Establishment of a Long-Term Survival Swine Model for the Observation of Transplanted Islets: a Preliminary Step in an Allogeneic Transplant Experiment.

BACKGROUND: Evaluation of an experimental and preclinical islet transplantation (IsletTx) model to elucidate associated clinical problems is vital. This study aimed to introduce a simple methodology for producing a swine autologous IsletTx model as a preliminary step in an allogeneic transplant experiment. METHODS AND MATERIALS: Twenty-seven pigs were included in the study. Total pancreatectomy (TP) was performed in 8 pigs (TP group), TP with autologous IsletTx in 9 (TP + IsletTx group), and distal pancreatectomy (DP) with autologous IsletTx in 10 (DP + IsletTx group). An open biopsy was performed on all pigs during postoperative day 14 using an infrared imaging (IRI) system. Laboratory data and postoperative survival were analyzed and compared according to the procedures done. RESULTS: Postoperative survival rate was significantly higher in the pigs with autologous IsletTx than in those without (P = .026). There were no significant differences in survival between the TP + IsletTx and DP + IsletTx groups (P = .746). Significant hyperglycemia was not observed in both groups, but the DP + IsletTx group remained relatively stable throughout the postoperative course. There were no differences in serum creatinine, aspartate aminotransferase, and alanine aminotransferase levels between the 2 groups. By selective liver lobe transplantation and administration of the IRI system, localization of the transplanted islets via open biopsy was achieved. CONCLUSIONS: We successfully developed an autologous IsletTx model and an open biopsy system using a swine model. This study will aid in the development of an allogeneic IsletTx experiment that may improve transplantation outcomes.

Dysregulation of sphingolipid metabolic enzymes leads to high levels of sphingosine-1-phosphate and ceramide in human hepatocellular carcinoma.

AIM: Sphingosine-1-phosphate (S1P) and ceramide are bioactive sphingolipids known to be important in regulating numerous processes involved in cancer progression. The aim of this study was to determine the absolute levels of sphingolipids in hepatocellular carcinoma (HCC) utilizing data obtained from surgical specimens. In addition, we explored the clinical significance of S1P in patients with HCC and the biological role of S1P in HCC cells. METHODS: Tumors and normal liver tissues were collected from 20 patients with HCC, and sphingolipids were measured by mass spectrometry. The Cancer Genome Atlas (TCGA) cohort was utilized to evaluate gene expression of enzymes related to sphingolipid metabolism. Immunohistochemistry of phospho-sphingosine kinase 1 (SphK1), an S1P-producing enzyme, was performed for 61 surgical specimens. CRISPR/Cas9-mediated SphK1 knockout cells were used to examine HCC cell biology. RESULTS: S1P levels were substantially higher in HCC tissue compared with normal liver tissue. Levels of other sphingolipids upstream of S1P in the metabolic cascade, such as sphingomyelin, monohexosylceramide and ceramide, were also considerably higher in HCC tissue. Enzymes involved in generating S1P and its precursor, ceramide, were found in higher levels in HCC compared with normal liver tissue. Immunohistochemical analysis found that phospho-SphK1 expression was associated with tumor size. Finally, in vitro assays indicated that S1P is involved in the aggressiveness of HCC cells. CONCLUSIONS: Sphingolipid levels, including S1P and ceramide, were elevated in HCC compared with surrounding normal liver tissue. Our findings suggest S1P plays an important role in HCC tumor progression, and further examination is warranted.

Genetic analysis in the clinical management of biliary tract cancer.

Biliary tract cancer (BTC) is clinically and pathologically heterogeneous and responds inadequately to treatment. A small section of patients develop resectable disease, although the relapse rates are high; the benefits of adjuvant capecitabine chemotherapy for BTC are now understood, and gemcitabine-based combination chemotherapy is the first line of therapeutic strategy for BTC; however, alternative therapy for BTC is not known. Genomic profiling can provide detailed information regarding the carcinogenesis, identification, and therapy for BTC. Currently, confirmed restorative targets for BTC are lacking. In this review, we aimed to analyze the preclinical and clinical implications of a spectrum of genomic alterations associated with new potentially remedial targets. We focused on eight draggable genes for BTC, which were described as having evidence of therapeutic impact (evidence level 2A-3B) based on the clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment; these include ERBB2, NTRK1, RNF43, CDK6, CDKN2B, FGFR2, IDH1, and IDH2. Moreover, some of the BTC present microsatellite instability, hypermutation, and germline variants, which we also reviewed. Finally, we discussed the therapeutic options based on the next-generation sequencing findings in BTC. Studies have demonstrated that BTC includes subgroups with individually distinct driver mutations, most of which will be targeted with new treatment plans.

