Clinical outcomes of ampullary neoplasms in resected margin positive or uncertain cases after endoscopic papillectomy

BACKGROUND Endoscopic papillectomy(EP) for benign ampullary neoplasms could be a lessinvasive alternative to pancreatoduodenectomy(PD). There are some problems and limitations with EP. The post-EP resection margins of ampullary tumors are often positive or uncertain because of the burning effect of EP. The clinical outcomes of resected margin positive or uncertain cases after EP remain unknown.AIM To investigate the clinical outcomes of resected margin positive or uncertain cases after EP.METHODS Between January 2007 and October 2018, all patients with ampullary tumors who underwent EP at Kobe University Hospital were included in this study. The indications for EP were as follows: adenoma, as determined by preoperative endoscopic biopsy, without bile/pancreatic duct extension, according to endoscopic ultrasound or intraductal ultrasound. The clinical outcomes of resected margin positive or uncertain cases after EP were retrospectively investigated.RESULTS Of the 45 patients, 29 were male, and 16 were female. The mean age of the patients was 65 years old. Forty-one patients(89.5%) underwent en bloc resection,and 4 patients(10.5%) underwent piecemeal resection. After EP, 33 tumors were histopathologically diagnosed as adenoma, and 12 were diagnosed as adenocarcinoma. The resected margins were positive or uncertain in 24 patients(53.3%). Of these cases, 15 and 9 were diagnosed as adenoma and adenocarcinoma, respectively. Follow-up observation was selected for all adenomas and 5 adenocarcinomas. In the remaining 4 adenocarcinoma cases,additional PD was performed. Additional PD was performed in 4 cases, and residual carcinoma was found after the additional PD in 1 of these cases. In the follow-up period, local tumor recurrence was detected in 3 cases. Two of these cases involved primary EP-diagnosed adenoma. The recurrent tumors were also adenomas detected by biopsy. The remaining case involved primary EPdiagnosed adenocarcinoma. The recurrent tumor was also an adenocarcinoma.All of the recurrent tumors were successfully treated with argon plasma coagulation(APC). There was no local or lymph node recurrence after the APC.The post-APC follow-up periods lasted for 57.1 to 133.8 mo. No ampullary tumor-related deaths occurred in all patients.CONCLUSION Resected margin positive or uncertain cases after EP could be managed by endoscopic treatment including APC, even in cases of adenocarcinoma. EP could become an effective less-invasive first-line treatment for early stage ampullary tumors.

Risk factors and prevention of biliary anastomotic complications in adult living donor liver transplantation

To evaluate risk factors of biliary anastomotic complications （BACs） and outcomes according to type of biliary reconstruction. METHODS： A total of 33 consecutive adult living donor liver transplantation （LDLT） were reviewed, 17 of which had undergone Duct-to-Duct anastomosis （D-D）. The remaining 16 patients received Roux-en-Y anastomosis （R-Y）. The perioperative factors, such as the type of graft and the number of graft bile ducts, were analyzed retrospectively. RESULTS： The overall incidence of BACs was 39.4%. The incidence of BACs was significantly higher in the patients with than without neoadjuvant chemotherapy （71.4% vs 10%, P = 0.050）. There was no significant difference in the incidence of biliary leakage in patients with D-D vs. those with R-Y. The incidence of biliary strictures following the healing of biliary leakage was significantly higher in D-D （60%） than in R-Y （0%） （P = 0.026）. However, the incidence of BACs related bacteremia was significantly higher in R-Y than in D-D （71.4% vs 0%, P = 0.008）. In D-D, use of T-tube stent remarkably reduced the incidence of 8ACs, compared with straight tube stent （0% vs 50%, P = 0.049）. CONCLUSION： Our experience showed an increase of BACs related bacteremia in the patients with R-Y. Therefore, D-D might be a preferred biliary reconstruction. However, the surgical refinement of D-D should be required because of the high incidence of biliary strictures. Use of the T-tube stent might lead to a significant reduction of BACs in D-D.

