Multi-institutional Cohort Study Research Articles

GWAS of Folate Metabolism With Gene-environment Interaction Analysis Revealed the Possible Role of Lifestyles in the Control of Blood Folate Metabolites in Japanese: The J-MICC Study.

The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites, as well as to detect related gene-environment interactions in Japanese. We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B12 (VB12) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene-environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed. For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5 × 10-8). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB12. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity >33% on Hcy (β = 0.039, 0.038 and -0.054, P = 0.018, 0.021 and <0.001, respectively) and the interaction of MTHFR C677T with ever drinking on FA (β = 0.033, P = 0.048). The present GWAS revealed the folate metabolism-associated genetic loci and gene-environment interactions with drinking and physical activity in Japanese, suggesting the possibility of future personalized cardiovascular disease prevention.

Abstract PO3-05-13: A Multi-Institutional Review of Contralateral Axillary Metastases: Time for Reclassification as Local-Regional Event?

Abstract Background Current American Joint Committee on Cancer (AJCC) breast cancer staging considers contralateral axillary metastasis (CAM) stage IV disease (M1). Retrospective studies suggest that women with CAM have improved overall survival (OS) compared to those with distant metastasis (M1) and/or comparable OS to locally advanced breast cancer (LABC). These studies support consideration of curative intent treatment; however, they contain heterogeneous cohorts with highly variable treatment strategies. We sought to evaluate treatment and outcomes in a well-defined CAM cohort treated with contemporary systemic and locoregional therapy. Methods We performed a retrospective multi-institution cohort study to compare OS of patients with CAM matched 1:3 on age +/- 5 years to LABC (defined as cN2-3 and/or pN2-3), and to non-CAM M1. CAM patients classified as type 1) de novo CAM, synchronous with the contralateral primary, 2) metachronous isolated CAM in the setting of prior surgical and/or radiation treatment to primary index cancer, 3) synchronous with, or 4) metachronous after an in-breast or axillary nodal recurrence of the primary index cancer. The M1 cohort included de novo and recurrent metastasis with varied sites and number of metastasis. OS was defined as time from CAM diagnosis to death or last follow-up for CAM patients; time from primary diagnosis to death or last follow-up for LABC; and time from metastatic diagnosis to death or last follow-up for M1. Unadjusted OS was estimated with the Kaplan-Meier method, and Cox proportional hazards models were used to estimate the association of group with OS after adjustment for covariates Results We identified 57 CAM and 155 LABC from 8 institutions (2016-2022), and 632 M1 from a single institution. The median age was similar between groups (CAM=59 years, LABC=58, M1=57, p=0.44), and there were no statistically significant differences in hormone receptor status (p=0.25). There were more Non-Hispanic Black patients in the M1 cohort compared to CAM or LABC (p&amp;lt; 0.001). The majority of CAM cases were delayed metachronous from the index cancer (type 2, 35.1%), or synchronous with a recurrence (type 3, 33.3%). Type 1 (de novo, 14%) and type 4 (delayed metachronous after breast cancer recurrence, 17.5%) were less frequent. Among CAM patients, 49.1% were hormone receptor positive (HR+)/HER2-negative (HER2-), 22.8% HR-/HER2-, 10.5% HR+/HER2+, and 5.3% HR-/HER2+. Comparing CAM versus LABC, invasive ductal carcinoma (IDC) was more commonly seen in CAM (82.5% vs 66.5%), as was grade 3 (45.6% vs 35.5%), and triple negative (22.8% vs 13.5%). Conversely, in LABC, treatment of the primary index cancer more frequently included chemotherapy (CAM=71.9%, LABC=92.3%), mastectomy (CAM=54.4%, LABC 74.2%), and adjuvant radiation (CAM=73.7%, LABC=90.3%). On multivariable analysis adjusting for age, race/ethnicity, and hormone receptor status, both CAM and M1 had inferior survival to LABC (Table 1), but with a 2.4-fold difference for CAM (95% CI 1.42-4.07, p=0.001) versus a 6.3-fold difference for M1 (95% CI 4.29-9.23, p=&amp;lt; 0.001). Discussion In this contemporary, multi-institution study, we demonstrated that CAM patients selected for presumed curative intent treatment experienced improved OS when compared to stage IV (M1) patients. Our data adds additional support for re-evaluating the current stage IV designation, in favor of N3, and consideration of curative intent treatment in this disease. Table. Adjusted* Overall Survival Comparing Patients with Breast Cancer Contralateral Axillary Metastasis (CAM) to those with Locally Advanced Breast Cancer (LABC) and Metastatic Disease (M1) *Adjusted for age, race/ethnicity, hormone receptors. Citation Format: Meghan R. Flanagan, Stephanie Downs-Canner, Samantha Thomas, Astrid Botty van de bruele, Margaret Lillie, Kristalyn Gallagher, Tammeza Gibson, James Jakub, Alexandra Verosky, Sarah Tevis, Malia Brennan, Francys Verdial, Jennifer Q. Zhang, Leisha Elmore, Jennifer Plichta, Laura Rosenberger. A Multi-Institutional Review of Contralateral Axillary Metastases: Time for Reclassification as Local-Regional Event? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-13.