Clinicopathological Characteristics and Surgical Outcomes of Primary Cystic Duct Carcinoma: A Multi-institutional Study.

BACKGROUND: The role of surgery in the management of primary cystic duct carcinoma (CDC) remains unclear especially in advanced disease. This study aimed to evaluate long-term outcomes in patients undergoing surgery for primary CDC. METHODS: From a multi-institutional database, we identified 41 patients who underwent surgery for primary CDC, defined as a part of gallbladder carcinoma with the tumor centre located in the cystic duct. RESULTS: Of the 41 patients, 31 (75.6%) underwent preoperative biliary drainage for jaundice. Twenty-eight (68.3%) patients underwent extensive resection including major hepatectomy (n = 21), pancreaticoduodenectomy (n = 4), or both procedures (n = 3). Thirty-four (82.9%) patients had ≥ pT3 tumor, while 31 (75.6%) patients had involvement of contiguous organs/structures. Nodal and distant metastasis was found in 26 (63.4%) and 7 (17.1%) patients, respectively. Most patients (90.2%) had perineural invasion. Median overall survival was 23.7 months in all 41 patients. Factors independently associated with both overall and disease-specific survival were pN (P = 0.003 and P = 0.007, respectively) and pM (P = 0.003 and P = 0.013, respectively) classification. Median survival was 75.3, 17.7, and 5.2 months for patients with pN0M0 (n = 14), pN1/2pM0 or pN0pM1 (n = 21), and pN1/2pM1 (n = 6) disease, respectively (P < 0.001). CONCLUSIONS: Primary CDC is characterized by locally advanced disease with aggressive histopathological characteristics at surgery, leading to extensive resection during treatment. Surgery provides potential benefits for patients with pN0pM0 disease, whereas pN1/2 and/or pM1 status appear to have strong adverse effects on survival.

Successful Surgical Intervention for Recurring Severe Hepatic Encephalopathy Caused by Portosystemic Collaterals After Living-Donor Liver Transplantation: A Case Report.

INTRODUCTION: Portosystemic collaterals (PsC) are a common finding in patients with cirrhosis who need liver transplantation (LT), and PsCs may cause several problems before and after LT. We report a case of successful surgical treatment of severe hepatic encephalopathy (HE) caused by PsC after living-donor LT (LDLT). CASE: A 71-year-old woman with hepatocellular carcinoma underwent LDLT for chronic hepatitis C virus infection at 64 years of age. The splenocaval collateral vein was ligated during LDLT to prevent portal flow steal. A recurrent episode of coma due to HE was triggered 7 years after LDLT and gradually became refractory to any drug treatments. Contrast-enhanced computed tomography revealed the development of the right gastroepiploic vein (RGEV), which flowed to the inferior vena cava via the inferior mesenteric vein (IMV). Owing to the chronic kidney disease (estimated glomerular filtration rate, 11-31 mL/min), interventional radiology (IVR) was not indicated, so surgical treatment was selected to treat the symptom. PsC was resected at the point of the RGEV and IMV, just before flowing into the IVC with vascular staplers. Antegrade portal blood flow was obtained by ultrasonography 2 days after surgery, and the patient was discharged from the hospital 26 days after the operation. After discharge, she has had no recurrent episode of HE. CONCLUSION: Surgical resection of the PsC was effective for treatment of HE caused by shunt flow after LDLT.

Primary lung squamous cell carcinoma and its association with gastric metastasis: A case report and literature review.

