Citations

INTRODUCTION: High-resolution manometry (HRM) and functional lumen imaging probe (FLIP) are primary and/or complementary diagnostic tools for the evaluation of esophageal motility. We aimed to assess the interrater agreement and accuracy of HRM and FLIP interpretations. METHODS: Esophageal motility specialists from multiple institutions completed the interpretation of 40 consecutive HRM and 40 FLIP studies. Interrater agreement was assessed using intraclass correlation coefficient (ICC) for continuous variables and Fleiss' κ statistics for nominal variables. Accuracies of rater interpretation were assessed using the consensus of 3 experienced raters as the reference standard. RESULTS: Fifteen raters completed the HRM and FLIP studies. An excellent interrater agreement was seen in supine median integral relaxation pressure (ICC 0.96, 95% confidence interval 0.95–0.98), and a good agreement was seen with the assessment of esophagogastric junction (EGJ) outflow, peristalsis, and assignment of a Chicago Classification version 4.0 diagnosis using HRM (κ = 0.71, 0.75, and 0.70, respectively). An excellent interrater agreement for EGJ distensibility index and maximum diameter (0.91 [0.90–0.94], 0.92 [0.89–0.95]) was seen, and a moderate-to-good agreement was seen in the assignment of EGJ opening classification, contractile response pattern, and motility classification (κ = 0.68, 0.56, and 0.59, respectively) on FLIP. Rater accuracy for Chicago Classification version 4.0 diagnosis on HRM was 82% (95% confidence interval 78%–84%) and for motility diagnosis on FLIP Panometry was 78% (95% confidence interval 72%–81%). DISCUSSION: Our study demonstrates high levels of interrater agreement and accuracy in the interpretation of HRM and FLIP metrics and moderate-to-high levels for motility classification in FLIP, supporting the use of these approaches for primary or complementary evaluation of esophageal motility disorders.

Background: Patellar instability has the highest incidence in adolescents aged between 14 and 18 years. The unique relationship between the medial patellofemoral ligament (MPFL) and the distal femoral physis in skeletally immature patients warrants precisely positioned MPFL graft insertion. A paucity of data are available evaluating the results of MPFL reconstruction using allograft tendon before skeletal maturity. Purposes: (1) To assess the results of MPFL reconstruction using allograft tendon in skeletally immature patients by analyzing redislocation and reoperation rates, radiological outcomes, and patient-reported outcomes and (2) to determine whether epidemiological, intraoperative, or radiographic factors influence recurrent instability and clinical outcomes. Study Design: Case series; Level of evidence, 4. Methods: Prospectively collected data were retrospectively analyzed for 69 skeletally immature patients who experienced a first-time or recurrent lateral patellar dislocation and were treated with anatomic MPFL reconstruction. Inclusion criteria were MPFL reconstruction using allograft and the availability of preoperative magnetic resonance imaging scans in the presence of open or partially open physes. Patients with <2 years of follow-up and patients with previous surgeries on the same knee were excluded from the study. Preoperative radiographic imaging was reviewed and analyzed. Trochlear dysplasia, tibial tubercle–trochlear groove distance, and patellar height were evaluated. Descriptive data, concomitant injuries, surgical procedure details, complications, and postoperative history were assessed via review of medical records and patient charts. Validated patient-reported and surgeon-measured outcomes were collected pre- and postoperatively, including Kujala score, Lysholm score, and Tegner activity score. Return-to-sports rate was assessed. The influence of epidemiological, intraoperative, and radiographic parameters on the redislocation rates and clinical outcomes was assessed using a multiple linear regression model. Results: A total of 79 physeal-sparing MPFL reconstructions (69 patients) met the inclusion criteria. The mean age of the patient cohort was 14.7 ± 1.8 years (range, 8.5-16.9 years). Within the mean follow-up time of 37.9 ± 12.1 months (range, 24-85 months after surgery, there were 12 patients with clinical failures resulting in reoperation. Eleven patients experienced a redislocation of the patella, and 1 patient sustained a transverse noncontact patellar fracture 6 months after index surgery that required operative fixation. No injuries to the distal femoral physes were clinically observed. At the final follow-up, patients had a mean Lysholm score (1-100) of 96.5 ± 6.7, a mean Kujala score (1-100) of 96.5 ± 7.4, and a mean Tegner Activity Scale score (1-10) of 4.9 ± 1.3. Patellar height and trochlear dysplasia did not influence redislocation or clinical scores. In total, 57 of the 63 patients (90.5%) who were engaged in sports before injury returned to the same or higher level of competition. In a subgroup analysis of patients who underwent isolated MPFL reconstruction (n = 44) without concomitant procedures, 9 patients (20.5%) experienced failure and had a redislocation. A univariate analysis of hazards for failure based on patient-specific variables was carried out. A body mass index ≥30 conveyed a hazard ratio of 2.51 (95% CI, 0.63-10.1; P = .19), and the tibial tubercle-trochlear groove distance by increments of 1 mm was associated with a hazard ratio of 2.02 (95% CI, 0.51-8.11; P = .32). Conclusion: Physeal-sparing anatomic reconstruction of the MPFL using an allograft tendon in skeletally immature patients was a safe and effective treatment for patellar instability, regardless of patellar height and trochlear dysplasia. Failure rates decreased when the MPFL reconstruction was performed concomitantly with a tibial tubercle osteotomy.