Prophylactic lateral pelvic lymph node dissection in stage Ⅳ low rectal cancer

AIM To assess the clinical significance of prophylactic lateral pelvic lymph node dissection (LPLND) in stage Ⅳ low rectal cancer.METHODS We selected 71 consecutive stage Ⅳ low rectal cancer patients who underwent primary tumor resection,and enrolled 50 of these 71 patients without clinical LPLN metastasis.The patients had distant metastasis such as liver,lung,peritoneum,and paraaortic LN.Clinical LPLN metastasis was defined as LN with a maximum diameter of 10 mm or more on preoperative pelvic computed tomography scan.All patients underwent primary tumor resection,27 patients underwent total mesorectal excision(TME) with LPLND(LPLND group),and 23 patients underwent only TME(TME group).Bilateral LPLND was performed simultaneously with primary tumor resection in LPLND group.R0 resection of both primary and metastatic sites was achieved in 20 of 50 patients.We evaluated possible prognostic factors for 5-year overall survival (OS),and compared 5-year cumulative local recurrence between the LPLND and TME groups.RESULTS For OS,univariate analyses revealed no significant benefit in the LPLND compared with the TME group (28.7% vs 17.0%,P = 0.523); multivariate analysis revealed that R0 resection was an independent prognostic factor.Regarding cumulative local recurrence,the LPLND group showed no significant benefit compared with TME group (21.4% vs 14.8%,P = 0.833).CONCLUSION Prophylactic LPLND shows no oncological benefits in patients with Stage Ⅳ low rectal cancer without clinical LPLN metastasis.

A potent chemotherapeutic strategy in prostate cancer： S-（methoxytrityl）-L-cysteine, a novel Eg5 inhibitor

Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 （kinesin spindle protein）, which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of $-（methoxytrityl）-L-cysteine （S（MeO）TLC）, a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S（MeO）TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S（MeO）TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S（MeO）TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S（Me0）TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S（MeO）TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S（MeO）TLC exhibited its significant inhibitory activity （P〈0.05） on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S（MeO）TLC is a potent promising anticancer agent in prostate cancer.

Impact of lipoprotein lipase gene polymorphisms on ulcerative colitis

AIM： To examine the influence of lipoprotein lipase （LPL） gene polymorphism in ulcerative colitis （UC） patients.METHODS： Peripheral blood was obtained from 131 patients with UC and 106 healthy controls for DNA extraction. We determined LPL gene polymorphisms affecting the enzyme at Ser447stop, as well as Hind Ⅲ and Pvu Ⅱ polymorphisms using PCR techniques. PCR products were characterized by PCR-RFLP and direct sequencing. Polymorphisms were examined for association with clinical features in UC patients. Genotype frequencies for LPL polymorphisms were also compared between UC patients and controls.RESULTS： In patients with onset at age 20 years or younger, C/G and G/G genotypes for Ser447stop polymorphism were more prevalent than C/C genotype （OR = 3.13, 95% CI = 0.95-10.33）. Patients with H^＋/- or H^-/- genotype for Hind Ⅲ polymorphism also were more nu merous than those with H^＋/＋ genotype （OR = 2.51, 95% CI = 0.85-7.45）. In the group with H^＋/＋ genotype for Hind Ⅲ polymorphism, more patients had serum triglyceride concentrations over 150 mg/dL than patients with H^＋/- or H^- genotype （P 〈 0.01, OR = 6.46, 95% CI = 1.39-30.12）. Hypertriglycemia was also more prevalent in patients with P^＋/＋ genotypes for Pvu Ⅱ polymorphism （P 〈 0.05, OR = 3.0, 95% CI = 1.06-8.50）. Genotype frequency for LPL polymorphism did not differ significantly between UC patients and controls.