Nearly 50% of primary lung carcinoma patients present with distant metastasis at their first visit. However, gastrointestinal tract (GIT) metastasis is an infrequent impediment. Herein, we report a case of progressive dysphagia and epigastralgia as an initial manifestation of recurrence as gastric metastasis of primary lung squamous cell carcinoma (SCC) after curative surgery. A 64-year-old man was diagnosed with primary lung SCC of the right lower lobe, and underwent thoracoscopic lower lobectomy. One year after lobectomy, computed tomography (CT) scan showed a gastric fundal mass located in the gastric cardia which measured 5 cm. Endoscopic biopsies and histopathology subsequently confirmed that tumor was SCC. The patient then underwent proximal gastrectomy with resection of the diaphragmatic crus. Following surgery, histopathological examination revealed gastric metastasis from primary lung SCC. KEY POINTS: Gastric metastasis of primary lung carcinoma is one of the rarest phenomena. Gastrointestinal symptoms should raise suspicion of the presence of advanced metastatic disease with poor prognosis.

Long-term outcomes of surgical resection for T1b gallbladder cancer: an institutional evaluation.

BACKGROUND: There is no comprehensive agreement concerning the overall performance of radical resection for T1b gallbladder cancer (GBC). This research focused on addressing whether T1b GBC may spread loco-regionally and whether radical resection is necessary. METHODS: A retrospective analysis was conducted of 1032 patients with GBC who underwent surgical resection at our centre and its affiliated institutions between January 1982 and December 2018. A total of 47 patients with T1b GBC, 29 (62%) of whom underwent simple cholecystectomy and 18 (38%) of whom underwent radical resection with regional lymph node dissection, were enrolled in the study. RESULTS: GBC was diagnosed pre-operatively in 16 patients (34%), whereas 31 patients (66%) had incidental GBC. There was no blood venous or perineural invasion in any patient on histology evaluation, except for lymphatic vessel invasion in a single patient. There were no metastases in any analysed lymph nodes. The open surgical approach was more prevalent among the 18 patients who underwent radical resection (open in all 18 patients) than among the 29 patients who underwent simple cholecystectomy (open in 21; laparoscopic in 8) (P = 0.017). The cumulative 10- and 20-year overall survival rates were 65 and 25%, respectively. The outcome following simple cholecystectomy (10-year overall survival rate of 66%) was akin to that following radical resection (64%, P = 0.618). The cumulative 10- and 20-year disease-specific survival rates were 93 and 93%, respectively. The outcome following simple cholecystectomy (10-year disease-specific survival rate of 100%) was equivalent to that following radical resection (that of 86%, P = 0.151). While age (> 70 years, hazard ratio 5.285, P = 0.003) and gender (female, hazard ratio 0.272, P = 0.007) had a strong effect on patient overall survival, surgical procedure (simple cholecystectomy vs. radical resection) and surgical approach (open vs. laparoscopic) did not. CONCLUSIONS: Most T1b GBCs represent local disease. As pre-operative diagnosis, including tumour penetration of T1b GBC, is difficult, the decision of radical resection is justified. Additional radical resection is not required following simple cholecystectomy provided that the penetration depth is restricted towards the muscular layer and that surgical margins are uninvolved.

Early-stage T1b adenocarcinoma arising in the remnant cystic duct after laparoscopic cholecystectomy: a case report and literature review.