Background: Osteochondritis dissecans (OCD) is a disorder originating in the subchondral bone, leading to focal lesions with risk of fragmentation and secondary damage of the articular cartilage. It remains controversial if surgical treatment of such lesions is equally successful in skeletally immature and mature patients. Purpose: To determine (1) the long-term clinical success rate after internal fixation of unstable OCD in skeletally immature and mature patients based on physeal status, (2) if patient-specific and procedural variables influence the risk of failure, and (3) patient-reported outcome measures over time. Study Design: Cohort study; Level of evidence, 3. Methods: A multicenter retrospective cohort study was conducted investigating skeletally immature and mature patients treated for unstable OCD lesions of the knee between 2000 and 2015. The healing rate was assessed by radiological imaging and clinical follow-up. Failure was defined as any definitive reoperation for the initially treated OCD lesion. Results: A total of 81 patients met inclusion criteria, including 25 skeletally immature patients and 56 patients with closed physes at the time of surgery. After a mean follow-up time of 11.3 ± 4 years, 58 (71.6%) patients had healed lesions, whereas the lesions failed to heal in 23 (28.4%) patients. No significant difference in risk of failure was observed based on physeal maturation status (hazard ratio, 0.78; 95% CI, 0.33-1.84; P = .56). Lateral versus medial condylar lesion location conferred an increased risk of failure ( P < .05) for both skeletally immature and mature patients. Multivariate analysis of skeletal maturity status showed that a lateral femoral condylar location was an independent risk factor for failure (hazard ratio, 0.22; 95% CI, 0.1-0.5; P < .05). The mean patient-reported outcome scores (International Knee Documentation Committee [IKDC] score and Knee injury and Osteoarthritis Outcome Score [KOOS]) increased significantly after surgery and remained high at the final follow-up ( P < .05). The final scores (mean ± SD) at a mean follow-up of 135.8 months (range, 80-249 months) were IKDC, 86.6 ± 16.7; KOOS Pain, 88.7 ± 18.1; KOOS Symptoms, 89.3 ± 12.6; KOOS Activities of Daily Living, 89.3 ± 21.6; KOOS Sport and Recreation, 79.8 ± 26.3; and KOOS Quality of Life, 76.7 ± 26.3. Conclusion: The long-term results after internal fixation of OCD fragments show high rates of healing and sustainable subjective improvement of knee function and quality of life. A healing rate of 72% was noted at a mean follow-up of 11.3 years. The stage of skeletal maturity had no significant influence on the rate of failure. Lateral femoral condylar lesion location is an independent risk factor for failure in skeletally mature and immature patients.

