Differentiating localized autoimmune pancreatitis and pancreatic ductal adenocarcinoma using endoscopic ultrasound images with deep learning.

Objectives: Localized autoimmune pancreatitis is difficult to differentiate from pancreatic ductal adenocarcinoma on endoscopic ultrasound images. In recent years, deep learning methods have improved the diagnosis of diseases. Hence, we developed a special cross-validation framework to search for effective methodologies of deep learning in distinguishing autoimmune pancreatitis from pancreatic ductal adenocarcinoma on endoscopic ultrasound images. Methods: Data from 24 patients diagnosed with localized autoimmune pancreatitis (8751 images) and 61 patients diagnosed with pancreatic ductal adenocarcinoma (20,584 images) were collected from 2016 to 2022. We applied transfer learning to a convolutional neural network called ResNet152, together with our innovative imaging method contributing to data augmentation and temporal data process. We divided patients into five groups according to different factors for 5-fold cross-validation, where the ordered and balanced datasets were created for the performance evaluations. Results: ResNet152 surpassed the endoscopists in all evaluation metrics with almost all datasets. Interestingly, when the dataset is balanced according to the factor of the endoscopists' diagnostic accuracy, the area under the receiver operating characteristic curve and accuracy were highest at 0.85 and 0.80, respectively. Conclusions: It is deduced that image features useful for ResNet152 correlate with those used by endoscopists for their diagnoses. This finding may contribute to sample-efficient dataset preparation to train convolutional neural networks for endoscopic ultrasonography-imaging diagnosis.

Role of Bile-Derived Extracellular Vesicles in Hepatocellular Proliferation after Partial Hepatectomy in Rats.

Although liver regeneration has been extensively studied, the effects of bile-derived extracellular vesicles (bile EVs) on hepatocytes has not been elucidated. We examined the influence of bile EVs, collected from a rat model of 70% partial hepatectomy (PH), on hepatocytes. We produced bile-duct-cannulated rats. Bile was collected over time through an extracorporeal bile duct cannulation tube. Bile EVs were extracted via size exclusion chromatography. The number of EVs released into the bile per liver weight 12 h after PH significantly increased. Bile EVs collected 12 and 24 h post-PH, and after sham surgery (PH12-EVs, PH24-EVs, sham-EVs) were added to the rat hepatocyte cell line, and 24 h later, RNA was extracted and transcriptome analysis performed. The analysis revealed that more upregulated/downregulated genes were observed in the group with PH24-EVs. Moreover, the gene ontology (GO) analysis focusing on the cell cycle revealed an upregulation of 28 types of genes in the PH-24 group, including genes that promote cell cycle progression, compared to the sham group. PH24-EVs induced hepatocyte proliferation in a dose-dependent manner in vitro, whereas sham-Evs showed no significant difference compared to the controls. This study revealed that post-PH bile Evs promote the proliferation of the hepatocytes, and genes promoting cell cycles are upregulated in hepatocytes.

[A new curriculum to strengthen pharmacology and clinical pharmacology training in fundamental nursing education].

Among medical care incidents in Japan, an increase in medicine-related errors by nurses have been reported. These errors may be caused by a lack of knowledge of clinical pharmacology and drug interactions. It is important for nurses to acquire risk-management skills based on clinical pharmacology. In order to improve fundamental knowledge in pharmacology and clinical pharmacology for nurses, various training programs exist. We reviewed a number of educational programs in medicine and report our results. Based on our results, it is necessary for medical education programs to include the following 5 essential elements: 1) An analysis of frequently-occurring medication errors in the field of clinical pharmacology, 2) drugs administer for patient characteristic and patient observation practices, 3) an emphasis on the interactions between drugs and food or other drugs, 4) assessment of patient symptoms, risk-management, and the efficacy of drugs, 5) the necessity of using the package inserts. In a new curriculum, it is necessary to have systematic, step by step training in pharmacology and clinical pharmacology. It is also necessary to develop these teaching methods in cooperation with specialists and experts in the field.

