Spontaneous clearance of serum HCV-RNA after splenectomy in a patient with HCV-related liver cirrhosis and portal hypertension: a case report.

BACKGROUND: Spontaneous clearance of chronic hepatitis C virus (HCV) is rare in adults. A T-lymphocyte response is thought to be involved in HCV-RNA clearance. Splenectomy reportedly has a beneficial effect on T cell immune function in patients with cirrhosis. To the best of our knowledge, the present report is the first to describe spontaneous clearance of serum HCV-RNA within 1 year after splenectomy in a patient with cirrhosis. CASE PRESENTATION: A 55-year-old man with HCV cirrhosis was transferred to our institution with advanced pancytopenia, splenomegaly, and gastric varices. He had a 1-year history of ascites, edema, and general fatigue. The patient had a Child-Pugh score of 8 and serological type 1 HCV; the HCV-RNA level was 4.7 log IU/mL. Contrast-enhanced computed tomography showed gastric varices and marked splenomegaly (estimated spleen volume of 2175 mL). Esophagogastroduodenoscopy revealed enlarged gastric varices with no red color sign, and the varices were larger than those 1 year prior. He was diagnosed with decompensated HCV-related liver cirrhosis and portal hypertension. We considered direct-acting antiviral (DAA) therapy; however, DAA therapy was not approved in Japan for patients with decompensated cirrhosis at that time. Hand-assisted laparoscopic splenectomy was performed to improve the worsening portal hypertension. Further, we planned the initiation of DAA therapy after surgery, when such therapy would become available. DAA therapy was approved 1 year after splenectomy. At that time, we measured the HCV-RNA level before the initiation of DAA therapy; unexpectedly, however, serum HCV-RNA was not detectable, and the virus continued to disappear during the following 4 years. His liver function (total bilirubin, albumin, and prothrombin time) and pancytopenia improved during the 5 years postoperatively. The serum aspartate and alanine aminotransferase levels normalized between 1 and 5 years postoperatively. Esophagogastroduodenoscopy showed no change in the gastric varices during the 5 years after surgery. The patient remained asymptomatic and continued to do well. CONCLUSIONS: We have presented a case of spontaneous clearance of HCV-RNA after splenectomy in a patient with cirrhosis and portal hypertension. Splenectomy may be associated with disappearance of HCV-RNA based on previous reports. More cases should be accumulated and evaluated.

The five-item modified frailty index predicts long-term outcomes in elderly patients undergoing colorectal cancer surgery.

BACKGROUND: Frailty has been globally recognized as a predictor of adverse postoperative outcomes. Frailty assessment using the five-factor modified frailty index (5-mFI) has recently gained traction; however, long-term outcomes are unknown in colorectal cancer (CRC) surgery. This study aimed to investigate whether the 5-mFI predicted long-term survival and cause of death on the basis of frailty severity in elderly patients who underwent CRC surgery and to determine the risk factors for mortality. METHODS: A total of 299 patients underwent CRC surgery with curative intent between January 2013 and December 2017. Patients were divided into three groups by the 5-mFI score: group 1 (5-mFI: 0 or 1; n = 164): no frailty; group 2 (5-mFI: 2; n = 91): moderate frailty; and group 3 (5-mFI: ≥ 3; n = 44): severe frailty. Clinicopathological variables, namely comorbidities, 5-mFI, prognostic nutrition index, operative/postoperative data, and outcome, including cause of death, were compared between the three groups. To identify factors associated with death from CRC- and non-CRC-related causes, univariate and multivariate analyses using a Cox regression model were performed. RESULTS: The immediate postoperative morbidity of patients with Clavien-Dindo grade ≥ III complications (9.1%) in group 3 was not significantly different from that in group 1 (9.1%) or group 2 (14.3%); however, the 30-day mortality rate (4.5%) in group 3 was significantly higher. Long-term disease-free survival was similar between frailty groups, suggesting that CRC surgery provides oncological benefit to patients irrespective of frailty. The 5-year survival rates in groups 1, 2, and 3 were 83.5%, 71.2%, and 47.9%, respectively, showing a significantly lower survival rate as frailty advanced. Sixty percent of the deaths in frail patients were due to respiratory failure and cardiovascular diseases. Multivariate analysis demonstrated that advanced age, higher 5-mFI score, and longer postoperative hospital stay were risk factors for mortality unrelated to CRC. Multivariate analysis also revealed that advanced tumor stage, carcinoembryonic antigen ≥ 5 ng/ml, undifferentiated tumor, and R1 resection were risk factors for CRC-related mortality. CONCLUSIONS: The 5-mFI score can predict postoperative short- and long-term outcomes and risk factors for mortality unrelated to CRC. Additionally, long-term survival was negatively associated with the 5-mFI score.

