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Background: Hypophosphatasia (HPP) is an inherited multisystem disorder predominantly affecting the mineralization of bones and teeth. HPP is caused by pathogenic variants in ALPL, which encodes tissue non-specific alkaline phosphatase (TNSALP). Variants of uncertain significance (VUS) cause diagnostic delay and uncertainty amongst patients and health care providers., Results: The ALPL gene variant database (https://alplmutationdatabase.jku.at/) is an open-access archive for interpretation of the clinical significance of variants reported in ALPL. The database contains coding and non-coding variants, including single nucleotide variants, insertions/deletions and structural variants affecting coding or non-coding sequences of ALPL. Each variant in the database is displayed with details explaining the corresponding pathogenicity, and all reported genotypes and phenotypes, including references. In 2021, the ALPL gene variant classification project was established to reclassify VUS and continuously assess and update genetic, phenotypic, and functional variant information in the database. For this purpose, the database provides a unique submission system for clinicians, geneticists, genetic counselors, and researchers to submit VUS within ALPL for classification. An international, multidisciplinary consortium of HPP experts has been established to reclassify the submitted VUS using a multi-step process adhering to the stringent ACMG/AMP variant classification guidelines. These steps include a clinical phenotype assessment, deep literature research including artificial intelligence technology, molecular genetic assessment, and in-vitro functional testing of variants in a co-transfection model to measure ALP residual activity., Conclusion: This classification project and the ALPL gene variant database will serve the global medical community, widen the genotypic and phenotypic HPP spectrum by reporting and characterizing new ALPL variants based on ACMG/AMP criteria and thus facilitate improved genetic counseling and medical decision-making for affected patients and families. The project may also serve as a gold standard framework for multidisciplinary collaboration for variant interpretation in other rare diseases., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We performed a mono-institutional study for evaluating the biological data, such as p53, Ki67 and BRCA mutations, as well as clinical characteristics of pregnancy associated breast cancer (PABC), its therapeutic management and the prognosis in a small cohort of patients., Materials and Methods: We retrospectively examined 26 patients with PABC. Clinical and histopathological characteristics along with Ki67, p53 and BRCA mutations were analysed. Information about chemotherapy, surgery and radiotherapy was recovered. Data about long-term prognosis was registered and computed by Kaplan-Meier analysis., Results: Of 26 patients, 17 (65%) were considered as having a locally advanced breast cancer. The majority of them (65.4%) had a ductal invasive carcinoma. Oestrogen and progesterone receptors were positive in 13 (50%) patients, resulting both negative in four (15.4%) subjects. HER-2 was positive in 5 subjects (19.2%). Ten patients underwent conservative surgery treatment, and 14 were sent to radical mastectomy (38 vs. 54%) associated with axillary lymph node dissection in 18 cases. Many patients (65%) were further treated with adjuvant chemotherapy and/or hormone therapy. Eight out of 11 patients undergoing the evaluation of BRCA mutation were positive while only 2 out of 3 patients had a mutation of p53. After a median follow-up of 110 months (range: 8.2-1227 mo.), 18 women were still alive, six patients (25%) died and two were lost. Three patients showed a loco-regional recurrence, after a median period of 26 months (range: 2-42 mo.). Distant metastases verified in six patients after a median period of 12.5 months (range: 2-108 mo.). The prognosis was less favourable in BRCA mutated patients than no-BRCA mutated group, although not statistically significant., Conclusions: In women with PABC, the initial stage of disease is more advanced requiring more aggressive treatment., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma may be unresectable for volumetric reasons. The future remaining liver after hepatectomy might be too small to ensure survival. Preoperative selective portal vein embolization of the tumorous lobe can induce hypertrophy of the future remaining liver and enable safer surgery. A 76-year-old patient with hepatocellular carcinoma needed right lobectomy however, the future remaining liver was judged insufficient to ensure an uneventful postoperative course. The left lobe to whole liver volumetric ratio was to small (29.7%) and a preoperative selective portal vein embolization of the right portal branch via a percutaneous, transhepatic, contralateral approach was performed without side effects. A Doppler estimation of left branch portal blood flow and velocity was carried out before and after preoperative selective portal vein embolization. After 21 days the left lobe volume increased by about 44.2% with a safe left lobe/whole liver ratio of 40.8%. The portal blood flow and portal blood flow velocity showed an increase of 253% and 122%, respectively. A right lobectomy was performed without complications. Three months later, computed tomography scan showed no hepatocellular carcinoma recurrence. Preoperative selective portal vein embolization is a safe technique which can enable major hepatectomy to be performed in situations otherwise judged unresectable for a life-threatening volumetric insufficiency. The portal blood flow and portal blood flow velocity evaluations can easily predict the hypertrophy rate of non-embolized liver segments.