A case of successful removal of a migrated fish bone in the bile duct after pancreaticoduodenectomy using overtube-assisted cholangioscopy.

Fish bone migration into the bile duct in patients with surgically altered anatomy is a very rare cause of bile duct stones. Recently, balloon-assisted endoscopic retrograde cholangiopancreatography (BAERCP) is performed for biliary lesions in patients with surgically altered anatomy. We report on a 73-year-old Japanese man with a history of pancreaticoduodenectomy for intraductal papillary mucinous adenoma. A 20 mm long linear hyperattenuating structure in the left intrahepatic bile duct was noted on routine follow-up computed tomography 14 years postoperatively. The linear structure persisted until follow-up computed tomography performed 15 years postoperatively, and the left intrahepatic bile duct was shown to be dilated. We performed BAERCP for the diagnosis and treatment of the linear structure but could not visualize the linear structure in the left intrahepatic bile duct via enteroscopy and fluoroscopy. We removed the enteroscope, leaving the overtube, and inserted the cholangioscope through the overtube over the guide wire. We observed a brown rod-shaped linear structure in the left intrahepatic bile duct and removed it under direct visualization via overtube-assisted cholangioscopy. We conclude that overtube-assisted cholangioscopy was useful for assessing undiagnosed biliary lesions using conventional BAERCP and removing fish bones in the bile duct of the patient with altered gastrointestinal anatomy.

Biosafety of a novel covered self-expandable metal stent coated with poly(2-methoxyethyl acrylate) in vivo.

Covered self-expandable metal stents (CSEMS) are often used for palliative endoscopic biliary drainage; however, the unobstructed period is limited because of sludge occlusion. The present study aimed to evaluate the biosafety of a novel poly(2-methoxyethyl acrylate)-coated CSEMS (PMEA-CSEMS) for sludge resistance and examine its biosafety in vivo. Using endoscopic retrograde cholangiopancreatography, we placed the PMEA-CSEMS into six normal porcine bile ducts and conventional CSEMS into three normal porcine bile ducts. We performed serological examination and undecalcified histological analysis at 1, 3, and 6 months during follow-up. In the bile ducts with PMEA-CSEMS or conventional CSEMS, we observed no increase in liver enzyme or inflammatory marker levels in the serological investigations and mild fibrosis but no inflammatory response in the histopathological analyses. Thus, we demonstrated the biosafety of PMEA-CSEMS in vivo.

A case of a smooth transition to subsequent percutaneous transjejunal biliary intervention for hepatolithiasis after biliary reconstruction by adding jejunostomy during an emergency operation for perforation due to balloon-assisted endoscopy.

Treatments for hepatolithiasis include peroral endoscopy, percutaneous cholangioscopy, and surgery. Balloon-assisted endoscopic retrograde cholangiopancreatography (BAERCP) has been widely performed in recent years for patients with hepatolithiasis after biliary reconstruction. However, accidental bowel perforation caused by BAERCP may need emergency surgery. Here, we describe a 77-year-old Japanese woman diagnosed with acute cholangitis due to hepatolithiasis after biliary reconstruction (a biliary diversion operation for pancreaticobiliary maljunction). She underwent BAERCP for treatment of hepatolithiasis, however, a small-bowel perforation occurred. She underwent an emergency operation to suture the perforation and add a catheter jejunostomy. She had no postoperative complications after surgery and was discharged 11 days after surgery. One month later, she was readmitted and underwent percutaneous transjejunal cholangioscopy-guided lithotripsy with complete removal of the calculi. Although endoscopists should be careful to avoid small-bowel perforation during BAERCP, if perforation occurs, addition of a catheter jejunostomy during emergency surgery can be easily transitioned to subsequent treatment of the hepatolithiasis.

Utility of Claudin-3 in extracellular vesicles from human bile as biomarkers of cholangiocarcinoma.

