The usefulness of preoperative bile cultures for hepatectomy with biliary reconstruction

[Background] Infectious complications can cause lethal liver failure after hepatectomy with biliary reconstruction. This study assessed the increased risk for postoperative infectious complications in patients who underwent hepatectomy with biliary reconstruction and explored the possibility of predicting pathogenic microorganisms causing postoperative infectious complications based on preoperative monitoring of bile cultures. [Methods] This study involved 310 patients who received major hepatectomy with or without biliary reconstruction at our institution between January 2010 and December 2019. The relationship between the microorganisms detected through perioperative monitoring of bile culture and those in the postoperative infectious foci was examined. [Results] Forty-nine patients underwent major hepatectomy with biliary reconstruction, and 261 received hepatectomy without biliary reconstruction. The multivariate analysis revealed hepatectomy with biliary reconstruction to be associated with an increased risk of postoperative infectious complications (odds ratio: 22.9, 95% confidence interval: 5.2–164.3) compared to hepatectomy without biliary reconstruction. In the patients with biliary reconstruction, the concordance rates between the microorganisms detected in the postoperative infectious foci and those in preoperative bile cultures were as follows: incisional surgical site infection (44.4%), organ/space surgical site infection (52.9%), bacteremia (47.1%), and pneumonia (16.7%); the concordance rates were high, and the risk of infection increased over time. [Conclusions] Biliary reconstruction is a significant risk factor for postoperative infectious complications, and preoperative bile cultures may aid in prophylactic and therapeutic antimicrobial agent selection

A unique profile of insulin antibody titer in islet‐transplanted patients

Insulin antibodies (IAs) can cause glycemic variability. Islet transplantation (ITx) is a treatment for insulin-deficient diabetes that aims to establish on-target glycemic control in the absence of hypoglycemia. To date, there has not been a detailed case study of the association between ITx and IA levels. In this study, we identified a unique profile of IA titers, which differed from glutamic acid decarboxylase antibody titers, in four ITx patients. IA levels decreased with intensified immunosuppressive therapy, whereas glutamic acid decarboxylase antibodies increased transiently after ITx. These data suggest the possibility that IAs, unlike other islet autoantibodies, were eliminated due to immunosuppression after transplantation therapy. The disappearance of IAs, as well as the restoration of regulated insulin secretion after ITx, might have a positive effect on glycemic control in recipients with diabetes. Furthermore, this unique feature is suggestive of immunological pathogenesis and has implications for the treatment of IA-causing disease conditions

Acute coronary syndrome after liver transplantation in a young primary biliary cholangitis recipient with dyslipidemia: a case report

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic, progressive liver disease associated with dyslipidemia. There is a consensus that PBC does not accelerate coronary artery disease despite high cholesterol levels, so the screening test for the coronary artery is not routinely performed before liver transplantation (LT). To date, no report has described the potential risk of PBC-related dyslipidemia for developing acute coronary syndrome (ACS) after LT. CASE PRESENTATION: A 40-year-old Asian female with a known history of PBC underwent ABO-incompatible living-donor LT, with her husband as the donor. Although she had high cholesterol and triglyceride levels that were refractory to medications, she passed all routine preoperative examinations, including cardiopulmonary function tests and infection screenings. One week after LT, she developed ACS with 90% stenosis of both the left anterior descending artery and left circumflex artery. Emergent stent implantation was successfully performed followed by dual antiplatelet therapy. The long history of PBC and associated severe dyslipidemia for 10 years would have accelerated the atherosclerosis, causing latent stenosis in the coronary artery. Inapparent stenosis might have become apparent due to unstable hemodynamics during the acute phase after LT. CONCLUSIONS: PBC-related dyslipidemia potentially brings a risk for developing ACS after LT. This experience suggests that the preoperative evaluation of the coronary artery should be considered for high-risk patients, especially those who have drug-resistant dyslipidemia

En bloc excision of giant polycystic liver with hepatic cava and its auto-transplant caval reconstruction as a safe surgical procedure for liver transplantation

Safely excising a giant liver while leaving the hepatic inferior vena cava intact is difficult. Hata et al. present images and videos describing their novel technique consisting of total hepatectomy including the hepatic cava; extracorporeal retrieval; and auto‐transplant inferior vena cava reconstruction, for an extremely enlarged polycystic liver weighing 24 kg.[Image: see text