BACKGROUND: The cystic duct has been included in the staging classification scheme for gallbladder cancer since the 2010 publication of the AJCC Cancer Staging Manual (7th edition). To our knowledge, only seven other cases of adenocarcinoma arising in the remnant cystic duct following cholecystectomy have been reported in the English-language literature, and none has been reported as primary early-stage T1b remnant cystic duct cancer (CDC). We report, herein, a case of primary adenocarcinoma arising in the remnant cystic duct in a patient with history of laparoscopic cholecystectomy for gallstone disease. CASE PRESENTATION: An 81-year-old female presented with abdominal pain. Her medical history included a laparoscopic cholecystectomy for cholecystolithiasis two years prior. Jaundice was observed; imaging studies suggested that this was caused by choledocholithiasis. Blood chemistry findings showed severe liver dysfunction. Endoscopic retrograde cholangiography revealed haemobilia from the common bile duct with no evidence of choledocholithiasis. A bile sample showed Papanicolaou class IV cytology. As the extent of tumour spread was undetermined by abdominal ultrasonography and endoscopic ultrasonography, peroral cholangioscopy (POCS) was performed, which revealed tiny papillary lesions within the confluence of cystic duct, and fine granular lesions in the centre of bile ducts, signifying early-stage remnant CDC. Extrahepatic bile duct resection with regional lymphadenectomy was done. Histopathological findings revealed a 42-mm tubular adenocarcinoma originating from the remnant cystic duct with the considerable shallow spread across the extrahepatic bile ducts. It invaded the fibromuscular layer, with no lymphovascular or perineural invasion, no lymph node metastasis (13 nodes examined), and uninvolved surgical resection margin (R0 resection), and was staged as pT1bN0M0, Stage I. CONCLUSIONS: Primary early-stage T1b remnant CDC is an uncommon condition for which early diagnosis is challenging; if intraoperatively recognized, it can complicate surgery. Our experience of this case and an overview of the English literature suggest that POCS is an efficient tool to diagnosis this tumour and assess its spread along the extrahepatic bile ducts.

Next-generation sequencing-based clinical sequencing: toward precision medicine in solid tumors.

Numerous technical and functional advances in next-generation sequencing (NGS) have led to the adoption of this technique in conventional clinical practice. Recently, large-scale genomic research and NGS technological innovation have revealed many more details of somatic and germline mutations in solid tumors. This development is allowing for the classification of tumor type sub-categories based on genetic alterations in solid tumors, and based on this information, new drugs and targeted therapies are being administered to patients. This has largely been facilitated by gene panel testing, which allows for a better understanding of the genetic basis for an individual's response to therapy. NGS-based comprehensive gene panel testing is a clinically useful approach to investigate genomic mechanisms, including therapy-related signaling pathways, microsatellite instability, hypermutated phenotypes, and tumor mutation burden. In this review, we describe the concept of precision medicine in solid tumors using NGS-based comprehensive gene panel testing, as well as the importance of quality control of tissue sample handling in routine NGS-based genomic testing, and we discuss issues for the future adoption of this technique in Japan.

Surgical management of carcinoma in situ at ductal resection margins in patients with extrahepatic cholangiocarcinoma.

Recent advances in dimensional imaging, surgical technique, and perioperative patient care have resulted in increased rates of complete resection with histopathologically negative margins and improved surgical outcomes in patients with extrahepatic cholangiocarcinoma. However, achieving cancer-free resection margins at ductal stumps in surgery for this disease remains challenging because of longitudinal extension, which is one of the hallmarks of extrahepatic cholangiocarcinoma. When the ductal resection margins are shown to be positive on examination of frozen sections, discrimination between carcinoma in situ and invasive carcinoma is clinically important because residual carcinoma in situ may lead to late local recurrence whereas residual invasive carcinoma is associated with early local recurrence. Residual invasive carcinoma at the ductal margins should be avoided whenever technically feasible. Residual "carcinoma in situ" at the ductal margins appears to be allowed in resection for the advanced disease because it has less effect on survival than other adverse prognostic factors (pN1 and/ or pM1). However, in surgery for early-stage (pTis-2N0M0) extrahepatic cholangiocarcinoma, residual carcinoma in situ at the ductal margins may have an adverse effect on long-term survival, so should be avoided whenever possible. In this review, we focus on the histopathological term "carcinoma in situ," the biological behavior of residual carcinoma in situ at ductal resection margins, intraoperative histological examination of the ductal resection margins, outcome of additional resection for positive ductal margins, and adjuvant therapy for patients with positive margins.

Immunotherapy for hepatocellular carcinoma: From basic research to clinical use.

Hepatocellular carcinoma (HCC) is a common cancer worldwide with a poor prognosis. Few strategies have been proven efficient in HCC treatment, particularly for those patients not indicated for curative resection or transplantation. Immunotherapy has been developed for decades for cancer control and is attaining more attention as a result of encouraging outcomes of new strategies such as chimeric antigen receptor T cells and immune checkpoint blockade. Right at the front of the new era of immunotherapy, we review the immunotherapy in HCC treatment, from basic research to clinical trials, covering anything from immunomodulators, tumor vaccines and adoptive immunotherapy. The mechanisms, efficacy and safety as well as the approach particulars are unveiled to assist readers to gain a concise but extensive understanding of immunotherapy of HCC.

