural communities across a sector in Northeastern USA. Indigenous and rural community outreach teams at an NCI-designated cancer center partnered with a community advisory board to provide an indigenized/ruralized version of the NCI Screen to Save program delivered to both Indigenous and rural/suburban communities. In total, n = 79 pre/post surveys were obtained from n = 82 participants, who had an average age of 49 years. Findings demonstrated that Indigenous/rural participants in both off-territory/non-reservation communities and a tribal community that received a culturally tailored version of NCI's S2S program were able to identify both smoking and tobacco use along with lack of physical activity as risk factors for colorectal cancer. Post-intervention, participants reported being more likely to increase physical activity. Most importantly, participants said they would be more likely to be screened for colorectal cancer along with their family and friends based on their cancer screening experiences. Culturally tailored CRC messaging is an effective means for increasing screening intentions and decreasing cancer health disparities among both indigenous and rural populations. Future research should include the relationship of diet to obesity-related cancers, greater integration of Indigenous-rural patient navigation programs, creation of more information on genetic screening, and quality improvement to service translational science initiatives.

Acute gastric conduit dilation after minimally invasive esophagectomy: a 10-year experience.

Despite decreasing overall morbidity with minimally invasive esophagectomy (MIE), conduit functional outcomes related to delayed emptying remain challenging, especially in the immediate postoperative setting. Yet, this problem has not been described well in the literature. Utilizing a single institutional prospective database, 254 patients who underwent MIEs between 2012 and 2020 were identified. Gastric conduit dilation was defined as a conduit occupying >40% of the hemithorax on the postoperative chest X-ray. Sixty-seven patients (26.4%) demonstrated acute conduit dilation. There was a higher incidence of conduit dilation in the patients who underwent Ivor Lewis esophagectomy compared to those with a neck anastomosis (67.2% vs. 47.1%; P = 0.03). Patients with dilated conduits required more esophagogastroduodenoscopies (EGD) (P < 0.001), conduit-related reoperations within 180 days (P < 0.001), and 90-day readmissions (P = 0.01). Furthermore, in 37 patients (25.5%) undergoing Ivor Lewis esophagectomy, we returned to the abdomen after intrathoracic anastomosis to reduce redundant conduit and pexy the conduit to the crura. While conduit dilation rates were similar, those who had intraabdominal gastropexy required EGD significantly less and trended toward a lower incidence of conduit-related reoperations (5.6% vs. 2.7%). Multivariable analysis also demonstrated that conduit dilation was an independent predictor for delayed gastric conduit emptying symptoms, EGD within 90 days, conduit-related reoperation within 180 days, and 30-day as well as 90-day readmission. Patients undergoing MIE with acute gastric conduit dilation require more endoscopic interventions and reoperations.

Detrimental Impact of Chemotherapy Dose Reduction or Discontinuation in Early Stage Triple-Negative Breast Cancer Treated With Pembrolizumab and Neoadjuvant Chemotherapy: A Multicenter Experience.

BACKGROUND: Pembrolizumab combined with neoadjuvant chemotherapy (NAC) is the current standard of care in early stage triple-negative breast cancer (TNBC) based on higher event-free survival and pathological complete response (pCR) in Keynote-522 (KN-522) clinical trial. However, this aggressive five-drug regimen is associated with increased risks for immune-related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen as well as factors predictive of pCR and irAEs. METHODS: We identified and abstracted data from 153 early-stage TNBC patients treated with the KN-522 regimen between July 1, 2021, and December 31, 2023, at 4 academic institutions in the U.S. Descriptive analysis was conducted, univariate and multivariate analyses were performed to identify factors associated with pCR and irAEs. RESULTS: The median age was 52 years (interquartile range, 42-60years), with 66% White and 24% Black patients with stage I/II (67%), node-negative disease (58%), grade 3 (86%) tumors, and ≥1 comorbidities (68%). Approximately 21% discontinued pembrolizumab, because of toxicity; ∼50% received a lower relative dose intensity (RDI) of chemotherapy (dose reduction or discontinuation). Of the 153 patients, 99 (64.7%) achieved pCR and 83 (54%) experienced an irAE, with 18 (12%) having ≥ grade 3 irAE. The majority (90%) of the irAEs were observed during neoadjuvant phase. Stage I/II versus stage III disease (OR 1.55, CI 1.04-2.33, P = .03), age (OR 0.96, CI 0.93-0.99, P = .01) and full versus reduced RDI of NAC (OR 1.53, CI 1.04-2.26, P = .03) were associated with higher pCR rates on multivariate analyses. Fewer cycles of pembrolizumab were associated with a higher likelihood of irAEs (OR 1.52, CI 1.07-2.16, P = .02), likely explained by the early discontinuation and receipt of less than 8 cycles of pembrolizumab in patients who experienced irAEs. CONCLUSIONS: Our study validates the clinical efficacy of KN-522 regimen; however, we observed a higher incidence of irAEs (54%) in this real-world population. Lower stage and younger age were associated with higher likelihood of achieving pCR. Toxicity-related chemotherapy dose reduction or discontinuation was observed to adversely impact the likelihood of achieving pCR.