Extracellular vesicles (EVs) are released from all cells. Bile directly contacts bile duct tumor; bile-derived EVs may contain high concentrations of cancer biomarkers. We performed a proteomic analysis of human bile-derived EVs and identified a novel biomarker of cholangiocarcinoma (CCA). EVs were isolated using ultracentrifugation, and chelating agents, ethylenediaminetetraacetic acid and ethylene glycol tetraacetic acid (EDEG) and phosphate buffered saline (PBS) were used as dissolution solutions. Bile was collected from 10 CCA and 10 choledocholithiasis (stones) cases. Proteomic analysis was performed; subsequently, ELISA was performed using the candidate biomarkers in a verification cohort. The vesicles isolated from bile had a typical size and morphology. The expression of exosome markers was observed. RNA was more abundant in the EDEG group. The proportion of microRNA was higher in the EDEG group. EDEG use resulted in the removal of more contaminants. Proteomic analysis identified 166 proteins as CCA-specific. ELISA for Claudin-3 revealed statistically significant difference. The diagnostic accuracy was AUC 0.945 and sensitivity and specificity were 87.5%. We report the first use of EDEG in the isolation of EVs from human bile and the proteomic analysis of human bile-derived EV-proteins in CCA. Claudin-3 in bile-derived EVs is a useful biomarker for CCA.

Pancreatic perfusion imaging method that reduces radiation dose and maintains image quality by combining volumetric perfusion CT with multiphasic contrast enhanced-CT.

OBJECTIVES: The aim of this study is to propose and evaluate a new method of volumetric perfusion computed tomography (PCT) incorporated into pancreatic multiphasic contrast enhanced (CE)-CT in the clinical setting. METHODS: In this ethically approved study, PCT was incorporated into our existing scanning protocol in 17 patients and effective doses related to PCT were evaluated. CT values and signal-to-noise ratio (SNR) of anatomical structure were compared in diagnostic images that were acquired using 320-detector volumetric scan mode and 64-detector helical scan mode. In addition, focal lesion depiction was qualitatively assessed in the two groups. Perfusion parameters in normal pancreas were measured by two radiologists and the interobserver-reliability was assessed. RESULTS: The effective dose of PCT was 5.1 ± 0.3 mSv. The actual effective dose (AED) including the dose used in volumetric scans for diagnostic imaging was 22.8 ± 5.3 mSv and the putative effective dose (PED) was 21.9 ± 9.1 mSv on average. There was no significant difference between AED and PED (p = 0.404). Compared with conventional helical scans, volumetric scans did not decrease CT values or SNR, but rather significantly increased those of the aorta in the arterial phase. Both groups had acceptable qualitatively assessed image quality with no significant difference in the depiction of each structure. There was almost perfect interobserver agreement in the measurement of perfusion parameters (mean ICCs > 0.9). CONCLUSIONS: Our scanning protocol for pancreatic perfusion CT provides high-quality images while requiring lower radiation doses than conventional methods.

Signet-ring cell carcinoma of the ampulla of Vater: a case diagnosed via repeated biopsies.

Signet-ring cell carcinoma of the ampulla of Vater is a rare tumor. A 74-year-old woman presented with epigastric pain and was diagnosed with cholangitis. Her liver enzyme levels were elevated. Computed tomography showed an enhanced area in the periampullary region and marked common bile duct dilatation. On endoscopic retrograde cholangiopancreatography (ERCP), the ampulla exhibited a normal appearance without ulcer or mass. Histological biopsy confirmed the absence of malignancy. During follow-up, the patient again presented with acute cholangitis multiple times and underwent ERCP each time. The ampulla had the appearance of a reddish and erosive mucosa. Although biopsy was repeated, histological examination did not show any malignancy. After a total of 13 biopsies, the patient was diagnosed with ampullary carcinoma of non-exposed protruded type following the third ERC-guided biopsy. Careful follow-up and frequent endoscopic biopsies are important in cases of papillary carcinoma of non-exposed protruded type with normal ampullary mucosa on initial endoscopy because this condition is challenging to diagnose with a single biopsy.