Establishment of patient-derived organoids and a characterization-based drug discovery platform for treatment of pancreatic cancer

BACKGROUND: Pancreatic cancer is one of the most lethal tumors. The aim of this study is to provide an effective therapeutic discovery platform for pancreatic cancer by establishing and characterizing patient-derived organoids (PDOs). METHODS: PDOs were established from pancreatic tumor surgical specimens, and the mutations were examined using a panel sequence. Expression of markers was assessed by PCR, immunoblotting, and immunohistochemistry; tumorigenicity was examined using immunodeficient mice, and drug responses were examined in vitro and in vivo. RESULTS: PDOs were established from eight primary and metastatic tumors, and the characteristic mutations and expression of cancer stem cell markers and CA19-9 were confirmed. Tumorigenicity of the PDOs was confirmed in subcutaneous transplantation and in the peritoneal cavity in the case of PDOs derived from disseminated nodules. Gemcitabine-sensitive/resistant PDOs showed consistent responses in vivo. High throughput screening in PDOs identified a compound effective for inhibiting tumor growth of a gemcitabine-resistant PDO xenograft model. CONCLUSIONS: This PDO-based platform captures important aspects of treatment-resistant pancreatic cancer and its metastatic features, suggesting that this study may serve as a tool for the discovery of personalized therapies

NF-κB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-α– and Fas-mediated apoptosis

AbstractBackground & Aims: Hepatocyte apoptosis is induced by tumor necrosis factor α (TNF-α) and Fas ligand. Although nuclear factor–κB (NF-κB) activation protects hepatocytes from TNF-α–mediated apoptosis, the NF-κB responsive genes that protect hepatocytes are unknown. Our aim was to study the role of NF-κB activation and inducible nitric oxide synthases (iNOSs) in TNF-α– and Fas-mediated apoptosis in hepatocytes. Methods: Primary cultures of hepatocytes from wild-type and iNOS knockout mice were treated with TNF-α, the Fas agonistic antibody Jo2, a nitric oxide (NO) donor (S-nitroso-N-acetylpenicillamine), an NO inhibitor (NG-methyl-L-arginine acetate), and/or adenovirus-expressing NF-κB inhibitors. Results: The IκB superrepressor and a dominant-negative form of IκB kinase beta (IKKβ) inhibited NF-κB binding activity by TNF-α or Jo2 and sensitized hepatocytes to TNF-α– and Jo2-mediated apoptosis. TNF-α and Jo2 induced iNOS messenger RNA and protein levels through the induction of NF-κB. S-nitroso-N-acetylpenicillamine inhibited Bid cleavage, the mitochondrial permeability transition, cytochrome c release, and caspase-8 and -3 activity, and reduced TNF-α– and Fas-mediated death in hepatocytes expressing IκB superrepressor. NG-methyl-L-arginine acetate partially sensitized hepatocytes to TNF-α– and Fas-mediated cell killing. TNF-α alone or Jo2 alone induced moderate cell death in hepatocytes from iNOS−/− mice. Conclusions: NO protects hepatocytes from TNF-α– and Fas-mediated apoptosis. Endogenous iNOS, which is activated by NF-κB via IKKβ, provides partial protection from apoptosis.GASTROENTEROLOGY 2001;120:1251-126

Properdin inhibition ameliorates hepatic ischemia/reperfusion injury without interfering with liver regeneration in mice

Hepatic ischemia/reperfusion injury (IRI) often causes serious complications in liver surgeries, including transplantation. Complement activation seems to be involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Properdin-targeted complement regulation in hepatic IRI. Male wild-type mice (B10D2/nSn) were exposed to 90-minute partial hepatic IRI to the left and median lobes with either monoclonal anti-Properdin-antibody (Ab) or control-immunoglobulin (IgG) administration. Since the complement system is closely involved in liver regeneration, the influence of anti-Properdin-Ab on liver regeneration was also evaluated in a mouse model of 70% partial hepatectomy. Anti-Properdin-Ab significantly reduced serum transaminases and histopathological damages at 2 and 6 hours after reperfusion (P <0.001, respectively). These improvements at 2 hours was accompanied by significant reductions in CD41+ platelet aggregation (P =0.010) and ssDNA+ cells (P <0.001), indicating significant amelioration in hepatic microcirculation and apoptosis, respectively. Characteristically, F4/80+ cells representing macrophages, mainly Kupffer cells, were maintained by anti-Properdin-Ab (P <0.001). Western blot showed decreased phosphorylation of only Erk1/2 among MAPKs (P =0.004). After 6 hours of reperfusion, anti-Properdin-Ab significantly attenuated the release of HMGB-1, which provokes the release of proinflammatory cytokines/chemokines (P =0.002). Infiltration of CD11b+ and Ly6-G+ cells, representing infiltrating macrophages and neutrophils, respectively, were significantly alleviated by anti-Properdin-Ab (both P <0.001). Notably, anti-Properdin-Ab did not affect remnant liver weight and BrdU+ cells at 48 hours after 70% partial hepatectomy (P =0.13 and 0.31, respectively). In conclusion, Properdin inhibition significantly ameliorates hepatic IRI without interfering with liver regeneration

