Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.

Although genome-wide association studies (GWAS) have successfully linked genetic risk loci to various disorders, identifying underlying cellular biological mechanisms remains challenging due to the complex nature of common diseases. We established a framework using human peripheral blood cells, physical, chemical and pharmacological perturbations, and flow cytometry-based functional readouts to reveal latent cellular processes and performed GWAS based on these evoked traits in up to 2,600 individuals. We identified 119 genomic loci implicating 96 genes associated with these cellular responses and discovered associations between evoked blood phenotypes and subsets of common diseases. We found a population of pro-inflammatory anti-apoptotic neutrophils prevalent in individuals with specific subsets of cardiometabolic disease. Multigenic models based on this trait predicted the risk of developing chronic kidney disease in type 2 diabetes patients. By expanding the phenotypic space for human genetic studies, we could identify variants associated with large effect response differences, stratify patients and efficiently characterize the underlying biology.

Fourteen years of pancreatic surgery for malignancy among ACS-NSQIP centers: Trends in major morbidity and mortality.

BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program was established to help participating hospitals track and report surgical complications with the goal of improving surgical care. We sought to determine whether this has led to improvements in surgical outcomes for pancreatic malignancies. METHODS: Patients with pancreatic malignancies who underwent surgical resection were identified from the American College of Surgeons National Surgical Quality Improvement Program database (2006-2019). Thirty-day postoperative major morbidity and mortality were analyzed by year. Major morbidity included organ and deep surgical site infection, venous thromboembolism, cardiac event, pneumonia, acute renal failure, sepsis, and respiratory failure. RESULTS: Of the 28,888 patients identified, 51% were male, the median age was 68, 74.3% underwent a pancreaticoduodenectomy, and 25.7% underwent a distal pancreatectomy. Among patients who underwent a pancreaticoduodenectomy, there was a significant increase in major morbidity (annual percent change 0.77, P = .012) driven by increases in organ space surgical site infection (annual percent change 3.52, P < .001) and venous thromboembolism (annual percent change 4.72, P = .005). However, there was a decrease in postoperative mortality (annual percent change -4.58, P = .001). For distal pancreatectomy patients, there was no change in rates of overall major morbidity (annual percent change -1.35, P = .08) or mortality (annual percent change -3.21, P = .25). CONCLUSION: Although major morbidity and mortality have not significantly changed for distal pancreatectomy patients, mortality has steadily decreased for patients undergoing pancreaticoduodenectomy, despite an increase in major morbidity. Whether this trend reflects a change in patient selection, an increase in detection of postoperative morbidities and/or an improvement in mitigation of these morbidities warrants further study.

Prognostic Significance of Primary Tumor-Infiltrating Lymphocytes in a Contemporary Melanoma Cohort.

BACKGROUND: The prognostic impact of tumor-infiltrating lymphocytes (TILs) on outcomes and treatment efficacy for patients with melanoma in the contemporary era remains poorly characterized. METHODS: Consecutive patients who underwent wide excision and sentinel lymph node biopsy for cutaneous melanoma 1 mm thick or thicker at a single institution were identified (2006-2019). The patients were stratified based on primary tumor TIL status as brisk (bTILs), non-brisk (nbTILs), or absent (aTILs). Associations between patient factors and outcomes were analyzed using multivariable analysis. RESULTS: Of the 1017 patients evaluated, 846 (83.2 %) had primary TILs [nbTILs (n = 759, 89.7 %) and bTILs (n = 87, 10.3 %)]. In the multivariable analysis, the patients with any type of TILs had higher rates of regression [odds ratio (OR), 1.86; p = 0.016], lower rates of acral lentiginous histology (OR, 0.22; p < 0.001), and lower rates of SLN positivity (OR, 0.64; p = 0.042) than those without TILs. The multivariable analysis found no association between disease-specific survival and bTILs [hazard ratio (HR), 1.04; p = 0.927] or nbTILs (HR, 0.89; p = 0.683). An association was found between bTILs and recurrence-free survival (RFS) advantage [bTILs (HR 0.46; p = 0.047), nbTILs (HR 0.71; p = 0.088)], with 5-year RFS rates of 84 % for bTILs, 71.8 % for nbTILs, and 68.4 % for aTILs (p = 0.044). For the 114 immune checkpoint blockade (ICB)-naïve patients who experienced a recurrence treated with ICB therapy, no association was observed between progression-free survival and bTILs (HR, 0.64; p = 0.482) or nbTILs (HR, 0.58; p = 0.176). CONCLUSIONS: The prognostic significance of primary TILs in the contemporary melanoma era appears complex. Further studies characterizing the phenotype of TILs and their association with regional metastasis and responsiveness to ICB therapy are warranted.

Massive macronodular juvenile xanthogranuloma of the eyelid in a newborn.

A newborn baby with a lump on his right upper eyelid that was unresponsive to warm compresses and oral antibiotics presented at 3 weeks of age with a yellow mass measuring 20 mm in diameter at the base. Preliminary diagnosis was benign choristomatous mass; and warm compresses were continued. The mass continued to enlarge and 5 weeks later was 35 mm, with a tight, atrophic overlying epidermis and greater pupillary occlusion. Concern for possible malignancy prompted surgical resection and reconstruction with a supraclavicular graft. Histopathology disclosed that the eyelid tissue was nearly completely replaced by a highly cellular histiocytic neoplasm with prominent eosinophilic, often foamy cytoplasm, and nuclear pleomorphism. Poorly formed Touton giant cells were found. The mass showed positive immunoreactivity, with histiocytic markers CD163 and factor XIII, and was negative for cytokeratin markers, smooth muscle actin, and desmin. These features were compatible with JXG.