Usefulness of rapid on-site evaluation specimens from endoscopic ultrasound-guided fine-needle aspiration for cancer gene panel testing: A retrospective study.

Pancreatic cancer (PC) is a highly lethal malignancy, with a 5-year survival rate of 6%. Cancer gene panel testing is expected to allow selection of suitable therapeutic drugs in individual patients with PC and improve their prognosis. Although somatic mutations can be identified in formalin-fixed, paraffin-embedded samples derived from surgical specimen, the rate of surgical indication among patients with PC is only 20%. To acquire genome information with a less invasive method, we used rapid on-site evaluation (ROSE) specimens from endoscopic ultrasound-guided fine-needle aspiration. The present study aimed to retrospectively evaluate the utility of comprehensive cancer gene panel testing with ROSE specimens. DNA was extracted from preserved ROSE specimens of 26 patients diagnosed with PC between 2011 and 2017. DNA sequences of oncogenes and cancer-related genes were determined using the Ion AmpliSeq Comprehensive Caner Panel. We compared KRAS mutations between cancer gene panel testing by next-generation sequencing (NGS) and KRAS mutation analysis by polymerase chain reaction. The mean yield of DNA per extraction from ROSE specimens was 171 ng (range, 34-478 ng). On cancer gene panel testing, we noted KRAS mutations (92%), TP53 mutations (50%), CDKN2A mutations (15%), and SMAD4 mutations (31%). The concordance rate of KRAS mutations between cancer gene panel testing by NGS using ROSE specimens and KRAS mutation analysis by the companion diagnostics using residual materials was 81%. Among five cases of KRAS discordance, three showed KRAS mutations in cancer gene panel testing but not in KRAS mutation analysis. Cancer gene panel testing with ROSE specimens can help stratify unresectable PC patients without additional invasive approaches, and it can be used for therapeutic drug selection.

Safety of bovine milk derived extracellular vesicles used for delivery of RNA therapeutics in zebrafish and mice.

Extracellular vesicles are endogenous biological nanoparticles that have potential for use as therapeutic nanoparticles or as delivery vehicles for therapeutic agents. Milk nanovesicles (MNV) are extracellular vesicles isolated from bovine milk that have been explored for use as delivery vehicles for RNA therapeutics such as small interfering RNA (siRNA). We performed in vivo toxicological studies of MNV or therapeutic MNV (tMNV) loaded with siRNA as a prelude to their clinical use. Development toxicity was assessed in zebrafish embryos. Acute toxicity was assessed in both mice and zebrafish whereas safety, biochemical, histological and immune effects after multiple dosing were assessed in mice. Zebrafish embryo hatching was accelerated with MNV and tMNV. While acute toxicity or effects on mortality were not observed in zebrafish, developmental effects were observed at high concentrations of MNV. There was a lack of discernable toxicity, mortality and systemic inflammatory or immunological responses in mice following administration of either MNVs or tMNVs. The tolerability and lack of discernable developmental or systemic in vivo toxicity support their use as biological nano-therapeutics. Adoption of a standardized protocol for systematic analysis of in vivo safety and toxicity will facilitate preclinical assessment of EV based formulations for therapeutic use.

A novel pathogenic variant of ATP-binding cassette subfamily B member 4 causing gallstones in a young adult.

