Therapeutic antibodies targeting the programmed cell death protein 1 (PD-1) pathway function as immune checkpoint inhibitors, allowing the immune system to recognize tumors which otherwise escape immune surveillance. However, these agents can also elicit an autoimmune response by inhibiting the ability of non-neoplastic tissues and regulatory cells to suppress the immune system. Here we present a fatal case of active myocarditis in a 55-year-old man with non-small-cell lung cancer which occurred following monotherapy with the PD-1 inhibitor nivolumab (Opdivo). He presented with acute right-sided heart failure and died 1 day after admission. Postmortem examination revealed multiple gelatinous lesions in the myocardium of the interventricular septum and the bilateral atria and ventricles which had microscopic features diagnostic of myocarditis. Subsequent studies failed to identify an infectious cause. Immune checkpoint inhibitors are an increasingly common addition to anticancer regimens and they should be considered in the evaluation of acute myocarditis.

Objective To look for previously unrecognized cardiac structural abnormalities and address the genetic cause for sudden unexplained nocturnal death syndrome (SUNDS). Methods and Results 148 SUNDS victims and 444 controls (matched 1:3 on gender, race, and age of death within 1 year) were collected from Sun Yat-sen University from January 1, 1998 to December 31, 2014 to search morphological changes. Additional 17 Brugada syndrome (BrS) patients collected from January 1, 2006 to December 31, 2014 served as a comparative disease cohort. The Target Captured Next Generation sequencing for 80 genes associated with arrhythmia/cardiomyopathy were performed in 44 SUNDS victims and 17 BrS patients to characterize the molecular spectrum. SUNDS had slight but statistically significantly increased heart weight and valve circumference compared to controls. 12/44 SUNDS victims (SCN5A, SCN1B, CACNB2, CACNA1C, AKAP9, KCNQ1, KCNH2, KCNJ5, GATA4, NUP155, ABCC9) and 6/17 BrS patients (SCN5A, CACNA1C, P>.05) carried rare variants in primary arrhythmia-susceptibility genes. Only 2/44 SUNDS cases compared to 5/17 BrS patients hosted a rare variant in the most common BrS causing gene, SCN5A (P=.01). Using the strict American College of Medical Genetics guideline-based definition, only 2/44 (KCNQ1) SUNDS and 3/17 (SCN5A) BrS patients hosted a “(likely) pathogenic” variant. The 14/44 SUNDS cases with cardiomyopathy-related variants had a subtle but significantly decreased circumference of cardiac valves, and tended to die on average 5–6 years younger compared to the remaining 30 cases (P=.02). Conclusions We present the first comprehensive autopsy evidence that SUNDS victims may have concealed cardiac morphological changes. SUNDS and BrS may result from different molecular pathological underpinnings. The distinct association between cardiomyopathy-related rare variants and SUNDS warrants further investigation.

Human omphalocele is a congenital defect of the abdominal wall in which the secondary abdominal wall structures (muscle and connective tissue) in an area centered around the umbilicus are replaced by a translucent membranous layer of tissue. Histological examination of omphalocele development and moreover the staging of normal human abdominal wall development has never been described. We hypothesized that omphalocele is the result of an arrest in the secondary abdominal wall development and predicted that we would observe delays in myoblast maturation and an arrest in secondary abdominal wall development. To look for evidence in support of our hypothesis, we performed a histological analysis of normal human abdominal wall development and compared this to mouse. We also conducted the first histological analysis of two human specimens with omphalocele. In these two omphalocele specimens, secondary abdominal wall development appears to have undergone an arrest around Carnegie Stage 19. In both specimens disruptions in the unidirectional orientation of myofibers were observed in the external and internal obliques, and rectus abdominis but not in the transversus abdominis. These latter findings support a model of normal abdominal wall development in which positional information instructs the orientation of myoblasts as they organize into individual muscle groups.

Background/Purpose We observed that fibroblast growth factor receptors 1 and 2 (Fgfr1, Fgfr2) are expressed during abdominal wall development in mice and hypothesized that conditional mutation of these genes would result in abdomial wall defects. Methods Section in situ hybridizations were performed for Fgfr1 and Fgfr2 on wild-type embryos at embryonic day (E) 11.5 and E13.5. Conditional mutation of Fgfr1 and Fgfr2 was achieved with a tamoxifen inducible Cre at E8.5. Litters were harvested at E17.5, whole mount photographs were taken, and paraffin sections were generated and stained with hematoxylin and eosin. Results Fgfr1 was expressed in ectoderm, lateral plate mesoderm, and myoblasts, whereas Fgfr2 was expressed almost exclusively in the early dermis and ectoderm of the abdominal wall. Conditional mutation of both Fgfr2 alleles and one Fgfr1 allele resulted in omphalocele in 38.7% of mutants. Histologic examination in mutants demonstrated disruptions in dermal and muscle development. Conclusions Mutant embryos with omphalocele arising from mutation in Fgfr1 and Fgfr2 exhibit disruptions in the development of the secondary abdominal wall structures. These findings are consistent with a model of ventral abdominal wall development in which organization of the muscles and connective tissue (secondary abdominal wall structures) is influenced by positional information emanating from the primary abdominal wall.

Methadone continues to be a widely used maintenance therapy for opiate dependence. However, methadone-related deaths have been reported frequently for over 4 decades now. Anoxic brain injury with pulmonary edema secondary to respiratory depression is the recognized mechanism of methadone death, although pathological intracranial findings are rarely described in methadone deaths. A selective area of brain injury has never been reported with methadone use. We present a case of a 23-year-old man who had acute necrosis of the bilateral globi pallidi in the brain and systemic rhabdomyolysis after ingesting methadone and nasally insufflating alprazolam. We also present a review of the literature on deaths following opioid use and associated brain injury.