Abstract The CD8 + T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1 + TCF1 + stem-like CD8 + T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS’s impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8 + T cells at 3 days. However, CD8 + T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1 + stem-like population.

Abstract Background The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. Methods We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. Results We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Conclusions Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Introduction: Hypothalamic amenorrhea (HA) is a neuroendocrine disorder characterized by ovulatory dysfunction, anovulation, and infertility, which can be prolonged for months to years. Menstrual cycle irregularity and amenorrhea identify individuals with higher CVD risk, but existing evidence has not examined HA separately from polycystic ovary syndrome (PCOS). It remains unknown whether HA is associated with CVD events across the lifecourse. Hypothesis: We hypothesized that the HA phenotype (oligo/amenorrhea without PCOS traits) would identify individuals at increased risk for CVD. Methods: Nurses’ Health Study II participants with available information on menstrual cycle characteristics who were premenopausal and free of CVD at baseline comprised the analytic sample (n=83,281). Menstrual cycle regularity was retrospectively reported for ages 18-22y on the baseline questionnaire in 1989 while the 1993 biennial questionnaire captured current menstrual cycle regularity (at ages 29-49y); PCOS traits (severe acne, hirsutism) were additionally ascertained in 1993. Participants were followed for confirmed incident CVD (MI, stroke, and fatal CHD) from 1993 through 2017. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the relationship between HA and CVD, adjusted for age, race/ethnicity, parental education, parental history of CVD <60y, and behavioral risk factors (smoking, physical activity, diet, alcohol intake, body mass index). Results: Thirteen percent of participants (n=11,071) ever had HA: 8.5% of participants (n=7,081) had HA at ages 18-22y while 6.5% (n=5,428) had HA at ages 29-46y. Persistent HA (HA at both 18-22y and 29-46 y) was identified in 1.7% of participants (n=1,438). CVD events occurred in 253 individuals who ever had HA (HA at either 18-22y or 29-46y) and 1,228 individuals without the HA phenotype. Individuals who ever had HA had a 20% higher rate of CVD (CI: 1.05-1.38). HA phenotype at ages 18-22y was not associated with CVD risk (HR=1.14; CI: 0.96-1.35) while HA phenotype at ages 29-46y was associated with a 30% higher rate of CVD (CI: 1.10-1.54) compared to individuals without HA phenotype. Individuals with persistent HA across both age ranges had a 69% higher rate of CVD (CI: 1.24-2.28). Underlying associations were strongest between ever HA and stroke (HR=1.25; CI: 1.03-1.51) and between persistent HA and CHD (HR=1.90; CI: 1.27-2.86), although case counts were small. Conclusions: HA phenotype in mid-adulthood identified individuals at increased risk of CVD compared to those without HA. As there are multiple HA subtypes, defined by varying combinations of psychosocial stress, anxiety, physical activity and weight loss, future studies should examine which HA subtypes are associated with CVD risk.

