2016 Laboratory Investigation  
Central Nervous System (CNS) anomalies are common congenital anomalies. The aim of this study was to compare the consistency of CNS anomalies detected by second trimester prenatal ultrasound examination with the findings in fetal autopsies following the termination of pregnancy (TOP) in the second trimester. Design: In a 10-year long prospective study,325 second-trimester TOP was performed at a tertiary referral center, due to fetal malformation diagnosed by second trimesterultrasound
more » ... n. Fetal autopsy was conducted on all of these cases to compare ultrasound findings with fetal autopsy findings. Results: Following the TOP, 325 prenatally diagnosed malformed fetuses were analyzed. In addition to 113 cases already diagnosed with CNS malformations, fetal autopsy revealed 3 additional CNS malformation cases. For these 116 CNS malformation cases, the results are as below: The mean maternal age was 25 years (range 14-42). The mean gestational age at the time of termination was 20 weeks (range 14-28). CNS anomalies were isolated in 52 (45 %) of the 116 cases. Hydrocephaly (34%) and spina bifida and myelomeningocele with or without hydrocephaly (32%) were two most common CNS anomalies, followed by anencephaly (14%) and encephalocele (13%). Six cases were diagnosed corpus callosum agenesis. The other cases were holoprosencephaly (n=3), Dandy-Walker syndrome (n=2) cerebellar vermis agenesis (n= 2), lissencephaly (n=1). In 64 cases, the CNS anomalies were associated with other systems' anomalies: cardiovascular (n=20), musculoskeletal (n=19), gastrointestinal (n=12), urinary system (n=15) and fascial anomalies (n= 16). Seven cases with encephalocele had associated malformations including multicystic renal dysplasia and polydactly consistent with Meckel-Gruber syndrome. Fetal autopsy confirmed all prenatally diagnosed CNS anomalies. However, Dandy-Walker syndrome (n=3), cerebellar vermis agenesis (n= 2) and corpus callosum agenesis (n= 2) were not confirmed during fetal autopsy due to postmortem autolysis and dissection difficulties. Fetal autopsy revealed additional findings in other systems except CNS. Conclusions: Fetal autopsy including gross and histopathological examination of CNS is important to establish a definitive diagnosis. Gross examination may point toward syndromic diagnosis like Meckel-Gruber syndrome. This study confirms that developmental anomalies of the CNS ara frequent and that ultrasound diagnoses are in concordance with the autopsy diagnoses. Background: Over the last 1.5 years, we have developed a large comprehensive Rapid Research Autopsy Program at our Cancer Center. This study describes key components of the program, which allows us to ask novel questions in cancer research about molecular heterogeneity, treatment response, and escape mechanisms of tumors. The program puts pathology in the driver seat for the next generation of clinical trials. Design: So far, 105 patients have been enrolled and studied by directed rapid ("warm") research autopsies. We studied: Tumor kinetics by integrating radiographic imaging findings and tumor burden; (2) metastases to distant organs and unusual sites; (3) presentation and metastatic spread of rare/unusual neoplasms; (4) systemic adverse effects of new targeted therapies/immunotherapy. The samples from our program are typically investigated by large-scale genome sequencing, transcriptomics, proteomics, and as living biobanks (organoids, xenografts). Results: In our series of 105 autopsies, patient age ranged from 24 to 86 years (median, 65 years) with 57 males and 48 females; cancer types were 21 GI, 13 respiratory tract, 18 GU, 17 melanomas, 9 GYN, 8 breast, 5 heme, 2 sarcomas, and 3 ENT. A striking finding was the high incidence of cardiac metastases (23.3%) with only 2 of these cases detected by pre mortem imaging. Over 10,838 sample units were banked for research (median, 71 per autopsy): frozen tissue (3822), FFPE (3311), whole blood (689), plasma (2223), serum (188), and frozen buffy coat (605). Metastases to lung, liver and lymph nodes accounted for the top three harvested tumor samples. From 21 high value autopsies, we have been using fresh tissues (>200 samples) for live-cell immunology, xenografting (pancreas, prostate), organoids (pancreas), and ctDNA (melanoma). Stringent quality assurance steps are built in the program and the median tumor cellularity across all banked tumors was 83.2%. RIN scores showed that a high-quality RNA is obtained from tumor tissues even up to nine hours after death. Conclusions: Striking underestimation of tumor burden by radiologic imaging was noted in virtually all patients. The high quality well annotated samples are a research gold mine for clinical trials and treatment resistance/heterogeneity research. The next generation of personalized molecularly driven clinical trials will benefit enormously from our rapid autopsy program because it will provide a unique opportunity for complete characterization of the mechanisms determining treatment response or treatment failure in clinical trials with pathology playing the key role. Background: Novel immune checkpoint blockade with antibodies that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have shown promising results in melanoma. CTLA-4 and PD-1/PD-L1 blockade results in adverse events termed immune-related adverse (irAEs) that are poorly characterized at the histological level. The aim of this study was to comprehensively characterize irAEs. Design: 12 advanced melanoma patients (6 male; 6 female) treated with immune checkpoint blockade were studied. A comprehensive histopathological study was done to investigate systemic side effects of immunotherapy on heart, liver, kidney, endocrine organs (pituitary, thyroid, adrenals), and CNS. We correlated observed histological changes related to irAEs with lab results and radiological imaging. Results: Patient age ranged from 24 to 70 years (median, 59 years). The mean duration of treatment for CTLA-4 and PD-1 was 63 days and 41 days. The median time from start date of treatment with immune checkpoint blockade to death was 226 days and 191 days for CTLA-4 and PD-1/PD-L1, respectively. Features attributed to immune activation were found in the CNS, thyroid, adrenal, kidney and liver as follows: neurologic irAEs characterized by demyelination, focal perivascular lymphocytic infiltrates and presence of macrophages; endocrinopathic changes including destructive thyroiditis, variable degrees of involutional changes and focal interstitial lymphocytic infiltrate in the adrenal cortex. Granulomas from possible immune activation were found in the liver and kidney of one patient. Other findings included renal focal tubular microcalcification, tubular epithelial isometric vacuolation changes, and sinusoidal obstruction-like syndrome in the liver. None of our patients developed autoimmune hepatitis syndrome. Conclusions: Little is known about histological correlates of irAEs. Preliminary results of this study suggest that irAEs may result in novel histological findings that may give insight into immune checkpoint inhibitor effects and pathogenesis. With the continuing and expanded usage of immune checkpoint blockade in various tumors, understanding their effects will be crucial to minimizing the morbidity associated with these agents. We believe this report is valuable in defining the possible multisystemic nature of these adverse effects that require clinical monitoring in patients treated with these novel agents. Background: Oil Red O staining (ORO) is often used to confirm the diagnosis of pulmonary fat emboli (PFE), a rare but important complication of blunt trauma and orthopedic procedures. PFE may also be seen in the setting of cardiopulmonary resuscitation (CPR). The threshold of ORO staining at which PFE can be considered an immediate cause of death is not well-defined. One obstacle to better defining this threshold is the inherent subjectivity in assessing the extent of ORO staining. Digital imaging analysis of ORO allows an objective quantification of PFE. To validate this method, we quantified ORO staining in lung tissue of known PFE cases and various control cohorts.
doi:10.1038/labinvest.2016.1 pmid:26813163 fatcat:pguwhsxwgfhtlky75fypggugzy