Intravenous methylprednisolone is used in most liver transplant centers as first-line therapy of acute hepatic cellular rejection in patients who undergo liver transplant. However, no controlled study has been performed to date to define the optimal dose and duration of the steroid regimen. The schedules that actually are used in most transplant centers are drawn from those that were developed empirically for the treatment of acute renal graft rejection. Thus, the aim of the study was to compare two schedules of steroid treatment of acute hepatic cellular rejection among those most widely used. Thirty-eight eligible patients with grade II or III acute hepatic cellular rejection were randomized to receive two different high-dose methylprednisolone schedules. Eighteen patients were randomized in group A (intravenous dose of 1,000 mg of methylprednisolone followed by a 6-day taper from 200 to 20 mg/d). Twenty patients were randomized in group B (intravenous dose of 1,000 mg of methylprednisolone for three consecutive days). The response to treatment was evaluated by means of a second liver biopsy. The treatment of group A proved to be more effective than treatment of group B. The resolution of acute hepatic cellular rejection was observed in 83.3% of cases in group A and 50.0% of cases in group B (P <.05). The treatment of group A proved to be safer also than treatment of group B. Patients randomized in group B showed a higher prevalence of infections (90.0% of cases versus 55.5% of cases; P <.01) mainly because of bacterial (80.0% versus 50.0%; P <.05) and viral (50.0% versus 16.6%; P <.05) agents. In conclusion, the study shows that intravenous administration of 1,000 mg of methylprednisolone followed by a 6-day taper from 200 to 20 mg/d is more effective and safer than intravenous dose of 1,000 mg of methylprednisolone for three consecutive days in the treatment of acute cellular rejection in patients with liver transplantation.

Background: Fistulous communications between the accessory right hepatic (ARHA), gastroduodenal (GD), and superior mesenteric (SMA) arteries and the portal vein (PV) may represent a contraindication for liver transplantation (LT)., Material: A patient with HCV-related liver cirrhosis and progressive liver decompensation underwent preoperative LT work-up. Doppler ultrasound (DU), Angiography and MRI revealed arteroportal fistulas (APF) and diversion of mesenteric-splenoportal flow through spontaneous splenorenal shunts (SSRS) in the systemic circulation. The patient was transplanted and the ARHA and GDA were distally sectioned; the HA was anastomosed to the donor HA; the superior mesenteric vein (SMV) was detached from the splenopancreatic venous bed by sectioning and ligating the Henle trunk, by ligating an posterior-inferior pancreatic vein and, finally, by positioning an iliac vein interposition graft between the SMV and the donor PV. The postanastomotic SMV trunk and recipient PV were ligated below and above the pancreatic head, respectively., Results: Reperfusion and late liver function were good. DU and MRI studies showed an effective portal flow and the maintenance of a normal splenopancreatic vein outflow through the SSRS., Discussion: APF represent a serious clinical problem, particularly in patients who need LT. The persistence of arterial flow into the PV is dangerous for the long-term liver function. A particular surgical strategy, strictly tailored to the hemodynamic conditions, has to be planned., Conclusions: Extrahepatic multiple APF would no longer to represent a contraindication to LT, although this claim needs to be confirmed in the light of further experience and a longer-term follow-up.

Orthotopic liver transplantation (OLT) may be feasible even in the presence of diffuse portal vein thrombosis (PVT) in the recipient, providing hepatopetal portal flow to the graft can be ensured. Cavoportal hemitransposition was used in selected cases in which no other salvage solutions were technically possible. We report our experience of two patients with diffuse thrombosis of the entire portal system. One patient also had thrombosis of a previous portacaval shunt with a synthetic interposition graft. Portal pedicle dissection and native hepatectomy (with or without vena cava removal) appeared difficult. Bleeding from the exposed area was severe, and in one case, a new laparotomy was necessary to stop the abdominal hemorrhage. The postoperative course was complicated by severe ascites (with fluid infection and surgically drained suprahepatic abscess in one case), renal insufficiency (requiring dialysis in one case), esophagogastric variceal bleeding (needing several sessions of endoscopic treatment), and bronchopneumonic infections (in one case, superinfection with Aspergillus fumigatus despite amphotericin B lipid complex therapy led to the patient's death from multiorgan failure). Our experience was compared with 17 other cases in the literature. Etiologic factors, preoperative diagnostics, surgical problems, and postoperative complications are focused on and discussed. Diffuse PVT no longer appears to be an absolute contraindication to OLT, although cavoportal hemitransposition needs further experience and long-term follow-up.