Efficacy and Safety of External-beam Radiation Therapy for Unresectable Primary or Local Recurrent Cholangiocarcinoma

Background/Aim: Treatment options for unresectable cholangiocarcinoma are limited. The aim of the study was to evaluate the clinical outcomes of definitive external-beam radiation therapy (EBRT) for patients with unresectable cholangiocarcinoma. Patients and Methods: Patients with unresectable primary cholangiocarcinoma, or local recurrent cholangiocarcinoma after primary surgery, without distant metastasis who received definitive EBRT (≥45 Gy) between January 2006 and December 2020 at our Institution were analyzed retrospectively. EBRT was basically performed using conventional fractionation (1.8-2 Gy per fraction). Prophylactic nodal irradiation was not performed. Results: A total of 21 consecutive patients were analyzed: 7 primary and 14 recurrent cases. The median age was 70 (range=38–85) years at initiation of EBRT. A median dose of 54 (range=45-60) Gy comprising 1.8 (range=1.8-3) Gy per fraction was administered to the primary/recurrent local tumor site. The median follow-up period was 21.6 months. The 2-year overall survival, cause-specific survival, progression-free survival, and local recurrence-free rates were 35.7, 35.7, 16.1, and 32.7%, respectively. Long-term local control (>2 years after EBRT) was achieved in 19.0%. Grade 3 toxicities related to EBRT were observed in 4.8% (duodenum hemorrhage). No grade 4 or higher toxicities were observed. Conclusion: Definitive EBRT for unresectable cholangiocarcinoma was feasible and achieved long-term local control in a subset of patients. As the avoidance of local recurrence may lead to the benefits of prolonging biliary patency and subsequently alleviating the need for an invasive procedure for biliary drainage, EBRT could be one sustainable therapeutic option for patients with unresectable cholangiocarcinoma

Antagonist of sphingosine 1-phosphate receptor 3 reduces cold injury of rat donor hearts for transplantation

Cold storage is widely used to preserve an organ for transplantation; however, a long duration of cold storage negatively impacts graft function. Unfortunately, the mechanisms underlying cold exposure remain unclear. Based on the sphingosine-1-phosphate (S1P) signal involved in cold tolerance in hibernating mammals, we hypothesized that S1P signal blockage reduces damage from cold storage. We used an in vitro cold storage and rewarming model to evaluate cold injury and investigated the relationship between cold injury and S1P signal. Compounds affecting S1P receptors (S1PR) were screened for their protective effect in this model and its inhibitory effect on S1PRs was measured using the NanoLuc Binary Technology (NanoBiT)-β-arrestin recruitment assays. The effects of a potent antagonist were examined via heterotopic abdominal rat heart transplantation. The heart grafts were transplanted after 24-hour preservation and evaluated on day 7 after transplantation. Cold injury increased depending on the cold storage time and was induced by S1P. The most potent antagonist strongly suppressed cold injury consistent with the effect of S1P deprivation in vitro. In vivo, this antagonist enabled 24-hour preservation, and drastically improved the beating score, cardiac size, and serological markers. Pathological analysis revealed that it suppressed the interstitial edema, inflammatory cell infiltration, myocyte lesion, TUNEL-positive cell death, and fibrosis. In conclusion, S1PR3 antagonist reduced cold injury, extended the cold preservation time, and improved graft viability. Cold preservation strategies via S1P signaling may have clinical applications in organ preservation for transplantation and contribute to an increase in the donor pool