ENDOSCOPIC ULTRASOUND-GUIDED RADIOFREQUENCY ABLATION FOR PANCREATIC ADENOCARCINOMA.

BACKGROUND AND AIMS: Emerging data suggest neoadjuvant chemotherapy (NAC) for resectable pancreatic ductal adenocarcinoma (PDAC) is associated with improved survival. However, less than 40% demonstrate a meaningful radiographic response to NAC. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has emerged as a new modality to treat PDAC. We hypothesize that NAC plus EUS-RFA can be used in the management of resectable PDAC. METHODS: Prospective review of PDAC patients meeting criteria of resectable tumor anatomy that underwent NAC chemotherapy plus EUS-RFA followed by pancreatic resection. Radiographic imaging, perioperative and short-term outcomes were recorded. Surgical pathology specimens were analyzed for treatment response. RESULTS: Three eligible patients with resectable PDAC received 4 months of NAC plus EUS-RFA. One month after NAC and EUS-RFA completion, all 3 patients underwent standard pancreaticoduodenectomy without complications. After a 6-week recovery, all patients completed 2 months of post-op adjuvant chemotherapy. CONCLUSIONS: In our institutional experience, this treatment protocol appears safe as patients tolerated the combination of chemotherapy and ablation. Patients underwent pancreatic resection with uneventful recovery. This novel neoadjuvant approach may provide a more effective alternative to chemotherapy alone.

Probiotic Limosilactobacillus reuteri DSM 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia and Chronic Hepatitis in Mice.

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids associated with autoimmune disease in SF mice, many of which were downregulated by DSM 17938. The upregulated lipids in SF mice demonstrated a significant correlation with gut bacteria known to be implicated in the pathogenesis of various autoimmune diseases. Chronic hepatitis in SF livers responded to DSM 17938 treatment with a reduction in hepatic inflammation. Altered gene expression associated with lipid metabolism and the positive correlation between lipids and inflammatory cytokines together suggest that autoimmunity leads to dyslipidemia with impaired fatty acid oxidation in SF mice. Probiotics are presumed to contribute to the reduction of lipids by reducing inflammatory pathways.

Yttrium-90 selective internal radiotherapy as bridge to curative hepatectomy for recurrent malignant solid pseudopapillary neoplasm of pancreas: case report and review of literature.

Recurrent malignant solid pseudopapillary neoplasms of the pancreas (SPNP) are rare tumors with unpredictable clinical and histopathological features. There is a lack of consensus regarding utilization of adjuvant modalities in conjunction with or in lieu of curative metastatectomy. We present a remarkable case where Yttrium-90 selective internal radiation therapy (Y-90 SIRT) was successfully utilized to elucidate underlying tumor biology and aid resection of a large multifocal recurrent metastatic SPNP in the right hemi-liver of a 59-year-old female. Thus, in cases where curative metastatectomy remains the treatment goal in management of recurrent and/or metastatic SPNPs, Y-90 SIRT is a safe and effective adjunct treatment to facilitate curative resection.

Bispecific human IL2-CCR4 immunotoxin targets human cutaneous T-cell lymphoma.

The majority of clinically diagnosed cutaneous T-cell lymphomas (CTCL) highly express the cell-surface markers CC chemokine receptor 4 (CCR4) and/or CD25. Recently, we have developed diphtheria toxin-based recombinant Ontak®-like human IL2 fusion toxin (IL2 fusion toxin) and anti-human CCR4 immunotoxin (CCR4 IT). In this study, we first compared the efficacy of the CCR4 IT vs IL2 fusion toxin for targeting human CD25+ CCR4+ CTCL. We demonstrated that CCR4 IT was more effective than IL2 fusion toxin. We further constructed an IL2-CCR4 bispecific IT. The bispecific IT was significantly more effective than either IL2 fusion toxin or CCR4 IT alone. The bispecific IT is a promising novel targeted therapeutic drug candidate for the treatment of refractory and recurrent human CD25+ and/or CCR4+ CTCL.

Liver and Kidney Recipient Selection of Hepatitis C Virus Viremic Donors: Meeting Consensus Report From the 2019 Controversies in Transplantation.

The development of multiple highly effective and safe direct-acting antivirals to treat hepatitis C virus (HCV) has resulted in greater ease and confidence in managing HCV infection in transplant recipients that in turn has impacted the solid organ transplant community as well. In the United States, the opioid epidemic has increased the number of overdose deaths with a concomitant increase in younger HCV viremic donors after brain death being identified. At the same time, a decrease in HCV viremic transplant candidates has led to a growing interest in exploring the use of HCV viremic liver and kidney donor allografts in HCV-negative recipients. To date, experience with the use of HCV viremic liver and kidney allografts in HCV-negative recipients is limited to a few small prospective research trials, case series, and case reports. There are also limited data on recipient and donor selection for HCV viremic liver and kidney allografts. In response to this rapidly changing landscape in the United States, experts in the field of viral hepatitis and liver and kidney transplantation convened a meeting to review current data on liver and kidney recipient selection and developed consensus opinions related specifically to recipient and donor selection of HCV viremic liver and kidney allografts.