Overexpression of ETS-1 is associated with malignan＇ biological features of prostate cancer

E26 transformation-specific-1 （ETS-1）, an ETS family transcription factor, has been reported to play an important role in a variety of physiological and pathological processes, but clinical implications of ETS-1 expression in prostate cancer （PCa）, particularly high-risk cases, including response to androgen-deprivation therapy （ADT） have yet to be elucidated. We examined the expression of ETS- 1 using immunohistochemical staining of paraffin-embedded prostate carcinoma tissue obtained by needle biopsy from 69 mostly advanced PCa patients. ETS-1 expression was compared with the clinicopathological characteristics of the 69 patients, including 25 who underwent ADT as a primary treatment. As a result, PCa patients with higher expression of ETS-1 were significantly more likely to be of high stage and high Gleason score （P〈O.05）. There was no significant association between ETS-1 expression and the initial prostate-specific antigen （PSA） level. In the 25 patients treated by ADT, the staining score for ETS-1 was significantly associated with rapid development of castration-resistant disease within 24 months （P〈O.05）, whereas the Gleason score and PSA level were not. In conclusion, increased ETS-1 expression was associated with a higher stage, higher Gleason score and shorter time to castration-resistant progression. These data suggest that immunostaining for ETS-1 could be a molecular marker for predicting a poor clinical outcome for PCa patients, oarticularlv those with hi^h-risk disease.

COVID-19 vaccination and liver disease

Various vaccines against severe acute respiratory syndrome coronavirus 2 have been developed in response to the coronavirus disease 2019(COVID-19)global pandemic,several of which are highly effective in preventing COVID-19 in the general population.Patients with chronic liver diseases(CLDs),particularly those with liver cirrhosis,are considered to be at a high risk for severe COVID-19 and death.Given the increased rates of disease severity and mortality in patients with liver disease,there is an urgent need to understand the efficacy of vaccination in this population.However,the data regarding efficacy and safety of COVID-19 vaccination in patients with CLDs is limited.Indeed,several organ-specific or systemic immune-mediated side effects following COVID-19 vaccination,including liver injury similar to autoimmune hepatitis,have been recently reported.Although the number of cases of vaccine-related liver injury is increasing,its frequency,clinical course,and mechanism remain unclear.Here,we review the current findings on COVID-19 vaccination and liver disease,focusing on:(1)The impact of COVID-19 in patients with CLD;(2)The efficacy,safety,and risk-benefit profiles of COVID-19 vaccines in patients with CLD;and(3)Liver injury following COVID-19 vaccination.

Understanding the biology of urothelial cancer metastasis

Management of unresectable urothelial cancer(UC)has been a clinical challenge for decades.While drug resistance is a key issue,precise understanding of biology of UC metastasis is another challenge for the improvement of treatment outcome of UC patients.Introduction of the cell biology concepts including epithelial-mesenchymal transition(EMT)and cancer stemness seems to explain UC metastasis.Molecular genetics based on gene expression profiling,next generation sequencing,and explosion of non-coding RNA world has opened the door to intrinsic molecular subtyping of UC.Next steps include,based on the recently accumulated understanding,the establishment of novel disease models representing UC metastasis in various experimental platforms,particularly in vivo animal systems.Indeed,novel knowledge molecular genetics has not been fully linked to the modeling of UC metastasis.Further understanding of bladder carcinogenesis is needed particularly with regard to cell of origin related to tumor characteristics including driver gene alterations,pathological differentiations,and metastatic ability.Then we will be able to establish better disease models,which will consequently lead us to further understanding of biology and eventually the development of novel therapeutic strategies for UC metastasis.

Susceptibility of Aedes flavopictus miyarai and Aedes galloisi mosquito species in Japan to dengue type 2 virus