Racial and Ethnic Disparity in Preoperative Chemosensitivity and Survival in Patients With Early-Stage Breast Cancer.

Importance: It remains unclear what survival benefit is associated with preoperative chemosensitivity after receiving neoadjuvant chemotherapy (NACT) among patients with resectable breast cancer from diverse racial and ethnic backgrounds. Objective: To investigate racial and ethnic disparities in chemosensitivity and association with survival in patients with early-stage breast cancer. Design, Setting, and Participants: This retrospective cohort study queried data from the National Cancer Database (NCDB) between calendar years 2010 and 2018. Participants included patients with breast cancer with clinical stage I to III disease treated with NACT. Preoperative chemosensitivity was defined as very sensitive (ypT0N0), sensitive (pathologic TNM stage less than clinical stage, excluding ypT0N0), and refractory (pathologic stage greater than or equal to clinical stage). Data were analyzed in November 2022. Exposure: Receipt of NACT and clinicopathologic and treatment factors contributing to racial and ethnic disparities in survival. Main Outcomes and Measures: Overall survival of patients from diverse racial and ethnic backgrounds who received NACT. Results: This study included 103 605 patients (median age, 53 [IQR, 44-62] years, 99.5% [n = 103 060] women, and 68.7% [n = 71 203] White race). Among them, breast cancer was refractory in 43.2% (n = 44 796), sensitive in 34.4% (n = 35 638), and very sensitive in 22.4% (n = 23 171) of patients. In the hormone receptor-positive ERBB2 negative (formerly HER2 negative) group, patients had more refractory disease regardless of race or ethnicity (all races and ethnicities refractory: 54%-59%; P < .001). Among ERBB2 positive disease, Black patients had a lower percentage of very sensitive disease (32% vs 37%-40%; P < .001) and among triple-negative breast cancer, more refractory disease was seen among Black patients compared with other races and ethnicities (38% vs 30%-35%; P < .001). In refractory (hazard ratio [HR], 1.53; 95% CI, 1.47-1.60; P < .001) and sensitive (HR, 1.25; 95% CI, 1.17-1.33; P < .001) disease, Black patients had a higher mortality risk compared with White patients in the overall cohort. Asian patients had a lower mortality risk compared with White patients in refractory (HR, 0.71; 95% CI, 0.63-0.80; P < .001), sensitive (HR, 0.58; 95% CI, 0.49-0.69; P < .001), and very sensitive (HR, 0.60; 95% CI, 0.43-0.82; P < .001) disease groups in the overall cohort. Conclusions and Relevance: In this cohort study, Black patients had a higher mortality risk compared with White patients among those with residual disease after NACT. This highlights the need for personalized treatment strategies for Black patients to help them attain pathologic complete response.

Small Endogeneous Peptide Mitigates Myocardial Remodeling in a Mouse Model of Cardioselective Galectin-3 Overexpression.

BACKGROUND: Myocardial Gal3 (galectin-3) expression is associated with cardiac inflammation and fibrosis. Increased Gal3 portends susceptibility to heart failure and death. There are no data reporting the causative role of Gal3 to mediate cardiac fibro-inflammatory response and heart failure. METHODS: We developed a cardioselective Gal3 gain-of-function mouse (Gal3+/+) using α-myosin heavy chain promotor. We confirmed Gal3-transgene expression with real-time polymerase chain reaction and quantified cardiac/circulating Gal3 with Western blot and immunoassays. We used echocardiogram and cardiac magnetic resonance imaging to measure cardiac volumes, function, and myocardial velocities. Ex vivo, we studied myocardial inflammation/fibrosis and downstream TGF (transforming growth factor) ß1-mRNA expression. We examined the effects of acute myocardial ischemia in presence of excess Gal3 by inducing acute myocardial infarction in mice. Two subsets of mice including mice treated with N-acetyl-seryl-aspartyl-lysyl-proline (a Gal3-inhibitor) and mice with genetic Gal3 loss-of-function (Gal3-/-) were studied for comparative analysis of Gal3 function. RESULTS: Gal3+/+ mice had increased cardiac/circulating Gal3. Gal3+/+ mice showed excess pericardial fat pad, dilated ventricles and cardiac dysfunction, which was partly normalized by N-acetyl-seryl-aspartyl-lysyl-proline. Cardiac magnetic resonance imaging showed reduced myocardial contractile velocities in Gal3+/+. The majority of Gal3+/+ mice did not survive acute myocardial infarction, and the survivors had profound cardiac dysfunction. Myocardial histology of Gal3+/+ mice showed macrophage/mast-cell infiltration, fibrosis and higher TGFß1-mRNA expression, which were mitigated by both Gal3 gene deletion and N-acetyl-seryl-aspartyl-lysyl-proline administration. CONCLUSIONS: Our study shows that cardioselective Gal3 overexpression leads to multiple cardiac phenotypic defects including ventricular dilation and cardiac dysfunction. Pharmacological Gal3 inhibition conferred protective effects with reduction of inflammation and fibrosis. Our study highlights the importance of translational studies to counteract Gal3 function and prevent cardiac dysfunction.