Characterization of Plasma Membrane Localization and Phosphorylation Status of Organic Anion Transporting Polypeptide (OATP) 1B1 c.521 T>C Nonsynonymous Single-Nucleotide Polymorphism.

PURPOSE: Membrane transport protein organic anion transporting polypeptide (OATP) 1B1 mediates hepatic uptake of many drugs (e.g. statins). The OATP1B1 c.521 T > C (p. V174A) polymorphism has reduced transport activity. Conflicting in vitro results exist regarding whether V174A-OATP1B1 has reduced plasma membrane localization; no such data has been reported in physiologically relevant human liver tissue. Other potential changes, such as phosphorylation, of the V174A-OATP1B1 protein have not been explored. Current studies characterized the plasma membrane localization of V174A-OATP1B1 in genotyped human liver tissue and cell culture and compared the phosphorylation status of V174A- and wild-type (WT)-OATP1B1. METHODS: Localization of V174A- and WT-OATP1B1 were determined in OATP1B1 c.521 T > C genotyped human liver tissue (n = 79) by immunohistochemistry and in transporter-overexpressing human embryonic kidney (HEK) 293 and HeLa cells by surface biotinylation and confocal microscopy. Phosphorylation and transport of OATP1B1 was determined using 32P-orthophosphate labeling and [3H]estradiol-17ß-glucuronide accumulation, respectively. RESULTS: All three methods demonstrated predominant plasma membrane localization of both V174A- and WT-OATP1B1 in human liver tissue and in cell culture. Compared to WT-OATP1B1, the V174A-OATP1B1 has significantly increased phosphorylation and reduced transport. CONCLUSIONS: We report novel findings of increased phosphorylation, but not impaired membrane localization, in association with the reduced transport function of the V174A-OATP1B1.

Perspective review on solid-organ transplant: needs in point-of-care optical biomarkers.

Solid-organ transplant is one of the most complex areas of modern medicine involving surgery. There are challenging opportunities in solid-organ transplant, specifically regarding the deficiencies in pathology workflow or gaps in pathology support, which may await alleviations or even de novo solutions, by means of point-of-care, or point-of-procedure optical biomarkers. Focusing the discussions of pathology workflow on donor liver assessment, we analyze the undermet need for intraoperative, real-time, and nondestructive assessment of the donor injuries (such as fibrosis, steatosis, and necrosis) that are the most significant predictors of post-transplant viability. We also identify an unmet need for real-time and nondestructive characterization of ischemia or irreversible injuries to the donor liver, earlier than appearing on morphological histology examined with light microscopy. Point-of-procedure laparoscopic optical biomarkers of liver injuries and tissue ischemia may also facilitate post-transplant management that is currently difficult for or devoid of pathological consultation due to lack of tools. The potential and pitfalls of point-of-procedure optical biomarkers for liver assessment are exemplified in breadth for steatosis. The more general and overarching challenges of point-of-procedure optical biomarkers for liver transplant pathology, including the shielding effect of the liver capsule that was quantitated only recently, are projected. The technological and presentational benchmarks that a candidate technology of point-of-procedure optical biomarkers for transplant pathology must demonstrate to motivate clinical translation are also foreseen.

Effects of capsule on surface diffuse reflectance spectroscopy of the subcapsular parenchyma of a solid organ.

We hypothesize that the capsular optical properties and thickness combined affect how accurate the diffuse reflectance on the surface of a capsular solid organ represents that on the subcapsular parenchyma. Monte Carlo simulations on two-layer geometries evaluated how a thin superficial layer with the thickness from 10 to 1000 µm affected the surface diffuse reflectance over a source-detector separation spanning 0.01 to 10 mm. The simulations represented the superficial layer presenting various contrasts concerning refractive index, anisotropy factor, absorption coefficient, and reduced scattering coefficient, versus those of the subsurface main medium. An analytical approach modeled the effects of the superficial layer of various thicknesses and optical properties on diffuse reflectance. Diffuse reflectance spectroscopy was performed ex vivo on 10 fresh human livers and 9 fresh human kidneys using a surface probe with a 3-mm source-detector separation. The difference of the device-specific diffuse reflectance on the organ between with the capsule and without the capsule has significantly greater spectral variation in the kidney than in the liver. The significantly greater spectral deviation of surface diffuse reflectance between with and without the capsule in the kidney than in the liver was analytically accountable by considering the much thicker capsule of the kidney than of the liver.

Dissecting Cellulitis of the Scalp: A Rare Dermatological Manifestation of Crohn's Disease.

Dissecting cellulitis is an inflammatory disease of the skin. We report a case of recurrent dissecting cellulitis in a patient with Crohn's disease. A 31-year-old man with a history of purulent scalp lesions presented with night sweats, weight loss, abdominal pain, and hematochezia. Colonoscopy revealed a diffuse friable mucosa with extensive pseudopolyps. Scalp biopsy demonstrated epidermoid inclusion cysts with granulation tissue and chronic inflammatory cell infiltration, indicative of dissecting cellulitis. The incidence of dissecting cellulitis with Crohn's disease is underreported. This dermatologic condition has a tendency to recur, and considering an underlying disease is key for its appropriate treatment.