Objective: To evaluate the potential of local mosquitoes to act as vectors for dengue transmission in Japan.Methods: Serotype 2 Th NH28/93 was used to test the dengue susceptibility profiles of Aedes flavopictus miyarai(Ae. f. miyarai), Aedes galloisi(Ae. galloisi) and Aedes albopictus(Ae.albopictus), which were collected in Japan. We used Aedes aegypti from Thailand as a positive control. The mosquitoes were infected with the virus intrathoracically or orally. At 10 or 14 days post infection, the mosquitoes were dissected and total RNA was extracted from their abdomens, thoraxes, heads and legs. Mosquito susceptibility to dengue virus was evaluated using RT-PCR with dengue virus-specific primers. Differences in the infection and mortality rates of the different mosquito species were tested using Fisher's exact probability test.Results: The infection rates for dengue virus administered intrathoracically to Ae. f. miyarai,Ae. galloisi and Aedes aegypti mosquitoes were identical by RT-PCR on Day 10 post infection.All of the body parts we tested were RT-PCR-positive for dengue virus. For the orally administered virus, the infection rates in the different body parts of the Ae. f. miyarai mosquitoes were slightly higher than those of Ae. albopictus mosquitoes, but were similar to the control mosquitoes(P > 0.05). The mortality rates for Ae. f. miyarai and Ae. albopictus mosquitoes were similar(P = 0.19). Our data indicated that dengue virus was able to replicate and disseminate to secondary infection sites in all of the four mosquito species(Japanese and Thai).Conclusions: Ae. albopictus is a well-known candidate for dengue transmission in Japan. However, our data suggest that Ae. f. miyarai from Ishigaki Island(near Okinawa Island) and Ae. galloisi from Hokkaido(Northern Japan) should also be regarded as potential vectors for dengue transmission in these regions. Further studies on these mosquitoes should be conducted.

Delayed immune-related sclerosing cholangitis after discontinuation of pembrolizumab:A case report

BACKGROUND Secondary sclerosing cholangitis,characterized by biliary obstruction,can be caused by drugs such as immune checkpoint inhibitors(ICIs).While there a few reports of sclerosing cholangitis after immune checkpoint inhibitor administration,no case has been reported after discontinuation of such drugs.CASE SUMMARY A 68-year-old man who underwent chemotherapy for lung adenocarcinoma with bone metastasis presented with abdominal pain and fever 4 mo after the final administration of pembrolizumab.Computed tomography revealed thickening of the gallbladder wall and dilatation of the common bile duct.Endoscopic retrograde cholangiopancreatography revealed an irregularly narrowed intrahepatic bile duct.Biopsy of the bile duct demonstrated that CD8+T cells were predominant over CD4+T cells.Liver biopsy showed dominant infiltration of CD8+T in the portal tract,but onion-skin lesions were not observed.The patient was diagnosed with immune-related sclerosing cholangitis induced by pembrolizumab.Administration of methylprednisolone and endoscopic nasobiliary drainage were performed,but the cholangiography and laboratory test findings did not improve.No further treatment was administered due to disease progression,and the patient was referred for palliative care.CONCLUSION Immune-related sclerosing cholangitis may have a late onset,and such cases occurring after discontinuation of ICIs should be carefully managed.

Clinical management for malignant afferent loop obstruction

Afferent loop obstruction(ALO)is defined as duodenal or jejunal mechanical obstruction at the proximal anastomosis site of a gastrojejunostomy.With advances in chemotherapy,the incidence of malignant ALO is increasing.Malignant ALO can be complicated by ischemia,gangrenous bowel,pancreatitis,and ascending cholangitis.Moreover,the general condition of patients with recurrent cancer is often poor.Therefore,accurate and rapid diagnosis and minimally invasive treatments are required.However,no review articles on the diagnosis and treatment of malignant ALO have been published.Through literature searching,we reviewed related articles published between 1959 and 2020 in the PubMed database.Herein,we present recent advances in the diagnosis and treatment of malignant ALO and describe future perspectives.Endoscopic transluminal self-expandable metal stent(SEMS)placement is considered the standard treatment for malignant ALO,as this procedure is well established and less invasive.However,with the development of interventional endoscopic ultrasound(EUS)in recent years,the usefulness of EUS-guided gastrojejunostomy has been reported.Moreover,through indirect comparison,this approach has been reported to be superior to transluminal SEMS placement.It is expected that a safer and less invasive treatment method will be established through the continued advancement and innovation of interventional endoscopy techniques.