Abstract Background Breast cancers in women with a germline BRCA1/2 mutation (gBRCAm) have homologous recombination deficiency (HRD) and are sensitive to therapies causing double-strand DNA breaks. In TBCRC 031 (INFORM), both neoadjuvant cisplatin and doxorubicin/cyclophosphamide (“AC”) in gBRCAm carriers resulted in a complete pathologic response in 18% and 26% respectively in patients with newly diagnosed HER2–negative breast cancer. Herein, we describe molecular features from tumor whole exome (WES) and transcriptome sequencing (RNAseq) associated with response. Methods TBCRC 031 (the INFORM Trial - NCT01670500) was a randomized phase II neoadjuvant trial comparing the efficacy of cisplatin versus AC in gBRCAm carriers with stage I-III HER2–negative breast cancer. Of 118 patients enrolled, 92 patients provided fresh frozen research biopsies, collected prior to chemotherapy initiation, which were subjected to WES and RNAseq. Variants were called using GATK best practices and intratumoral heterogeneity was inferred from mutations and variant allele frequencies using Mutant Allele Tumor Heterogeneity (MATH) scores. Mutational Signature 3 (Sig3) and Genomic Instability Score (GIS) were calculated with SigMA and scarHRD, respectively. RNAseq data were utilized to perform differential gene expression and functional analyses, while cellular deconvolution was performed with CIBERSORTx trained against breast cancer single cell data. Patients were grouped according to their residual cancer burden (RCB) as responders (RCB-0 or 1), or non-responders (RCB-2 or 3). P-values ≤ 0.05 were considered statistically significant and when appropriate, adjustment for multiple testing was performed using a false discovery rate ≤ 5%. Results Of the 92 patients with gBRCAm, 59 (64%) had triple-negative and 33 (36%) were hormone-receptor positive HER2-negative breast cancer, 40 (43%) were classified as responders and 52 (57%) as non-responders. WES analysis revealed that indices of HRD were high (Sig3 exposure predominant and GIS ≥ 42) across most samples irrespective of receptor status and not significantly different among responders and non-responders. In contrast, responders exhibited lower levels of intratumor heterogeneity than non-responders (median MATH 42.9 vs. 33.5, p = 0.01). 223 genes were differentially expressed between responders and non-responders following control for tumor hormone receptor status, BRCA1/2 mutation, and menopausal status. Pathways identified as significantly enriched in upregulated genes were indicative of intrinsic immune activation in responders (e.g., T-cell activation, immune response-signaling, and regulation of leukocyte activation). Cellular deconvolution of the tumor microenvironment confirmed that responders presented a higher proportion of T-cells (p = 0.025) and myeloid cells (p = 0.003) in the tumor samples, while perivascular-like cells were enriched in non-responders (p = 0.034). Conclusion In this analysis of the largest cohort of treatment-naïve gBRCAm breast cancer to date, we found that response to cytotoxic chemotherapy is associated with a transcriptional program of intrinsic immune activation and an increased population of intratumoral T-cells and myeloid cells. Lower levels of intratumor heterogeneity and higher immune activation were associated with response to chemotherapy gBRCAm carriers while HRD scores were not. Citation Format: Felipe Batalini, Doga C. Gulhan, Xanthi Lida Katopodi, Nikolas Kalavros, Antuan Tran, Dimitra Karagkouni, Emily Stern-Gatof, Stuart Schnitt, Judy E. Garber, Gerburg M. Wulf, Peter J. Park, Ioannis Vlachos, Nadine Tung. Intratumor heterogeneity and intrinsic immune activation are associated with response to chemotherapy in BRCA-related breast cancers [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 P5-12-03.

Abstract Through its classic ATP‐dependent ion‐pumping function, basolateral Na/K‐ATPase (NKA) generates the Na + gradient that drives apical Na + reabsorption in the renal proximal tubule (RPT), primarily through the Na + /H + exchanger (NHE3). Accordingly, activation of NKA‐mediated ion transport decreases natriuresis through activation of basolateral (NKA) and apical (NHE3) Na + reabsorption. In contrast, activation of the more recently discovered NKA signaling function triggers cellular redistribution of RPT NKA and NHE3 and decreases Na + reabsorption. We used gene targeting to test the respective contributions of NKA signaling and ion pumping to the overall regulation of RPT Na + reabsorption. Knockdown of RPT NKA in cells and mice increased membrane NHE3 and Na + /HCO 3 − cotransporter (NBCe1A). Urine output and absolute Na + excretion decreased by 65%, driven by increased RPT Na + reabsorption (as indicated by decreased lithium clearance and unchanged glomerular filtration rate), and accompanied by elevated blood pressure. This hyper reabsorptive phenotype was rescued upon crossing with RPT NHE3 −/− mice, confirming the importance of NKA/NHE3 coupling. Hence, NKA signaling exerts a tonic inhibition on Na + reabsorption by regulating key apical and basolateral Na + transporters. This action, lifted upon NKA genetic suppression, tonically counteracts NKA's ATP‐driven function of basolateral Na + reabsorption. Strikingly, NKA signaling is not only physiologically relevant but it also appears to be functionally dominant over NKA ion pumping in the control of RPT reabsorption.