Colorectal cancer surgery in elderly patients 80 years and older: a comparison with younger age groups.

Background: A reduction in complications and mortality can be observed over the last few decades among elderly patients in the early postoperative period for colorectal cancer (CRC) surgery, but long-term outcomes are largely unknown. This study aimed to investigate the long-term outcomes of elderly patients 80 years and older after CRC surgery in comparison with younger age groups. The influence of clinical, oncological, and physical parameters on outcome were retrospectively analyzed. Methods: A total of 346 patients underwent CRC surgery with curative intent between January 2013 and December 2017. Patients were divided into three age groups: younger than 60 (n=47), between 60 and 79 (n=218), and 80 and older (n=81). Clinicopathological variables including comorbidity, modified frailty index, prognostic nutrition index (PNI), operative/postoperative data, and outcome including cause of death were compared among age groups. To identify factors associated with death from CRC and other causes, univariate and multivariate analyses using the Cox proportional hazards model were performed. Results: Immediate postoperative morbidity of patients with Clavien-Dindo grades of III or greater (16.0%) and the 30-day mortality rate (2.5%) of patients 80 years and older were not statistically different from those of younger age groups. Long-term disease-free survival was also similar among age groups, suggesting CRC surgery provides oncological benefit to patients irrespective of age. Multivariate analysis revealed that R1 resection, advanced tumor stage, carcinoembryonic antigen (CEA) level of >5 ng/mL, undifferentiated tumor, and longer postoperative hospital stay were risk factors for CRC death. Long-term overall survival was significantly reduced in comparison to younger age groups. Seventy percent of deaths in elderly patients during follow-up were primarily from respiratory failure and cardiovascular disease. Multivariate analysis demonstrated that advanced age, frailty, low PNI, and open procedure were risk factors for other causes of mortality. Conclusions: Elderly patients undergoing CRC surgery appeared to enjoy similar oncological benefits as younger age groups. Since both modified frailty index and PNI were correlated with mortality unrelated to CRC, preoperative assessment of these factors can be important for predicting outcome and selecting patients for prehabilitation.

A rare case of symptomatic grossly-visible biliary intraepithelial neoplasia mimicking cholangiocarcinoma.

BACKGROUND: Biliary intraepithelial neoplasia (BilIN) is often distinguished by what it is not: the precancerous lesions are not mass-forming, are not the cause of bile duct obstruction, and are small enough (less than 5 mm long) to evade detection by the naked eye. Here, we describe an atypical case of BilIN resembling cholangiocarcinoma (CC) that was large enough to be identified by diagnostic imaging and presented with obstructive jaundice caused by a hematoma in the common bile duct (CBD). CASE PRESENTATION: A 64-year-old man presented to our hospital with upper abdominal pain and anorexia. Initial laboratory examinations revealed increased total bilirubin and a computed tomography (CT) scan revealed a dilated CBD. Gastroenterologists performed an endoscopic sphincterotomy (EST), which revealed that the cause of obstructive jaundice was a hematoma in the CBD. Enhanced CT scan and magnetic resonance cholangiopancreatography (MRCP) performed after the hematoma was drained showed improved dilation of the CBD and an enhanced wall thickness of bile duct measuring 25 × 10 mm at the union of the cystic and common hepatic ducts. A cholangioscope detected an elevated tumor covered by sludge in the CBD, and we performed an extrahepatic bile duct resection and cholecystectomy. The postoperative course was uneventful and the pathological examination of the resected tumor revealed that although the ulcerated lesion had inflammatory granulation tissue, it did not contain the components of invasive carcinoma. Many consecutive intraepithelial micropapillary lesions spread around the ulcerated lesion, and the epithelial cells showed an increased nucleus-to-cytoplasm ratio, nuclear hyperchromasia, and architectural atypia. The pathological diagnosis was BilIN-1 to -2. Immunohistochemical staining showed that S100P was slightly expressed and MUC5AC was positive, while MUC1 was negative and p53 was not overexpressed. CONCLUSION: We experienced an atypical case of BilIN mimicking CC that presented with obstructive jaundice caused by a hematoma in the CBD. Our case suggested that the occurrence of BilIN can be triggered by factors other than inflammation, and can grow to a size large enough to be detected by image analyses.

Dendritic cells conditioned with NK026680 prolong cardiac allograft survival in mice.