Gender and age variations in the association between multigenerational cohabitation and self-rated health among middle-aged and older adults in Japan.

Despite encouraging multi-generational cohabitation, the population of Japanese people living alone has increased. However, little is known about the association between health and multigenerational cohabitation. This study examined the relationship between self-rated health and living arrangements among Japanese adults using data from the Japan Multi-Institutional Collaborative Cohort Study (2013-2017). The analysis employed multivariate logistic regression to examine the associations. Our results showed no association between living arrangements and self-rated health when stratified by gender. Living alone was found to be associated with poor self-rated health among women aged 65 and above. A similar association may exist among men in the same age group. Among women aged < 65 years, two-generation cohabitation was associated with a good self-rated health, similar to those living alone. Among men aged < 65 years, neither living alone nor two-generation cohabitation was significantly associated with good self-rated health. We found no association between three- or plus-generation cohabitation and self-rated health. Therefore, our findings indicate associations between multigenerational cohabitation and self-rated health, but they vary by gender and age. Invested stakeholders in the public health field should consider the potential impact of living arrangements on health based on gender and age.

The real-world data of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study.

The real-world efficacy, feasibility, and prognostic factors of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer are not fully established. This multi-institutional retrospective cohort study evaluated 71 consecutive patients treated with immune-checkpoint inhibitor combination therapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, safety, and long-term survival. In patients with measurable lesions, the response rate was 58%, and the disease control rate for all enrolled patients was 80%. Five patients (7.0%) underwent successful conversion surgery. Grade 3 or higher immune-related adverse events occurred in 13% of patients, and one patient (1.4%) died due to cholangitis. Median progression-free survival was 9.7 (95% confidence interval: 6.5-not reached). C-reactive protein levels and performance status were identified as significant predictors of progression-free survival through Cox proportional hazards analysis. Immune-checkpoint inhibitor combination therapy for esophageal cancer demonstrated comparable tumor response, safety, and long-term survival to previous randomized clinical trials. Patients with good performance status and low C-reactive protein levels may be suitable candidates for this treatment.

Assessing Uveitis Risk following Pediatric Down Syndrome Diagnosis: A TriNetX Database Study.

Background and Objectives: The risks of uveitis development among pediatric patients with Down syndrome (DS) remain unclear. Therefore, we aimed to determine the risk of uveitis following a diagnosis of DS. Materials and Methods: This multi-institutional retrospective cohort study utilized the TriNetX database to identify individuals aged 18 years and younger with and without a diagnosis of DS between 1 January 2000 and 31 December 2023. The non-DS cohort consisted of randomly selected control patients matched by selected variables. This included gender, age, ethnicity, and certain comorbidities. The main outcome is the incidence of new-onset uveitis. Statistical analysis of the uveitis risk was reported using hazard ratios (HRs) and 95% confidence intervals (CIs). Separate analyses of the uveitis risk among DS patients based on age groups and gender were also performed. Results: A total of 53,993 individuals with DS (46.83% female, 58.26% white, mean age at index 5.21 ± 5.76 years) and 53,993 non-DS individuals (45.56% female, 58.28% white, mean age at index 5.21 ± 5.76 years) were recruited from the TriNetX database. Our analysis also showed no overall increased risk of uveitis among DS patients (HR: 1.33 [CI: 0.89-1.99]) compared to the non-DS cohort across the 23-year study period. Subgroup analyses based on different age groups showed that those aged 0-1 year (HR: 1.36 [CI: 0.68-2.72]), 0-5 years (HR: 1.34 [CI: 0.75-2.39]), and 6-18 years (HR: 1.15 [CI: 0.67-1.96]) were found to have no association with uveitis risk compared to their respective non-DS comparators. There was also no increased risk of uveitis among females (HR: 1.49 [CI: 0.87-2.56]) or males (HR: 0.82 [CI: 0.48-1.41]) with DS compared to their respective non-DS comparators. Conclusions: Our study found no overall increased risk of uveitis following a diagnosis of DS compared to a matched control population.