The low phospholipid-associated cholelithiasis (LPAC) syndrome was reported in European adults with cholelithiasis and a mutation of the ATP-binding cassette subfamily B member 4 (ABCB4). The ABCB4 encodes multidrug resistance 3, which is a phospholipid translocator. Reduced phospholipid transport can lead to the formation of biliary cholesterol stones. Here, we describe a 31-year-old Japanese man diagnosed with recurrent biliary colic. Although he recovered quickly after endoscopic treatment for the most recent presentation, he had a family history of similar problems. His mother had required endoscopic treatment for choledocholithiasis and his maternal aunt had died at age 29 years because of liver failure (etiology unknown). We, therefore, performed genetic analysis, which revealed a heterozygous ABCB4C717S. LPAC syndrome was diagnosed and the patient has received ursodeoxycholic acid for 2 years with no recurrence. The same variant was identified in the patient's mother, who was subsequently found to have a left intrahepatic calculus requiring left-sided lobectomy. She has received ursodeoxycholic acid for 1 year with no recurrence. ABCB4C717S is a novel pathogenic variant, and this is the first patient diagnosed with LPAC syndrome in Japan. We should consider LPAC syndrome in young adults with recurrent cholesterol gallstones to ensure early therapy.

Extracellular Vesicle-Based Therapeutic Targeting of ß-Catenin to Modulate Anticancer Immune Responses in Hepatocellular Cancer.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although HCC can respond to immune checkpoint inhibitors, such as monoclonal antibodies against programmed death 1 (PD-1), many patients fail to respond or develop secondary resistance. Activation of Wnt/ß-catenin signaling can contribute to immune evasion. Mutations in ß-catenin are among the most frequent mutations associated with HCC. Thus, our aim was to directly target ß-catenin to enhance the therapeutic response to immune checkpoint inhibition. A synthetic transgenic mouse model of experimental HCC induced by tyrosine-protein kinase Met/ß-catenin expression and extracellular vesicles (EVs) as a therapeutic delivery agent was used to evaluate the efficacy of directly targeting ß-catenin on the response to anti-PD-1. These studies showed that (1) oncogenic ß-catenin could be therapeutically targeted using a biological nanoparticle-based delivery approach, (2) targeting ß-catenin using small interfering RNA (siRNA) delivered within EVs can reduce tumor growth, and (3) the therapeutic response to anti-PD-1 can be enhanced by concomitantly targeting ß-catenin using therapeutic EVs. These preclinical studies establish the efficacy of the use of biological nanoparticles as an endogenous delivery vehicle for therapeutic RNA delivery and support the use of therapeutic strategies targeting tumor-intrinsic ß-catenin as an adjunct to anti-PD-1-based therapy. Conclusion: Combination therapy with anti-PD-1 and ß-catenin siRNA delivered using biological nanoparticles provides an effective strategy for the treatment of HCC. This strategy could be further exploited into targeted approaches for immune potentiation by countering oncogene-mediated resistance to immunotherapies.

Pharmacokinetic Drug Interaction Between Rosuvastatin and Tanjin in Healthy Volunteers and Rats.