Background/aims: The recipient hepatectomy with vena cava in situ in liver transplantation has overcome the need of venous-venous bypass thanks to temporary porta caval shunt or portal clamping., Methodology: 150 orthotopic liver transplants in 137 patients were performed and the vena cava in situ technique was used in 142 (venous bypass in 7, temporary porta caval shunt in 49, portal clamping in 87). The suprahepatic cava veins anastomosis was performed with Belghiti in 97 and piggyback techniques in 45., Results: There were no differences in operative and warm ischemia times nor in blood requirements, while a greater stability of body temperature was documented in the vena cava In Situ group: in the latter temporary porta caval shunt preserved the temperature better than portal clamping (P < 0.01). In anhepatic phase mean artery pressure decreased in veno-venous bypass and increased in the vena cava In situ groups (P < 0.01). The venous return and the cardiac performances (anhepatic phase) were better preserved in the vena cava In Situ group. (P < 0.0001)., Conclusions: Temporary portal caval shunt or portal clamping and piggyback or Belgiti Techniques allow a better hemodynamic stability through out the procedure, obviating the need for veno-venous bypass or fluid overload, if selectively used.

The aim of this study was to clarify whether chemoembolization (TACE) before liver resection (LR) can reduce postoperative hepatocellular carcinoma (HCC) recurrence and improve disease-free and overall survival. Eighty-nine patients with tumor-stage (TNM) I-II HCC were evaluated for LR. Patients were prospectively allocated to LR alone or TACE plus LR based on their place of residence. Twenty nonlocal patients (24%) were selected for LR, while 69 (77.5%) local patients were selected for TACE plus LR. Following TACE, the tumor stage could be confirmed in only 20 patients (29%) who then underwent LR. Operative mortality was 0%, but in the TACE-LR group, 3 patients died of liver failure between 2 and 5 months after surgery. Early recurrence (<24 months) was 59% for LR versus 20% for TACE plus LR (P <.05). Late recurrence was 18% for LR versus 10% for TACE plus LR (P = not significant [NS]). The overall recurrence rate was 76% for LR versus 30% for TACE plus LR (P <.02). Death due to HCC recurrence was 70% for LR versus 15% for TACE plus LR (P <.05). The overall 1- and 5-year survival rates did not differ significantly (71% to 38% for LR v 85% to 43% for TACE + LR; P = NS), whereas the difference in 1- and 5-year disease-free survival was highly significant (64% to 21% for LR v 82% to 57% for TACE + LR; P <.02). TACE was able to improve the HCC staging process and significantly reduce the incidence of early and overall HCC recurrence and related death after LR; it improved the disease-free interval, but not the overall survival, due to an increase in liver failure in the first 5 months.

Clinical and experimental data show that beta-IFN enhances the effect of tamoxifen on advanced breast cancer. There is a similarity between breast and liver as far as the proliferating effect on normal and neoplastic tissue of estrogen and progestin receptors is concerned. The authors tested this pharmacological association in unresectable liver neoplasms. They considered 76 (not randomized) patients affected with HCC; 38 were treated by trans-arterial chemoembolization (TACE) and 38 to beta-INF and tamoxifen (the 2 groups were comparable according to age, sex, Child-Pugh score, Okuda and TNM stages, cirrhosis etiology). The treatment response (positive when a tumor diameter decreased or stabilization was observed) was similar in the two groups; in the TACE group, the presence of a peritumoral capsula had a significant influence on survival (p < 0.02); on the other hand, in the patients treated with beta-INF and tamoxifen important factors for a better prognosis were the TNM stage (I and II, p < 0.02) and a symptom-free condition (p < 0.04). The authors believe the beta-INF and tamoxifen treatment could represent an effective alternative in the management of unresectable HCC. A better knowledge of the presence and meaning of estrogen and progestin receptors in the neoplastic tissue may allow a better selection of patients.

The effects of splenic transplantation of hepatocytes on survival time and hepatic regeneration were studied in adult rats subjected to: 1) 90% hepatectomy plus portocaval shunt (graft of 4 x 10(6) hepatocytes) and 2) 90% hepatectomy (graft of 4 x 10(6) and 8 x 10(6) hepatocytes); data were compared with those obtained in hepatectomized rats. Hepatic regeneration was significantly higher in transplanted rats and, within animals with grafted hepatocytes more pronounced in rats without porto-caval shunt. This support the hypothesis that a hepatotrophic factor is produced by grafted hepatocytes: its activity is more pronounced in the absence of porto-caval shunt since all splenic blood reach the liver. The activity of the putative hepatocyte growth factor does not depend on the number of grafted hepatocytes since no significant differences in survival time and hepatic regeneration was observed between rats grafted with 4 x 10(6) and 8 x 10(6) hepatocytes.