120 Outcome Related Thresholds of Near Infrared Spectroscopy Based Cerebrovascular Reactivity Metrics in Moderate Severe TBI: A Canadian High Resolution-TBI (CAHR-TBI) Cohort Study

INTRODUCTION: Dysfunctional cerebrovascular reactivity (CVR)/autoregulation contributes to secondary injury following traumatic brain injury (TBI). Currently, monitoring of CVR relies on intracranial pressure (ICP) monitoring and has known thresholds at which outcomes worsen. Interest has shifted to less invasive near infrared spectroscopic (NIRS) regional cerebral oxygen saturation (rSO2) based measures of CVR. However, threshold levels at which outcomes worsen have not yet been determined for these indices. METHODS: A retrospective multi-institutional cohort study utilizing the CAnadian High Resolution TBI (CAHR-TBI) Research Collaborative database was performed. The cohort included TBI patients with ICP, arterial blood pressure (ABP), and rSO2 monitoring treated in adult intensive care units (ICU). COx (using rSO2 and cerebral perfusion pressure) as well as COx_a (using rSO2 and ABP) were calculated for each subject as the rSO2 based indices of CVR. 2 x 2 tables were created grouping patients by alive/dead and favorable/unfavorable outcomes at various thresholds of COx and COx_a as well as rSO2 itself. Chi-square values were calculated and the threshold producing the highest value was identified as providing the best discriminative value. RESULTS: A total of 129 patients were included. For both COx and COx_a an optimal threshold value of 0.2 was identified for both survival (χ2 = 9.57, p = 0.0020; χ2 = 13.04, p = 0.0003 respectively) and favorable outcomes (χ2 = 5.98, p = 0.0145; χ2 = 8.94, p = 0.0028 respectively) with values above this associated with worse outcomes. Notably, there was no identifiable threshold for raw rSO2 values at which outcomes were identified to worsen. CONCLUSIONS: In this multi-institutional cohort study, COx and COx_a were found to have a uniform threshold of 0.2, above which clinical outcomes worsened. This study lays the groundwork to transition to less invasive means of continuously measuring CVR.

(921) - The Outcomes of Old Age Lung Transplantation: National Multi-Institutional Cohort Study

(921) - The Outcomes of Old Age Lung Transplantation: National Multi-Institutional Cohort Study

The Incidence of Residual Neuromuscular Block in Pediatrics: A Prospective, Pragmatic, Multi-institutional Cohort Study.

Introduction Residual neuromuscular block, defined as a quantitatively measured train-of-four ratio (TOFr) <0.9, is common postoperatively.Using a pragmatic trial design, we hypothesized that qualitative and/or clinical assessment of neuromuscular block would inadequately detect residual block following antagonism with neostigmine or sugammadex. Method After IRB approval and written informed consent, 74 children (aged 2-17 years), undergoing elective surgery and receiving rocuronium, were prospectively enrolled in the study at Children's Hospital Colorado and Children's Healthcare of Atlanta. Routine clinical practice at both institutions consisted of clinical signs and/or qualitative assessment with peripheral nerve stimulators. Children at the Colorado hospitalroutinely received sugammadex antagonism; whereas children at the Atlanta hospital received neostigmine. Residual neuromuscular block was assessed postoperatively using quantitative electromyography. If TOFr was <0.9, patients received sugammadex until TOFr ≥0.9. Result Qualitative and clinical assessment failed to detect residual block in 29.7% of patients in the neostigmine reversal cohort (adjusted odds ratio (aOR) 29.8, 95% confidence interval (CI): 2.7 to 5,559.5, p-value = 0.002). No residual block was detected in the sugammadex reversal cohort. A correlation between increasing patient weight and incidence of postoperative residual block was observed in the neostigmine cohort (aOR 1.05, 95% CI: 1.02 to 1.10, p-value = 0.002). Conclusion Qualitative and/or clinical assessment of neuromuscular block inadequately detects residual block following neostigmine antagonism.