BACKGROUND: Tanjin is an herbal medicine made from the root of salvia miltiorrhiza. It is predominantly given to arteriosclerotic patients as a supplement to ameliorate the clinical symptoms of cardiovascular diseases. In China, tanjin is used frequently in combination treatment for hypercholesterolemia. Thus, there is a high probability of combination of tanjin and statins in these arteriosclerotic patients. This study investigated the interaction between tanjin and rosuvastatin. METHODS: We performed a randomized single-blind, two-period crossover clinical trial on six healthy male volunteers. Volunteers were administered rosuvastatin with placebo or a tanjin-containing drug randomly. The blood samples were collected before drug administration, and at 0.5, 1, 1.5, 2, 4, 8, and 12 hours after administration. Lymphocytes were isolated from blood samples before and 12 hours after drug administration to measure mRNA. As an animal experiment, an in situ intestinal injection with portal vein sampling model was used to examine the interaction between tanjin and rosuvastatin during the absorption phase. Rosuvastatin or rosuvastatin combined with tanjin solution was injected into the intestine. After injection, blood from the portal vein was collected and the concentration of rosuvastatin was measured by LC/MS/MS analysis. A portion of the intestine and liver from the rats was collected and stored at -80°C for mRNA measurement. RESULTS: In the clinical trial, co-administration of tanjin decreased the maximum plasma concentration (Cmax) of rosuvastatin by 26.85% compared with rosuvastatin alone, and also decreased the area under the plasma concentration-time curve of rosuvastatin from 0 to 12 h (AUC0-12) by 19.43%. The relative expression of BCRP and OATP mRNA in human lymphocytes was increased by co-administration of tanjin. In the animal experiment, co-administration of tanjin extract reduced the concentration of rosuvastatin to 84.4, 64.4, and 50.0% at 15, 30, and 45 minutes, respectively. The tanjin-containing drug had a similar effect to tanjin extract. Furthermore, tanjin significantly reduced the absorption of rosuvastatin and the inhibitory effects lasted for at least 24 hours. Tanjin increased the relative expression of BCRP mRNA in the intestine, but it did not change the expression of OATP. Moreover, the concentration of rosuvastatin in the portal vein and systemic blood was reduced. In the liver, tanjin increased both BCRP and OATP mRNA expression, which was consistent with the results from human lymphocytes. CONCLUSION: The clinical trial and animal experiment revealed that tanjin can significantly reduce the absorption of rosuvastatin. This interaction occurred, at least, at the absorption phase in the small intestine due to the enhanced efflux transport. Thus, as tanjin and rosuvastatin were found to interact, their combination needs to be paid attention to.

[Hypopituitarism associated with autoimmune pancreatitis: a case report].

We herein report the case of a 64-year-old male patient with hypopituitarism associated with autoimmune pancreatitis (AIP). The patient was previously diagnosed with AIP based on the presence of a swollen pancreas, elevated serum immunoglobulin G4, and narrowing of the pancreatic duct by imaging. Magnetic resonance imaging revealed a pituitary stem tumor, and loading test showed a decrease in the function of the anterior lobe suggesting severe failure of growth hormone secretion. Treatment with steroids was effective in reducing the pituitary lesion and improving the function of the anterior lobe. The present case illustrates the importance of pituitary function evaluation before steroid treatment in patients with AIP.

Therapeutic Efficacy of Vitamin D in Experimental c-MET-ß-Catenin-Driven Hepatocellular Cancer.

Aberrant activation of ß-catenin signaling is frequently observed in hepatocellular cancer. Although Wnt/ß-catenin signaling can be targeted by vitamin D, therapeutic use of vitamin D for this purpose is not currently established. We evaluated the therapeutic use of vitamin D or its analogs using a synthetic transgenic mouse of hepatocarcinogenesis induced by mutant ß-catenin, and MET overexpression in which 75% of mice develop well-differentiated HCC within 8 weeks in the absence of fibrosis. Vitamin D receptor expression was similar in both tumoral and nontumoral tissue. There was no significant difference in overall survival, or in tumor progression assessed by imaging, biochemical, or tumor cell burden assessments in mice receiving a vitamin D-supplemented diet containing 12.0 IU VD/g (HVD) compared with a standard diet (SD) containing 2.3 IU VD/g. Furthermore, systemic treatment with calcitriol [vitamin D analog 1α,25(OH)2D3] or EB1089 (synthetic vitamin D analog) by intraperitoneal injection for 4 weeks prolonged median survival but did not increase overall survival compared with controls. Although tumor formation was delayed in males compared with that in females, there was no difference in overall survival between males and females. In conclusion, although 1α,25(OH)2D3 is reported to inhibit ß-catenin signaling, as well as proliferation, migration, and differentiation in cancer cells, neither dietary supplementation with vitamin D nor treatment with vitamin D analogs altered the formation or growth of HCC associated with ß-catenin activation. These results conclusively demonstrate the lack of utility of targeting vitamin D for therapy of HCC in this setting.

Milk-derived Extracellular Vesicles for Therapeutic Delivery of Small Interfering RNAs.