Surgical resection and outcome of pancreatic cystic neoplasms in China: analysis of a 16-year experience from a single high-volume academic institution.

BACKGROUND: To investigate the clinicopathological features of surgically resected pancreatic cystic neoplasms (PCNs) at a single institution in China. METHODS: The medical charts of patients who operated in the Second Affiliated Hospital, Zhejiang University School of Medicine between 1 January 1997 and 30 June 2013, were pathologically shown to have PCNs. RESULTS: There was a reliable increase trend not just in the overall number of patients (3 to 75) but additionally in the number of incidentally diagnosed patients across the periods (33.3% to 48.0%). In 83 of 111 cases, preoperative diagnoses matched with pathology, whereas the remaining cases (16/28) were misdiagnosed as pancreatic cancer. The proportion of malignancy in mucin producing neoplasms was 24.3% (9 out of 37). Elevated serum carbohydrate antigen (CA19-9) or carcinoembryonic antigen (CEA) was independently associated with malignancy. The overall survival rate was 96.4%. CONCLUSIONS: The proportion of PCNs within this series differs with that revealed in Western countries. Appropriate preoperative differential diagnosing of PCNs remains challenging. It is strongly recommended that patients with elevated CA19-9 or CEA levels undergo surgical resection.

Role of vascular clamping in hepatic resection: a review.

Hepatic resection is usually a complicated surgical procedure. In the course of liver organ resection overwhelming safety measures are extremely important simply because this organ has parallel vascular source. Expensive machines are launched in schedule operative practice without the proper evidence of their efficaciousness or efficiency in excess of less complicated procedures. Intermittent clamping of 10 minutes could be accomplished in the affected person with disadvantaged liver organ performance for instance in cirrhosis. Blended utilization of a balloon occlusion catheter, electrocautery and/or ultrasonic coagulating shear and endo-GIA staplers, generally seem to preserve satisfactory homeostasis which helps prevent gas embolization in the course of laparoscopic hepatectomy in human beings. Selection of clamping is perfectly up to the surgeons. For minimal hepatic resection some experts do not implement any clamping strategy. Collaboration amongst specialists and anesthetists is significant to ascertain this challenge throughout resection.

''Sandwich'' treatment for diospyrobezoar intestinal obstruction: a case report.

Intestinal obstruction is a common clinical entity encountered in surgical practice. The objective of this report is to corroborate an atypical scenario of intestinal obstruction in a Chinese patient and to focus on the diagnosis and treatment. A 27-year-old male presented with a history of gastric pain combined with nausea and abdominal distension that had been present for 5 d. The presence of a foreign body was detected by computed tomography and observed as an abnormal density within the stomach. A diospyrobezoar was revealed during gastroscopy, the extraction of which was prevented due to its size and firmness. An endoscopic holmium laser joined with a snare was used to fragment the obstruction, which was followed by management with a conservative "sandwich" treatment strategy involving intestinal decompression with an ileus tube and Coca-Cola lavage between endoscopic lithotripsy fragmentation procedures. This strategy resulted in the successful removal of the diospyrobezoar along with multiple small bowel obstructions. The patient was discharged after abatement of symptoms. The case presented here demonstrates the implementation of a conservative, yet successful, treatment as an alternative to conventional surgical removal of intestinal obstructions.

Screening ultrasonography of 2,204 patients with blunt abdominal trauma in the Wenchuan earthquake.