Prognostic value of near-infrared spectroscopy regional oxygen saturation and cerebrovascular reactivity index in acute traumatic neural injury: a CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Cohort Study

BackgroundNear-infrared spectroscopy regional cerebral oxygen saturation (rSO2) has gained interest as a raw parameter and as a basis for measuring cerebrovascular reactivity (CVR) due to its noninvasive nature and high spatial resolution. However, the prognostic utility of these parameters has not yet been determined. This study aimed to identify threshold values of rSO2 and rSO2-based CVR at which outcomes worsened following traumatic brain injury (TBI).MethodsA retrospective multi-institutional cohort study was performed. The cohort included TBI patients treated in four adult intensive care units (ICU). The cerebral oxygen indices, COx (using rSO2 and cerebral perfusion pressure) as well as COx_a (using rSO2 and arterial blood pressure) were calculated for each patient. Grand mean thresholds along with exposure-based thresholds were determined utilizing sequential chi-squared analysis and univariate logistic regression, respectively.ResultsIn the cohort of 129 patients, there was no identifiable threshold for raw rSO2 at which outcomes were found to worsen. For both COx and COx_a, an optimal grand mean threshold value of 0.2 was identified for both survival and favorable outcomes, while percent time above − 0.05 was uniformly found to have the best discriminative value.ConclusionsIn this multi-institutional cohort study, raw rSO2was found to contain no significant prognostic information. However, rSO2-based indices of CVR, COx and COx_a, were found to have a uniform grand mean threshold of 0.2 and exposure-based threshold of − 0.05, above which clinical outcomes markedly worsened. This study lays the groundwork to transition to less invasive means of continuously measuring CVR.

Prognostic factors among patients with pathological Grade Group 5 prostate cancer based on robot-associated radical prostatectomy specimens from a large Japanese cohort (MSUG94).

There are no definitive prognostic factors for patients with pathological Grade Group 5 (pGG 5) prostate cancer (PCa) undergoing robot-associated radical prostatectomy (RARP). This study aimed to explore the prognostic factors among patients with pGG 5 PCa in a large Japanese cohort (MSUG94). This retrospective, multi-institutional cohort study was conducted between 2012 and 2021 at ten centers in Japan and included 3195 patients. Patients with clinically metastatic PCa (cN1 or cM1) and those receiving neoadjuvant and/or adjuvant therapy were excluded. Finally, 217 patients with pGG5 PCa were analyzed. The median follow-up period was 28.0months. The 3- and 5-year biochemical recurrence-free survival (BCRFS) rates of the overall population were 66.1% and 57.7%, respectively. The optimal threshold value (47.2%) for the percentage of positive cancer cores (PPCC) with any GG by systematic biopsy was chosen based on receiver operating characteristic curve analysis. Univariate analysis revealed that the prostate-specific antigen level at diagnosis, pT, pN, positive surgical margins (PSMs), lymphovascular invasion, and PPCC were independent prognostic factors for BCRFS. A multivariate analysis revealed that PSMs and PPCC were independent prognostic factors for BCRFS. Using these two predictors, we stratified BCRFS, metastasis-free survival (MFS), and castration-resistant PCa-free survival (CRPC-FS) among patients with pGG 5 PCa. The combination of PSMs and PPCC may be an important predictor of BCRFS, MFS, and CRPC-FS in patients with pGG 5 PCa undergoing RARP.

Oncologic safety of breast conserving surgery after neoadjuvant chemotherapy in patients with multiple ipsilateral breast cancer: A retrospective multi-institutional cohort study

