Expression of high molecular weight cytokeratin-A novel feature of aggressive and innate hormone-refractory prostatic adenocarcinoma.

BACKGROUND: Castration-resistance is common in advanced prostatic adenocarcinomas (PACs) treated with androgen deprivation therapy (ADT) and usually occurs after 2 years following treatment. A minority of PACs confer innate ADT resistance without prior hormonal treatment. The expression of HMWCK in PAC cells has not been studied. This study aimed to investigate the clinicopathologic and genomic features of HMWCK-expressing PACs and the relationship to ADT resistance. METHODS: A total of 469 PACs were studied for HMWCK expression (39 postradiotherapy, 57 post-ADT, 373 treatment-naïve PACs). Clinicopathologic correlations of the HMWCK expression with tumor grade groups, specific tumor morphologies, tumor stages and disease recurrence/persistence/progression were performed. Five HMWCK+ PACs were also sequenced for genetic alterations. RESULTS: Thirty one of the 469 cases (6.6%) showed variable HMWCK+ PAC. The HMWCK+ PAC often focally presented in the tumor and vast majority were associated with high Gleason scores and unfavorable growth patterns (cribriform, comedo-necrosis, and intraductal carcinoma) as well as high tumor stages. A small percentage of the HMWCK+ PCA (2/31, 6.5%) presented with frank squamous histomorphology. Vast majority (22/31, 87%) had no history of prior ADT. The HMWCK+ PAC all displayed diminished to lost expression of AR/NKX3.1. Most of the cases progressed within 12 months of ADT or disease persisted despite ADT. Of the 5 HMWCK+ PACs subjected to gene sequencing, 4 presented with PTEN/PI3K/MAPK pathway alterations. CONCLUSION: The study demonstrated HMWCK+ PAC to be a novel type of innate ADT-resistant PAC. Overexpression of HMWCK in PAC can be potentially used as a surrogate biomarker for aggressive and innate hormone-refractory PACs. The genetic alterations imply potential therapeutic implications of PI3K/MAPK inhibitors in the treatment of these deadly diseases.

Clinicopathologic Features of IDEDNIK (MEDNIK) Syndrome in a Term Infant: Histopathologic Features of the Gastrointestinal Tract and Report of a Novel AP1S1 Variant.

Inherited syndromes of congenital enteropathy are rare, with many genetic causes described. Mutations of the AP1S1 gene results in the syndrome of intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (IDEDNIK, formerly in the medical literature as MEDNIK). The clinicopathologic features of the enteropathy in IDEDNIK syndrome have not been fully explored. We describe a female infant who presented with metabolic acidosis, lethargy, and 14 watery stools per day. In the intensive care unit she required parenteral nutrition. She was found to have a novel homozygous pathogenic variant in the AP1S1 gene c.186T>G (p.Y62*). Esophagogastroduodenoscopy and colonoscopy at 6 months of age were grossly normal. However, histologic sections of the duodenum showed mild villous blunting and enterocytes with cytoplasmic vacuoles. CD10 immunostaining highlighted the disrupted brush border. MOC31 immunostaining was wild-type with a membranous pattern of expression. Electron microscopy of the duodenum showed scattered enterocytes cells with shortened and disrupted apical microvilli. Although there is a mixed gap diarrhea and disrupted brush border, there are no significant inclusions typical of microvillus inclusion disease, nor tufted enterocytes typical of tufting enteropathy, making the clinical and histopathologic features for this syndrome unique.

The Major Histocompatibility Complex Class II-CD4 Immunologic Synapse in Alcoholic Hepatitis and Autoimmune Liver Pathology: The Role of Aberrant Major Histocompatibility Complex Class II in Hepatocytes.