BACKGROUND: Pharmacologically modulated dendritic cells (DCs) can potentially regulate alloimmune responses. We examined the characteristics of immunoregulatory DCs induced by a novel triazolopyrimidine derivative, NK026680, which has been previously shown to inhibit DC maturation. METHODS: DCs were generated from bone marrow progenitor cells from C57BL/6 (B6, H-2 haplotype) mice with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. DCs were cultured with allogeneic BALB/c (H-2) splenocyte lysates with or without NK026680. DC functions were examined in vitro after stimulation of tumor necrosis factor α and in vivo by the intravenous injection of C3He/J (C3H, H-2) DCs cultured with B6 cell lysates and NK026680 into C3H mice. Seven days later, DC-treated mice received B6 heart allografts, and graft survival and alloimmune responses were assessed. RESULTS: In NK026680-treated DCs (NK-DCs), significant inhibition of the up-regulation of surface activation markers (CD40, CD80, CD86, and major histocompatibility complex class II) and IL-12 p40 production was observed after stimulation of tumor necrosis factor α compared with that of control DCs. Furthermore, NK-DCs suppressed alloreactive T-cell proliferation. The modulation of NK-DCs was likely associated with the inhibition of phosphorylation of p38 mitogen-activated protein kinase and the up-regulation of indolamine 2,3-dioxygenase expression. Compared with both noninjected and control DC-injected mice, mice that received a single in vivo infusion of NK-DCs showed significant increases in splenocyte IL-10 production and the splenic CD4 IL-10 T-cell population 7 days after injection, a significantly increased splenic CD4CD25FoxP3 T-cell population 14 days after injection, and markedly prolonged cardiac allograft survival. CONCLUSIONS: Ex vivo NK026680 conditioning allows DCs to acquire immunoregulatory properties that suppress alloimmune responses and prolong cardiac allograft survival.

Successful transplantation of rat hearts subjected to extended cold preservation with a novel preservation solution.

Since prolonged cold preservation of the heart deteriorates the outcome of heart transplantation, a more protective preservation solution is required. We therefore developed a new solution, named Dsol, and examined whether Dsol, in comparison to UW, could better inhibit myocardial injury resulting from prolonged cold preservation. Syngeneic heterotopic heart transplantation in Lewis rats was performed after cold preservation with UW or Dsol for 24 or 36 h. In addition to graft survival, myocardial injury, ATP content, and Ca(2+) -dependent proteases activity were assessed in the 24-h preservation group. The cytosolic Ca(2+) concentration of H9c2 cardiomyocytes after 24-h cold preservation was assessed. Dsol significantly improved 7-day graft survival after 36-h preservation. After 24-h preservation, Dsol was associated with significantly faster recovery of ATP content and less activation of calpain and caspase-3 after reperfusion. Dsol diminished graft injury significantly, as revealed by the lower levels of infarction, apoptosis, serum LDH and AST release, and graft fibrosis at 7-day. Dsol significantly inhibited Ca(2+) overload during cold preservation. Dsol inhibited myocardial injury and improved graft survival by suppressing Ca(2+) overload during the preservation and the activation of Ca(2+) -dependent proteases. Dsol is therefore considered a better alternative to UW to ameliorate the outcome of heart transplantation.

Immunomodulatory effect of nuclear factor-κB inhibition by dehydroxymethylepoxyquinomicin in combination with donor-specific blood transfusion.

BACKGROUND: Nuclear factor-κB (NF-κB) is a key molecule in alloimmune responses, however, its role in tolerance induction is not clear. We have previously reported that dehydroxymethylepoxyquinomycin (DHMEQ), a novel NF-κB inhibitor, prolongs cardiac allograft survival. In this study, we evaluated the immunomodulatory effects of DHMEQ when combined with a donor-specific blood transfusion (DST), and assessed whether the treatment induces tolerance in a mouse heart transplantation model. METHODS: DST (20×10 splenocytes) was given intravenously at day -7. DHMEQ (30 mg/kg/day) was administered intraperitoneally for 14 days after DST. Graft survival and histology were evaluated. The underlying mechanisms of immunomodulation by DST and DHMEQ treatments were investigated by assessing alloimmune responses after transplantation. RESULTS: In fully mismatched H2-to-H2 heart transplants, DST alone prolonged allograft median survival time to 15 days, whereas when DST was combined with DHMEQ treatment, the graft median survival time was prolonged to 39.5 days. When the donor-recipient strain combination was reversed, that is, H2-to-H2, heart transplants were accepted (>150 days survival) in more than 60% of recipients treated with a DST and DHMEQ, whereas control allografts were all rejected within 8 days. The combined therapy markedly inhibited immune responses by both the direct and indirect allorecognition pathways mainly attributed to promotion of activation-induced cell death and Treg generation. CONCLUSIONS: Our results demonstrate the distinctive ability of NF-κB inhibition in combination with donor alloantigen to promote transplantation tolerance through multiple cellular mechanisms.

NK026680 inhibits T-cell function in an IL-2-dependent manner and prolongs cardiac allograft survival in rats.