IntroductionThe recent ACOSOG Z11102 trial demonstrated low recurrence rates with breast conserving surgery (BCS) in women with multiple ipsilateral breast cancers (MIBC). Questions remain regarding the oncologic safety of BCS in women with MIBC receiving neoadjuvant chemotherapy (NAC). MethodsWe conducted a retrospective cohort study of adult patients who underwent BCS following NAC for stage I-III breast cancer from 2012 to 2021 at two academic centers. Descriptive statistics were used to summarize the data and the Kaplan-Meier method was used to provide estimates for recurrence and survival outcomes. MIBC was defined as ≥2 foci of malignancy. ResultsA total of 544 patients were included; 29.4% (n = 160) ER+/HER2-, 17.7% (n = 96) ER+/HER2+, 18.2% (n = 99) ER-/HER2+, and 34.7% (n = 189) with ER-/HER2-disease. Overall, 80.5% (n = 438) had unifocal breast cancer while 19.5% (n = 106) had MIBC. Of patients with MIBC, 90.6% (n = 96) had multifocal and 9.4% (n = 10) had multicentric disease. Pathologic complete response was achieved in 41.1% of patients with MIBC versus 41.5% of patients with unifocal disease (p = 0.94). At a median follow-up of 55 months (IQR 32-83); 4.8% of patients in the unifocal group and 4.7% of patients in the MIBC group had had a local recurrence (p = 0.97). There was no difference in 5-year local recurrence-free survival (p = 0.92), recurrence-free survival (p = 0.06), or overall survival (p = 0.07) between the groups. ConclusionIn this large cohort of women undergoing BCS post-NAC, there was no significant difference in in breast tumor recurrence or survival outcomes between patients with unifocal disease and those with MIBC.

Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study

The objective of our study was to report real-world data on the safety and efficacy of standard-of-care teclistamab in patients with relapsed/refractory multiple myeloma (MM). This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of teclistamab up until August 2023. One hundred and ten patients were included, of whom, 86% had triple-class refractory disease, 76% penta-refractory disease, and 35% had prior exposure to B-cell maturation antigen (BCMA)-targeting therapies. The overall response rate (ORR) in our cohort was 62%, with a ≥ very good partial remission (VGPR) rate of 51%. The ORR in patients with and without prior BCMA-targeted therapies was 54% vs 67%, respectively (p = 0.23). At a median follow-up of 3.5 months (range, 0.39–10.92), the estimated 3 month and 6 month progression free survival (PFS) was 57% (95% CI, 48%, 68%) and 52% (95% CI, 42%, 64%) respectively. The incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) was 56% and 11% respectively, with grade ≥3 CRS and ICANS noted in 3.5% and 4.6% of patients respectively. 78 unique infections were diagnosed in 44 patients, with the incidence of all-grade and grade ≥3 infections being 40% vs 26% respectively. Primary prophylaxis with intravenous immunoglobulin (IVIG) was associated with a significantly lower infection risk on multivariate analysis (Hazard ratio [HR] 0.33; 95% CI 0.17, 0.64; p = 0.001).

Use of SGLT2 Inhibitors vs GLP-1 RAs and Anemia in Patients With Diabetes and CKD

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with lower anemia risk, based on findings from post hoc analyses of the CREDENCE and DAPA-CKD trials; however, the effectiveness of SGLT2 inhibitors in a more generalizable type 2 diabetes (T2D) and chronic kidney disease (CKD) population, with active comparisons pertinent to current practice, is unknown. To evaluate and compare anemia incidence between SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among patients with T2D and CKD stages 1 to 3. This retrospective cohort study used target trial emulation of an expanded CREDENCE and DAPA-CKD study framework. The study was conducted among adults with T2D and CKD initiating SGLT2 inhibitors or GLP-1 RAs between January 1, 2016, and December 31, 2021, with follow-up until December 31, 2022. The study was conducted at the Chang Gung Medical Foundation, the largest multi-institutional hospital system in Taiwan. Initiation of SGLT2 inhibitors or GLP-1 RAs. The primary outcome was a composite of anemia outcomes, including anemia event occurrence (hemoglobin level <12-13 g/dL or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes) or anemia treatment initiation. Changes in hematological parameters, including hemoglobin level, hematocrit level, and red blood cell count, were evaluated during the follow-up period for as long as 3 years. The cohort included a total of 13 799 patients with T2D and CKD, initiating SGLT2 inhibitors (12 331 patients; mean [SD] age, 62.4 [12.3] years; 7548 [61.2%] male) or GLP-1 RAs (1468 patients; mean [SD] age, 61.5 [13.3] years; 900 [61.3%] male). After the median follow-up period of 2.5 years, patients receiving SGLT2 inhibitors had lower incidence of composite anemia outcomes (hazard ratio [HR], 0.81; 95% CI, 0.73-0.90) compared with those receiving GLP-1 RAs. SGLT2 inhibitors were associated with a lower incidence of anemia events (HR, 0.79; 95% CI, 0.71-0.87) but not with a lower rate of anemia treatment initiation (HR, 0.99; 95% CI, 0.83-1.19). Changes in hematological parameters for SGLT2 inhibitors and GLP-1 RAs throughout the 3-year follow-up period supported the primary analyses. In this multi-institutional cohort study with target trial emulation, SGLT2 inhibitors were associated with a decreased risk of composite anemia outcomes, especially anemia event occurrences. SGLT2 inhibitors may be considered as an adjunct therapy to reduce anemia incidence in patients with T2D and CKD.