Influence of the period between onset of IgA nephropathy and medical intervention on renal prognosis

Background. The clinical course of IgA nephropathy (IgAN) is highly variable. In order to verify the necessity of early medical intervention in IgAN patients, the present study investigated the clinical impact of the duration between disease onset and first medical intervention on renal prognosis. Methods. We enrolled 57 patients diagnosed with IgAN on the basis of biopsy performed at our hospital. The medical records of these patients were traceable to the last 10 years, during which they had not undergone dialysis or treatment at any other hospital. On the basis of histological assessment of prognosis, these patients were classified according to the Japanese guidelines into the following groups: groups I, good prognosis;group II, relatively good prognosis;group III, relatively poor prognosis;and group IV, poor prognosis. We investigated the correlation between the duration of disease onset and the first consultation with a nephrologist and the rate of increase in serum creatinine over a 10 year period. In addition to the abovementioned patients, 6 patients with IgAN who underwent dialysis within the 10 years were separately evaluated. These patients came under the poor prognosis category;i.e., they belonged to group IV. Results. The duration between disease onset and medical consultation was significantly longer in younger patients or in those with asymptomatic proteinuria at onset when compared to that in older patients or in those with other urinary abnormalities. There was a significant correla tion between this duration and renal prognosis, particularly in group III patients. Although the duration between onset and consultation was not correlated to the serum creatinine level at the time of first medical intervention, urinary protein level among group IV patients at the time of first consultation was significantly higher in patients with dialysis than that in those without dialysis. Conclusions. Early medical intervention may lead to a better renal prognosis, particularly in group III patients, who form a major portion of the IgAN population. It therefore appears that early diagnostic screening and subsequent intervention are important for a good prognosis in IgAN patients.

Aquaporin 8 mRNA expression after intestinal resection in rat

Backgrounds: Aquaporins (AQPs), the mammalian water channels, have been localized in various organs, including the gastrointestinal (GI) tract. We examined AQPs expression in rat models of massive intestineal resection to determine the functions of AQPs in the GI tract. Methods: Female Sprague-Dawley rats (n = 15) underwent 90% resection of the small intestine, and Female Wistar-Kyoto rats (n = 10), received subtotal colectomy, and were sacrificed following the operations. RNase protection assay and quantitative reverse transcription-polymerase chain reaction (RT-PCR) were performed to measure the AQPs mRNA expression in the GI tract. Immunohistochemistry was performed to confirm AQP8 protein expression. Results: AQP8 mRNA expression (mean ± standard error), was enhanced in the jejunum of the short bowel rats at days 7 and 14 (37.6% ± 1.4% and 18.5% ± 2.4%, respectively, p < 0.01). Enhancement of AQP8 mRNA was also observed in the remnant rectum of the subtotal colectomized rats at both days 21 and 42 (116.1% ± 4.5% and 143.3% ± 7.4%, respectively, p < 0.01). Immunohistochemistry demonstrated enhanced AQP8 expression in the remnant rectum of the subtotal colectomized rats. No intensive change was observed with other AQPs in both models. Conclusions: Our results suggest a compensatory role of AQP8 in the maintenance of intestinal fluid balance.

编织针用含铌高碳钢的开发

我们研究了Nb的加入量小于0.05 mass%时对编织针用球化处理共析钢的淬火和回火行为的影响,获得如下结果:(1)添加0.01 mass%Nb可显著提高加热硬化性;(2)与无Nb钢相比,加入0.01 mass%Nb的钢的淬火延伸率和延伸率的标准偏差均有所下降;(3)在低温回火过程中,Nb的加入对硬度几乎没有影响,但添加0.01mas%Nb不仅能提高冲击韧性,而且能提高疲劳耐久性;(4)原子探针断层扫描(APT)分析表明,由于微量Nb的加入,碳在钢中的析出直接导致碳含量为25 at%的ε碳化物和θ碳化物的形成,但是,没有碳含量为10~15 at%的团簇的形成;(5)对于同样的P含量,当加入0.05 mass%Nb时.马氏体相中P的平均体积浓度显著增加;(6)关于低温回火马氏体的各种力学性能的最佳Nb含量,可以认为力学性能取决于正反两方面作用的平衡,正面作用是,由于Nb的加入,促进了低温回火过程中碳化物的析出,负面作用是,当加入0.02 mass%Nb时,由于增加了马氏体相中的磷的体积浓度,恶化了韧性。