NK026680 is a triazolopyrimidine derivative that has been shown to inhibit dendritic cell maturation and activation. Here, we examined the immunosuppressive properties of NK026680 on T-cell function and assessed its immunosuppressive efficacy in an ACI (RT1(av1) haplotype) to Lewis (RT1(l)) rat heart transplantation model. The effects of NK026680 on T-cell proliferation, activation, and cytokine production were investigated in vitro. Heart transplant recipient rats were administered NK026680 daily for 14 days post-transplantation. In addition to graft survival time, alloimmune responses and graft histology at 4-10 days post-transplantation were assessed. NK026680 was found to inhibit proliferation, CD25 upregulation, IL-2 production, and cell cycle progression in αCD3/αCD28-stimulated murine T cells. These effects were likely due to suppression of the p38 mitogen-activated protein kinase pathway and the subsequent inhibition of p65, c-Fos, and to a lesser extent, c-Jun. Daily NK026680 treatment suppressed alloimmune responses, prevented cellular infiltration into allografts, and prolonged graft survival. The anti-rejection effects of NK026680 were enhanced by tacrolimus. In conclusion, NK026680 inhibits the activation of T cells and prolongs cardiac allograft survival in rats. These features make it a potential candidate immunosuppressant for the treatment of organ transplant patients in the future.

Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone.

OBJECTIVE: We have previously synthesized a novel piperidine compound, 3-[(dodecylthiocarbonyl)methyl]glutarimide (DTCM-glutarimide), that inhibits LPS-induced NO production, and in the present research we studied further the anti-inflammatory activity of DTCM-glutarimide in a macrophage cell line and in mice bearing transplanted hearts. MATERIALS AND METHODS: Mouse macrophage-like RAW264.7 cells were employed for the evaluation of cellular inflammatory activity. DTCM-glutarimide was synthesized in our laboratory. The AP-1 activity was measured by nuclear translocation and phosphorylation. For the heart transplantation experiment, male C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donor and recipient, respectively. DTCM-glutarimide was administered intraperitoneally. RESULTS: DTCM-glutarimide inhibited the LPS-induced expression of iNOS and COX-2 in macrophages; but, unexpectedly, it did not inhibit LPS-induced NF-κB activation. Instead, it inhibited the nuclear translocation of both c-Jun and c-Fos. It also inhibited LPS-induced c-Jun phosphorylation. Moreover, it inhibited the mixed lymphocyte reaction in primary cultures of mouse spleen cells; and furthermore, in mice it prolonged the graft survival in heart transplantation experiments. CONCLUSION: The novel piperidine compound, DTCM-glutarimide, was found to be a new inhibitor of macrophage activation, inhibiting AP-1 activity. It also inhibited graft rejection in mice, and thus may be a candidate for an anti-inflammatory agent.

Risk factors for portal vein complications in pediatric living donor liver transplantation.

BACKGROUND: Portal vein (PV) complications in pediatric living donor liver transplantation (LDLT) are often asymptomatic in the early stages after transplantation and can be serious enough to lead to graft failure. There have been few reports on risk factors for PV complications in LDLT. The aim of this study is to investigate the influence of hepatic inflow upon PV complications and to predict patients at risk for these complications. MATERIAL/METHOD: From 1997 to 2008, 46 pediatric patients underwent LDLT at our center. Portal venous and hepatic arterial flows and PV diameter were analyzed. RESULTS: PV complications were identified in seven patients (15.2%) and occurred at a younger age and lower weight. As a result of appropriate treatment, none of the patients suffered graft failure. Analysis of the 46 patients and 27 patients under two yr of age identified smaller PV diameter in recipient and larger discrepancy of PV diameter as risk factors. Portal venous flow tended to be low, in contrast to hepatic arterial flow, which tended to be high. CONCLUSION: PV size strongly influences PV complications. Other factors such as younger age, low portal venous flow, and high hepatic arterial flow may be risk factors for PV complications.

[A case of local recurrence of rectal cancer in long-term responding to combined therapy of low-dose CPT-11 and 5'-DFUR].

A 68-year-old man underwent Miles'operation for advanced rectal cancer. Local recurrence occurred 9 months following the operation. We started the combined therapy of low-dose CPT-11 and doxifluridine (5'-DFUR). CPT-11 was administered at 80 mg/body biweekly and 5'-DFUR was orally administered at 800 mg/day/body on day 3-7. We then reduced the CPT-11 dose to 60 mg/body because of neutropenia. Four months later,we obtained a decrease in the tumor marker (carcinoembryonic antigen: CEA) to the normal serum level, and stopped the medication. However, 3 months later the serum CEA level was increased, and we restarted the same therapy. Six months after restarting this therapy, the serum CEA level decreased to the normal level,and the local recurrence was decreased in size. We finished this combined therapy and changed to 5'-DFUR only. No tumor progression or recurrences in this patient are seen 2 years after completing this combined therapy.