Induction immunochemotherapy followed by definitive chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a multi-institutional retrospective cohort study.

This study aimed to evaluate the efficacy and safety of induction immunochemotherapy followed by definitive chemoradiotherapy (CRT) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). We identified unresectable stage III NSCLC patients who received induction immunochemotherapy. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. From February 2019 to August 2022, 158 patients were enrolled. Following the completion of induction immunochemotherapy, the objective response rate (ORR) and disease control rate (DCR) were 52.5% and 83.5%, respectively. The ORR of CRT was 73.5%, representing 68.4% of the total cohort. The median PFS was 17.8 months, and the median OS was 41.9 months, significantly higher than in patients who received CRT alone (p<0.001). Patients with concurrent CRT demonstrated markedly improved PFS (p=0.012) and OS (p=0.017) than those undergoing sequential CRT. Additionally, those with a programmed-death ligand 1 (PD-L1) expression of 50% or higher showed significantly elevated ORRs (72.2%vs. 47.2%, p=0.011) and superior OS (median 44.8vs. 28.6 months, p=0.004) compared to patients with PD-L1 expression below 50%. Hematologic toxicities were the primary severe adverse events (grade ≥ 3) encountered, with no unforeseen treatment-related toxicities. Thus, induction immunochemotherapy followed by definitive CRT demonstrated encouraging efficacy and tolerable toxicities for unresectable LA-NSCLC.

Cancer type and histology influence cutaneous immunotherapy toxicities: a multi-institutional cohort study.

Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. This retrospective cohort study included patients recruited between 1 December 2011 and 30 October 2020. They received ICI from 2011 to 2020 with follow-up of outcomes through October 2021. We identified 3668 recipients of ICI therapy who were seen at Massachusetts General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. Compared with other nonepithelial cancers (neuroendocrine, leukaemia, lymphoma, myeloma, sarcoma and central nervous system malignancies), cutaneous squamous cell carcinoma [cSCC; hazard ratio (HR) 3.57, P < 0.001], melanoma (HR 2.09, P < 0.001), head and neck adenocarcinoma (HR 2.13, P = 0.009), genitourinary transitional cell carcinoma (HR 2.15, P < 0.001) and genitourinary adenocarcinoma (HR 1.53, P = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR 0.37, P < 0.001) and cSCC (HR 0.51, P = 0.011). The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICI therapies. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counselling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.

BMI and Cardiometabolic Traits in Japanese: A Mendelian Randomization Study.

Although many observational studies have demonstrated significant relationships between obesity and cardiometabolic traits, the causality of these relationships in East Asians remains to be elucidated. We conducted individual-level Mendelian randomization (MR) analyses targeting 14,083 participants in the Japan Multi-Institutional Collaborative Cohort Study and two-sample MR analyses using summary statistics based on genome-wide association study data from 173,430 Japanese. Using 83 body mass index (BMI)-related loci, genetic risk scores (GRS) for BMI were calculated, and the effects of BMI on cardiometabolic traits were examined for individual-level MR analyses using the two-stage least squares estimator method. The β-coefficients and standard errors for the per-allele association of each single-nucleotide polymorphism as well as all outcomes, or odds ratios with 95% confidence intervals were calculated in the two-sample MR analyses. In individual-level MR analyses, the GRS of BMI was not significantly associated with any cardiometabolic traits. In two-sample MR analyses, higher BMI was associated with increased risks of higher blood pressure, triglycerides, and uric acid, as well as lower high-density-lipoprotein cholesterol and eGFR. The associations of BMI with type 2 diabetes in two-sample MR analyses were inconsistent using different methods, including the directions. The results of this study suggest that, even among the Japanese, an East Asian population with low levels of obesity, higher BMI could be causally associated with the development of a variety of cardiometabolic traits. Causality in those associations should be clarified in future studies with larger populations, especially those of BMI with type 2 diabetes.