Epidemiology and Management of Drug-induced Liver Injury: Importance of the Updated RUCAM

Drug-induced liver injury(DILI)is a major cause of acute liver injury,liver failure,and liver transplantation worldwide.In recent years,immune checkpoint inhibitors have become widely used.This has led to an increase in DILI,for which pathophysiology and management methods differ significantly from the past.As the number of cases of acute liver injury and liver transplantation due to DILI is expected to increase,information about a DILI is becoming more valuable.DILI is classified into two types according to its etiology:intrinsic DILI,in which the drug or its metabolites cause liver damage that is dose-dependent and predictable;and idiosyncratic DILI,in which liver damage is also dose-independent but unpredictable.In addition,depending on the course of the disease,chronic DILI or drug-induced autoimmune hepatitis may be present.The number of DILI cases caused by antimicrobial agents is decreasing,whereas that caused by drugs for malignant tumors and health foods is increasing.The Roussel Uclaf Causality Assessment Method is widely used to assess causality in DILI.Liver injury is a type of immune-related adverse event.The pattern of hepatic injury in immune-related adverse events is mostly hepatocellular,but mixed type and bile stasis have also been reported.Sclerosing cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of injury.Treatment mainly comprises withdrawal of immune checkpoint inhibitors and steroid administration;however,mycophenolate mofetil may be considered if the disease is refractory to steroids.

Pan-peroxisome proliferator-activated receptor agonist lanifibranor as a dominant candidate pharmacological therapy for nonalcoholic fatty liver disease

As obesity incidence increases worldwide,nonalcoholic fatty liver disease(NAFLD)has become the most common form of liver disease,with a reported global prevalence of 25.2%(1).Nonalcoholic steatohepatitis(NASH)is a severe form of NAFLD.However,the precise natural history of NAFLD/NASH remains unclear.NASH is rapidly becoming the leading cause of end-stage liver disorders and liver transplants and is associated with increased cardiovascular disease risk(2).As a result,it poses critical health issues globally from both medical and socioeconomic perspectives.

Hepatocellular carcinoma and type 2 diabetes mellitus: two cases highlighting changes in tumor glycogen content

This article reports two patients with hepatocellular carcinoma(HCC)and type 2 diabetes mellitus(T2DM),who showed marked changes in hepatocellular glycogen content.Periodic acid-Schiff(PAS)-positive and diastase-PAS-negative(glycogen-storing)hepatocytes were detected in both background liver parenchyma and in HCC tissues.In HCC tissues,the number of glycogen-storing cells resembling hepatocytes was considerably reduced and unevenly distributed as compared with hepatocytes in background liver.To be known,changes in hepatocellular glycogen content in T2DM patients have not been previously described.It is hypothesized that the reduction in glycogen content in both patients was likely associated with the emergence of Warburg type of glycolysis.

Pancreatolithiasis with an anatomic variant of Wirsung duct:a case report

Introduction In contrast to familiar developmental anomalies,such as pancreatobiliary maljunction and pancreas divisum,a double orifice of the ampulla of Vater is a much more rare congenital malformation.We encountered a patient with pancreatolithiasis associated with anatomic variation of Wirsung duct showing a single major duodenal papilla with a double orifice and no minor papilla.

Tropifexor,a selective non-acid farnesoid X receptor agonist,improved nonalcoholic steatohepatitis in a phase 2 trial,but several issues remain to be resolved

As obesity continues to escalate worldwide,nonalcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of liver disease,with a reported global prevalence of 30.1%(1).The prevalence of NAFLD,which was around 25%in the 1990s,has been increasing year by year in recent years and has exceeded 35%in the past few years(1).The spectrum of disease includes nonalcoholic fatty liver(NAFL),characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation,and nonalcoholic steatohepatitis(NASH),which is additionally characterized by the presence of inflammation and cellular injury(2).