The major histocompatibility complex class II (MHC II)-CD4 immunologic synapse is classically described between the T-cell receptor of CD4-positive lymphocytes and MHC II on antigen-presenting cells. This interaction and others between surrounding costimulatory and checkpoint molecules promote differentiation of naïve CD4 T lymphocytes into helper T cells subtypes, including types 1, 2, and 17 helper T cells, that have more tailored immunologic responses. Although MHC II is mainly produced by professional antigen-presenting cells, it can be aberrantly produced by other cell types, including hepatocytes in various liver pathologies, such as autoimmune hepatitis and alcoholic hepatitis. This can lead to direct targeting of hepatocytes by CD4-positive lymphocytes, which form an immunologic synapse with the hepatocyte. The lymphocytes internalize the MHC II-CD4 complexes in a phagocytosis-like mechanism and in the process eat the hepatocyte piece by piece. We review the evidence for this mechanism and the role of these autoimmune responses in various liver diseases, including alcoholic hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. The role of aberrant MHC II in malignancy, including hepatocellular carcinoma, is also reviewed. Further understanding of this mechanism can lead to better understanding of the immune mechanisms involved in these liver pathologies, with potential diagnostic and therapeutic applications.

Piecemeal necrosis is due to the immunologic synapse formation and internalization of intact TCR-MHC II complexes by CD4 T cells.

The nature of the immunologic synapse in autoimmune hepatitis is defined. This process involves the T cell receptor (TCR) which binds to the hepatocyte antigen presenting major histocompatibility complex (MHC) on the plasma membrane. This complex is quickly removed from the liver cell and taken into the T cell cytoplasm to be digested by the lysosome. The liver cell is gradually diminished to the point of its total removal by the lymphocytes binding to it.

Histological Changes in the Rat Femoral Artery Following the Use of the Empty-and-Refill Test.

BACKGROUND: This study examines the effects of the empty-and-refill patency test on rat femoral arteries in the longer postoperative time period. METHODS: A simple arterial anastomosis was performed bilaterally on 20 rats. The empty-and-refill test was performed unilaterally in all rats, leaving the contralateral artery as an internal control. Rats were divided into two cohorts of 10 rats and survived for 48 hours and 2 weeks. Vessel patency was assessed prior to closing and immediately prior to sacrifice. The femoral arteries were harvested bilaterally and hematoxylin and eosin stains were performed. The femoral artery distal to the anastomosis in the region of the empty-and-refill test was histologically evaluated. RESULTS: All vessels were patent at the time of sacrifice. There was no statistical difference in the numeric scoring between the experimental and control vessels in the 48-hour cohort. Almost all vessels harvested at 48 hours showed endothelial cell loss distal to the anastomosis regardless of whether they underwent the empty-and-refill test. The only statistically significant difference in the 2-week cohort was an increase in adventitial smooth muscle proliferation in the experimental group. There were no other statistically significant results between the experimental and control groups at 2 weeks. An overall comparison of both cohorts revealed a statistically significant increase in endothelial cell number and intimal proliferation by 2 weeks postsurgery. CONCLUSION: The empty-and-refill test does not compromise rat femoral artery anastomotic patency, nor does it produce histological damage either 48 hours or 2 weeks postsurgery.

Hepatocellular carcinoma with neuroendocrine differentiation: a case report.

Hepatocellular carcinoma with neuroendocrine differentiation, where tumor cells stain for both hepatocellular and neuroendocrine markers, is extremely rare. We report a case of a 65-year-old man who presented with a 14-cm rapidly growing mass in the right lobe of his liver with local extension into the gallbladder and portal vein. Serum AFP was 4625ng/mL. Liver biopsy showed a poorly differentiated neoplasm with cells showing nuclear pleomorphism, high nuclear/cytoplasmic ratio, and numerous mitoses. The tumor cells stain for AFP, glutamine synthase, arginase, and glypican-3. The same tumor regions also stain positively for synaptophysin, chromogranin, and CD56. Given this histological pattern, this tumor was ultimately diagnosed as hepatocellular carcinoma with neuroendocrine differentiation.

Host-species transferrin receptor 1 orthologs are cellular receptors for nonpathogenic new world clade B arenaviruses.

The ability of a New World (NW) clade B arenavirus to enter cells using human transferrin receptor 1 (TfR1) strictly correlates with its ability to cause hemorrhagic fever. Amapari (AMAV) and Tacaribe (TCRV), two nonpathogenic NW clade B arenaviruses that do not use human TfR1, are closely related to the NW arenaviruses that cause hemorrhagic fevers. Here we show that pseudotyped viruses bearing the surface glycoprotein (GP) of AMAV or TCRV can infect cells using the TfR1 orthologs of several mammalian species, including those of their respective natural hosts, the small rodent Neacomys spinosus and the fruit bat Artibeus jamaicensis. Mutation of one residue in human TfR1 makes it a functional receptor for TCRV, and mutation of four residues makes it a functional receptor for AMAV. Our data support an in vivo role for TfR1 in the replication of most, if not all, NW clade B arenaviruses, and suggest that with modest changes in their GPs the nonpathogenic arenaviruses could use human TfR1 and emerge as human pathogens.