BACKGROUND: Abdominal injuries constitute a small proportion of all earthquake-related traumas; however, it often resulted in fatal hemorrhage. Ultrasonography has been described as an effective triage tool in the evaluation of blunt abdominal trauma. We aimed to present an overview of the diagnostic accuracy of screening ultrasonography for patients with blunt abdominal trauma admitted to various hospitals during the Wenchuan earthquake in China. METHODS: We retrospectively analyzed the patients with blunt abdominal trauma who underwent ultrasonography after admission to various hospitals. Ultrasonography findings were considered positive if evidence of free fluid or a parenchymal injury was identified. Ultrasonography findings were compared with the findings of computed tomography, diagnostic peritoneal lavage, repeated ultrasonography, cystography, operation, and/or the clinical course. RESULTS: Findings from 2,204 ultrasonographic examinations were evaluated. Findings of 199 ultrasonographic examinations (9.0%) were considered positive. Of the patients, 12 (0.5%) had a false-negative ultrasonographic findings; of this group, 3 (25%) required exploratory laparotomy. Ultrasonography had a sensitivity of 91.9%, specificity of 96.9%, and an accuracy of 96.6% for detection of abdominal injuries. Positive predictive value was 68.3%, and negative predictive value was 99.4%. CONCLUSION: Screening ultrasonography is highly reliable in the setting of blunt abdominal trauma after earthquake. It should be used as an initial diagnostic modality in the evaluation of most blunt abdominal trauma. LEVEL OF EVIDENCE: Diagnostic study, level III.

A meta-analysis of perioperative outcomes of laparoscopic splenectomy for hematological disorders.

BACKGROUND: Due to changes in surgical trends, laparoscopic splenectomy (LS) has become the standard approach for most splenectomies performed for hematological disorders, barring any contraindications. The perioperative outcomes of LS for this indication have not been updated for several years. Controversy still surrounds whether LS should be performed for massive splenomegaly. The purpose of this meta-analysis was to evaluate the perioperative outcomes of laparoscopic splenectomy for hematological disorders. METHODS: Literature searches were conducted to identify studies comparing the perioperative outcomes of the laparoscopic and open approaches for hematological disorders. The results were pooled by using standard meta-analysis methods. RESULTS: Thirty-eight studies with a total of 2,914 patients comparing LS to open splenectomy (OS) for hematological disorders were identified. Mortality was low in both groups. The pooled complications of the LS group were significantly fewer than those of the OS group (-0.11, p < 0.001), and the NNT was 9 (95 % confidence interval, 6-20). For massive spleens, a similar result was observed (-0.12, p = 0.009). Accessory spleen resection and blood loss also were comparable between the two approaches. Additionally, LS was associated with longer operative times (57.38 min, p < 0.00001) and shorter hospital stays (2.48 days, p < 0.00001). CONCLUSIONS: LS is preferred compared to OS, based on lower complication rates and better handling of comorbid conditions. LS is associated with shorter hospital stays but longer operative times. We conclude that LS may be considered an acceptable option even in cases of a massive spleen. To strengthen the clinical evidence, more high-quality clinical trials on different issues are necessary.

Synchronous intraoperative radiofrequency ablation for multiple liver metastasis and resection of giant solid pseudopapillary tumors of the pancreas.

The solid pseudopapillary tumors of the pancreas (SPTP) are rare tumors, which are commonly found in adolescent women. Radical surgical resection of the primary tumor or metastases is the standard treatment for SPTP and could achieve long-term survival. We reported a case of a 20-year-old female with multiple liver metastases of SPTP, and performed surgical resection for primary tumor 14 cm in diameter and 2 major liver metastases (both 5 cm in diameter), radiofrequency ablation (RFA) for small lesions and one major liver metastase 6 cm in diameter successfully. No evidence of recurrence in situ or in the liver was found by computed tomography (CT) scan 3 months after the operation. RFA is a safe and effective treatment for unresectable multiple liver metastases of SPTP.

Mechanical and preventable factors of bile duct injuries during laparoscopic cholecystectomy.

Bile duct injury (BDI) occurring during cholecystectomy has been proposed as the most serious and important cause of morbidity after this procedure. A literature review was performed about the mechanical and preventable factors of bile duct injury listed on Medline databases. Although most injuries occur within the surgeon's first 100 laparoscopic cholecystectomies, it has been suggested that most general surgeons may encounter bile duct injuries. Several techniques have been proposed to avoid this injury. Sound knowledge of anatomy regarding the hepatobiliary system, good surgical skills, awareness of this problem, and referral to higher centres if injury ensues, seem to be the appropriate course of action towards prevention.