As endogenous biological nanoparticles capable of uptake by cells, extracellular vesicles (EVs) have the capacity to deliver their RNA cargo to recipient cells. The use of EVs as a drug delivery system remains in its infancy, and there are several barriers to the use of EV for this purpose. Amongst these is the need to ensure that adequate amounts of EV are available. The use of milk-derived EV provides a scalable approach and loading of these EVs with RNA is possible with the use of chemical transfection reagents. This method describes the use of milk-derived EV for delivery of small interfering RNA. These EVs were shown to be taken up by hepatocellular carcinoma cells in vitro, with a reduction in the expression of target gene.

A case of pancreatic intraepithelial neoplasia-3 with autoimmune pancreatitis.

We report a case of pancreatic intraepithelial neoplasia-3 (PanIN-3) with autoimmune pancreatitis (AIP). The patient, a 75-year-old man, had been diagnosed to have AIP with stenosis of the main pancreatic duct. After six years, computed tomography demonstrated dilatation of the main pancreatic duct in the mid-pancreas. Although we could not confirm the presence of any pancreatic tumor on the basis of imaging modalities alone, cytological examination of the pancreatic juice obtained by endoscopic retrograde pancreatography revealed atypical cells. Therefore, we performed pancreatoduodenectomy and obtained a pathologic diagnosis of PanIN-3 with AIP. The present case is informative in the context of pancreatic carcinogenesis in AIP.

The Rapid Development of Squamous Cell Carcinoma on the Nasal Dorsum of a Patient Receiving Immunosuppressive Therapy.

The risk of cancer is significantly increased in patients undergoing renal transplant surgery than in the general population. In particular, skin cancer is the most commonly occurring cancer in these patients.A 34-year-old man underwent living renal transplantation for focal segmental glomerulosclerosis. After 18 months, he developed a lesion on the nasal dorsum, approximately 1 cm in size, and the lesion rapidly expanded to cover the entire dorsum.Owing to its rapid expansion, the lesion was suspected to be a malignant tumor and wide excision was planned.We removed the lesion with a 6-mm margin. Squamous cell carcinoma was diagnosed through intraoperative rapid pathological examination. The nasal bone and septum were invaded by the tumor and, as a result, the entire external nose was removed. The patient's nose was subsequently reconstructed using a free forearm flap for lining, iliac bone graft for the nasal frame, and a scalping forehead flap for skin coverage.Selective target radiotherapy was administered at the closest margin around the lesion, and the dosage of immunosuppressants was reduced.At >2 years postoperatively, the patient showed good cosmetic results with no relapse or metastasis of the tumor.We report the unusual case of a young man who developed a rapidly progressing squamous cell carcinoma on his nasal dorsum after 18 months of immunosuppression. Squamous cell carcinoma in organ transplant recipients may be more aggressive and may progress differently than in regular patients. Therefore, special attention is required for patients who take immunosuppressive drugs after renal transplant surgery.

Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury.

Hepatic ischemia/reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSCs) have been reported to reduce hepatic IRI because of their reparative immunomodulatory effects in injured tissues. Recent studies have highlighted beneficial effects of extracellular vesicles from mesenchymal stem cells (MSC-EV) on tissue injury. The effects of systemically administered mouse bone marrow-derived MSC-EV were evaluated in an experimental murine model of hepatic IRI induced by cross-clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of up to 6 hours. Compared with controls, intravenous administration of MSC-EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase 3-positive and apoptotic cells, and reduced serum aminotransferase levels. MSC-EV increased hepatic messenger RNA (mRNA) expression of NACHT, LRR, and PYD domains-containing protein 12, and the chemokine (C-X-C motif) ligand 1, and reduced mRNA expression of several inflammatory cytokines such as interleukin 6 during IRI. MSC-EV increased cell viability and suppressed both oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. In conclusion, the administration of extracellular vesicles derived from bone marrow-derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.Liver Transplantation 23 791-803 2017 AASLD.