Integration of pretreatment tumor markers in a nomogram model for prognostic prediction of FIGO stage I endometrial cancer: A multi-institutional cohort study.

Traditionally, the prognosis of patients with FIGO stage I endometrial cancer is determined by clinicopathological risk factors. In this study, we assessed the potential contribution of pretreatment carcinoembryonic antigen (CEA) and carbohydrate antigen-125 (CA-125) levels to estimating the prognosis of these patients and aimed to develop and validate a prognostic nomogram. This retrospective study included patients with FIGO stage I endometrial cancer who underwent treatment between January 2009 and December 2021 in the four institutes of Chang Gung Memorial Hospital. To identify optimal cutoff values of CEA and CA-125 for predicting survival, receiver operating characteristic (ROC) curves were generated, the Kaplan-Meier method was used to estimate survival, and a Cox regression model was used to analyze the independent prognostic factors. Finally, a nomogram and calibration curve were constructed to predict patient survival probability. Of the 1559 patients evaluated, the optimal cutoff values of CEA and CA-125 were 1.44 ng/mL (area under the ROC curve [AUC] 0.601) and 39.77 U/mL (AUC 0.503), respectively. Multivariate Cox regression analysis showed that pretreatment CEA (hazard ratio [HR] 2.11, 95% confidence interval [95% CI] 1.35-3.28), CA-125 (HR 2.07, 95% CI 1.31-3.27), age >70 years (HR 12.54, 95% CI 5.05-31.11), myometrial invasion >50% (HR 1.69, 95% CI 1.03-2.73), non-endometrioid histology (HR 1.83, 95% CI 1.14-2.95), high-grade tumor (HR 2.41, 95% CI 1.46-3.97), and lymphovascular space invasion (HR 2.32, 95% CI 1.26-4.25) were significant variables associated with overall survival. These factors were used to construct the nomogram model, which showed good concordance and accuracy. Integration of pretreatment CEA and CA-125 in a prognostic nomogram is feasible. Our prediction model has the potential to assist clinicians in guiding appropriate clinical practice.

Timing of cutaneous immune-related adverse events impacts survival in patients with cancer treated with immune-checkpoint inhibitors: A multi-institutional cohort study

Timing of cutaneous immune-related adverse events impacts survival in patients with cancer treated with immune-checkpoint inhibitors: A multi-institutional cohort study

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

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. 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. 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. 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.

A prospective cohort study to identify clinical diagnostic and prognostic markers of primary immune thrombocytopenia in dogs.

Primary immune thrombocytopenia (pITP) in dogs presents a diagnostic challenge, and clinical markers of severity are lacking. Identify clinicopathologic features that differentiate pITP from secondary ITP (sITP) and markers related to bleeding severity, transfusion, and survival of dogs with pITP. Ninety-eight thrombocytopenic dogs (58 pITP and 40 sITP). Client-owned dogs with platelet counts <50 000/μL were enrolled in a prospective, multi-institution cohort study. History and treatment information, through a maximum of 7 days, was recorded on standard data forms. Bleeding severity was scored daily using a bleeding assessment tool (DOGiBAT). At-admission blood samples were collected for CBC, biochemistry, C-reactive protein concentration, and coagulation panels, and to measure platelet surface-associated immunoglobulin G (PSAIg) and expression of platelet membrane proteins and phospholipids. Dogs with evidence of coincident disease were classified as sITP. No definitive pITP diagnostic test was found. However, pITP cases were characterized by lower platelet counts, D dimer concentrations, and platelet membrane protein expression than sITP cases. Differentiation between pITP and sITP was further enhanced using logistic regression modeling combining patient sex, coagulation profile, platelet count, D dimer, and PSAIg. A second model of pITP severity indicated that low hematocrit and high BUN concentration were associated with non-survival. Low hematocrit at admission, but not platelet count or DOGiBAT score, was associated with transfusion. Pending validation studies, models constructed from at-admission clinicopathologic findings may improve differentiation of pITP from sITP and identify the most severe pITP cases at the time of presentation.