Expression of hepatocyte epidermal growth factor receptor, FAS and glypican 3 in EpCAM-positive regenerative clusters of hepatocytes, cholangiocytes, and progenitor cells in human liver failure.

Liver regeneration under normal circumstances proceeds through proliferation of all cellular elements of the liver. Studies with rodent models have shown that when proliferation of hepatocytes is inhibited, progenitor cells arising from the biliary compartment transdifferentiate into "oval/progenitor" cells, which proceed to differentiate into hepatocytes. Recent studies have shown that the same pathways may operate in human liver failure. The growth factor receptors (HGF [hepatocyte growth factor] receptor) and epidermal growth factor receptor are key mitogenic receptors for both hepatocytes and progenitor cells. Our current study used the biliary and progenitor marker EpCAM (epithelial cell adhesion molecule) to detect "regenerative clusters" of mixed cholangiocyte-hepatocyte differentiation. We determined that expression of metabolic equivalent and epidermal growth factor receptor occurs in biliary cells, progenitor cells, and hepatocytes, whereas activation of metabolic equivalent and epidermal growth factor receptor is limited to regenerative cluster hepatocytes. These histologic events are associated with expression of apoptosis-inducing FAS and mitoinhibitory protein glypican 3. Cell proliferation was overall suppressed in regenerative clusters. Transdifferentiation of biliary and progenitor cells appears to be regulated by a complex interaction of signals promoting and arresting growth.

Acute autoimmune hepatitis presenting with peripheral blood eosinophilia.

 Peripheral blood eosinophilia has been described in a broad variety of allergic, infectious, neoplastic and autoimmune diseases. To the best of our knowledge blood eosinophilia has never previously been reported in association with isolated autoimmune hepatitis (AIH) in the absence of other autoimmune conditions. Herein we report an interesting case of an 18 year old man who presented to our hospital with an acute autoimmune hepatitis diagnosed on the basis of clinical features, serology and histopathology. He was noted to have a moderate peripheral eosinophilia at diagnosis which resolved within days of initiation of corticosteroids for treatment of the AIH. Given the absence of other systemic conditions or drugs which may have produced the eosinophilia and its rapid resolution with treatment of the underlying liver disease, we wished to highlight this rather novel presentation of AIH.

Modified multivisceral transplantation with spleen-preserving pancreaticoduodenectomy for patients with familial adenomatous polyposis "Gardner's Syndrome".

BACKGROUND: Liver-sparing "modified" multivisceral transplantation (MMVTx) has recently been more used for patients with diffuse gastrointestinal disorders and preserved hepatic functions. Evisceration techniques with preservation of native spleen were also introduced to reduce risk of posttransplant lymphoproliferative disorders. This study focuses on the indications of MMVTx for patients with familial adenomatous polyposis (FAP) and the technical feasibility of performing spleen-preserving pancreaticoduodenectomy (SPPD). METHODS: Between 1993 and 2009, 10 FAP patients required MMVTx. Nine were adults and one was a child, with a female:male ratio of 1:1. RESULTS: Short gut with duodenal adenomatosis and extensive desmoid tumors with pancreaticoduodenal involvement dictated need for MMVTx. SPPD was technically feasible in four recipients, and conventional evisceration including splenectomy was performed in remaining six recipients. With an overall cumulative survival of 90% at 1 year and 77% at 10 years, all SPPD recipients were alive with no single example of posttransplant lymphoproliferative disorder, graft-versus-host disease, or chronic rejection. However, SPPD was associated with an increase (P>0.3) in total ischemia time, operative time, and packed red blood cells requirement but with shorter (P=0.6) length of hospital stay. With a mean follow-up of 50±45 months (range 18-128 months), none of the 10 recipients experienced intraabdominal desmoid tumor recurrence or developed de novo visceral allograft neoplasm. CONCLUSION: MMVTx is a valuable therapeutic option for FAP patients who are in need for visceral transplantation with pathologic involvement of the pancreaticoduodenal complex. SPPD is technically feasible, and efforts should always be made to preserve native spleen because of the reported herein therapeutic advantages.

Development of a Sleeping Beauty-based telomerase gene delivery system for hepatocytes.

Telomerase is a particular reverse transcriptase that not only synthesizes and maintains the telomere but also promotes the proliferation of resting cells and prevents cellular senescence. The advantages of the Sleeping Beauty transposon system include prolonged transgene expression without eliciting an immunogenic response, no possibility of RCV and ease of construction. Tissue-specific therapeutic gene expression is extremely important in gene therapy, because non-specific expression can cause an immune response of the transduced cells that can severely limit the stability of the transgene. The SB system containing the telomerase gene controlled by two chimeric transthyretin (TTR) gene promoters/enhancers, the human alcohol dehydrogenase gene promoter (ADHp), and the SV40 viral enhancer (SV40VE) was constructed in order to activate hepatocyte cell growth. The higher expression was achieved using these elements and FACS analysis showed that this system was effective in hepatocyte targeted gene therapy. Our new SB mediated telomerase delivery system for hepatocytes can be used in human gene therapy applications.