Overexpression of MHCII by hepatocytes in alcoholic hepatitis (AH) compared to non-alcoholic steatohepatitis (NASH) and normal controls.

Previously we have shown that in autoimmune hepatitis CD4 positive lymphocytes form an immunologic synapse with hepatocytes, leading to gradual diminishing and elimination of the hepatocyte. We wondered whether a similar mechanism may occur in alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH). We conducted immunofluorescence studies of expression of MHCII, the binding partner of CD4, on patient liver biopsies of AH, NASH, and normal controls. In cases of alcoholic hepatitis, there was prominent sinusoidal expression of MHC II; In NASH biopsies there was comparatively lower expression of MHC II, but still more than control tissue. Immunohistochemical stain for CD4 showed CD4 positive lymphocytes closely associated with hepatocytes in AH biopsies. Furthermore, expression levels of the multifunctional cytokine IL-1α was higher in AH compared to NASH and control biopsies. These results underlie the more severe nature of alcoholic hepatitis and underscore the autoimmune mechanisms involved in the liver damage found in alcoholic hepatitis.

Traumatic bile duct neuroma presenting with acute cholangitis: A case report and review of literature.

Traumatic neuroma of the biliary tree has been previously reported as isolated case reports. In literature, these typically present following prior liver transplant or cholecystectomy, wherein the bile ducts have been disrupted in some form. Here we report the case of a 41-year old male who initially presented with acute cholangitis ten years after an open cholecystectomy complicated by a bile leak. Endoscopic retrograde cholangiography revealed a stricture within the mid distal common hepatic duct. The patient temporarily resolved his initial episode with stent placement, and he was eventually taken to the operating room for bile duct resection and hepaticojejunostomy given a persistent stricture and concern for underlying malignancy. Final pathology demonstrated a traumatic bile duct neuroma. This unusual entity should be considered in patients with benign appearing strictures presenting years after surgery, and awareness may aid in preoperative counseling as well.

Short-term reduction in intrinsic heart rate during biventricular pacing after cardiac surgery: a substudy of a randomized clinical trial.

BACKGROUND: The Biventricular Pacing After Cardiac Surgery trial investigates hemodynamics of temporary pacing in selected patients at risk of left ventricular dysfunction. This trial demonstrates improved hemodynamics during optimized biventricular pacing compared with atrial pacing at the same heart rate 1 and 2 hours after bypass and reduced vasoactive-inotropic score over the first 4 hours after bypass. However, this advantage of biventricular versus atrial pacing disappears 12 to 24 hours later. We hypothesized that changes in intrinsic heart rate can explain variable effects of atrial pacing in this setting. METHODS: Heart rate, mean arterial pressure, cardiac output, and medications depressing heart rate were analyzed in patients randomized to continuous biventricular pacing (n = 16) or standard of care (n = 18). RESULTS: During 30-second testing periods without pacing, intrinsic heart rate was lower in the paced group 12 to 24 hours after bypass (76.5 ± 17.5 vs 91.7 ± 13.0 beats per minute; P = .040) but not 1 or 2 hours after bypass. Cardiac output (4.4 ± 1.2 vs 3.6 ± 1.9 L/min; P = .054) and stroke volume (53 ± 2 vs 42 ± 2 mL; P = .051) increased overnight in the paced group. Vasoactive medication doses were not different between groups, whereas dexmedetomidine administration was prolonged over postoperative hours 12 to 24 in the paced group (793 ± 528 vs 478 ± 295 minutes; P = .013). CONCLUSIONS: These observations suggest that hemodynamic benefits of biventricular pacing 12 to 24 hours after cardiopulmonary bypass lead to withdrawal of sympathetic drive and decreased intrinsic heart rate. Depression of intrinsic rate increases the apparent benefit of atrial pacing in the chronically paced group but not in the control group. Additional study is needed to define clinical benefits of these effects.