Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor.

VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.

Outcomes in Renal Cell Carcinoma With IVC Thrombectomy: A Multiteam Analysis Between an NCI-Designated Cancer Center and a Quaternary Care Teaching Hospital.

INTRODUCTION: Interteam performance and Clavien-Dindo (C-D) complications in renal cell carcinoma with inferior vena cava thrombectomy (RCC-IVCT) have not been reported. We aimed to describe complications by the degree of complexity and surgical teams in a collaborative effort between a National Cancer Institute-designated Comprehensive Cancer Center and a Quaternary Care Teaching Hospital. METHODS: Between January 2011 and May 2019, 73 consecutive RCC-IVCT were included. C-D grades III or higher were captured. Teams involved were urologic-oncology, vascular, hepatobiliary/transplant, and cardiothoracic. The Mayo Clinic tumor thrombus classification was used. RESULTS: Overall complication rate was 42% (n = 31). Nineteen percent had grade III, 18% had grade IV, and 6% had grade V complications. Patients with level IV thrombus had the highest in-hospital mortality rate (75%). Thrombus level did not show a correlation to complication rates (14% level I, 45% level II, 32% level III, 42% level IV). A positive correlation found between the number of teams involved and complication rates (35% with 2-team, 59% with 3-team, P = .059). Thromboembolic events (6% vs 24%, P = .02) and disposition other than home (22% vs 48%, P = .01) were statistically lower for the 2-team groups. Two-team in-hospital mortality was 1/51 (2%) versus 3-team (3/22,14%, (P = .07). No statistical differences were found in infections, thromboembolic events, and grades of complications between surgical teams. CONCLUSIONS: Despite similar interteam performance, the consistency of surgeons in high complexity cases could improve outcomes further. Complexity was higher for hepatobiliary/transplant and cardiothoracic teams. A combination of intraoperative events and patient selection (comorbidities and age) contributed to death. Overall, in-hospital mortality was lower than in most reported series.

Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant.

The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation.

Outcomes of abdominal surgeries in cirrhotic patients performed by liver transplant surgeons: Are these safe?

BACKGROUND: Elective abdominal surgeries in patients with cirrhosis have been discouraged due to the high risk of complications. This study investigates the outcomes and safety of surgeries for hernias, and laparoscopic cholecystectomies in cirrhotic patients. METHODS: A retrospective cohort study that compared 91 cirrhotic patients to a control group of non-cirrhotic patients operated by liver transplant surgeons was conducted between 2009 and 2015. RESULTS: No statistical significance found in re-admission rates or complication rates (p = 0.21). Hernia recurrent rates were similar (p = 0.27). Survival rates among cirrhotic versus non cirrhotic group was 93.4% and 98.9% respectively (p = 0.0539). Amongst the 91 cirrhotic patients, there was a 100% survival rate for both ventral herniorrhaphies and laparoscopic cholecystectomy. Survival in umbilical and inguinal herniorrhaphies was 88.2% and 89.5% respectively. Mortality rate for umbilical and inguinal hernias was 11.7% and10.5% respectively. Mortality by Child-Pugh (CP) class were; 8.8% for CP B and 10.7% for CP class C. All CP class A patients survived. CONCLUSIONS: Our study indicates that elective operations could be performed safely with acceptable mortality in cirrhotic patients.

Successful Liver Transplantation for Hyperammonemic Fibrolamellar Hepatocellular Carcinoma.

Fibrolamellar hepatocellular carcinoma is a rare hepatocellular tumor usually arising in noninfected and noncirrhotic livers. Only 2 cases accompanied by hyperammonemia due to intrahepatic shunting have been reported. A 23-year-old white woman presented with a 2-week history of nausea, vomiting, generalized weakness, and intermittent right upper quadrant pain. Abdominal computerized tomography revealed a 13 x 9-cm hepatic mass. Core-needle biopsy revealed fibrolamellar hepatocellular carcinoma. She presented with coma due to hyperammonemia levels (peak at 437 mcg/dL) but without metastatic disease. She was urgently transplanted, started on daily sorafenib 8 weeks after transplantation, and was free of disease at 1 year after transplantation.

Building the multidisciplinary team for management of patients with hepatocellular carcinoma.

Optimal care of the patient with hepatocellular carcinoma (HCC) necessitates the involvement of multiple providers. Because the patient with HCC often carries 2 conditions with competing mortality risks (cancer and underlying cirrhosis), no single provider is equipped to deal with all of these patients' needs adequately. Multidisciplinary teams (MDTs) have evolved to facilitate care coordination, reassessments of clinical course, and nimble changes in treatment plans required for this complex group of patients. Providers or sites that elect to manage patients with HCC thus are increasingly aware of the need to build their own MDT or communicate with an established one. The availability of new communication technologies, such as teleconferencing or teleconsultation, offers the possibility of MDT expansion into underserved or rural areas, as well as areas such as correctional facilities. Although the availability of resources for HCC patient care varies from site to site, construction of an MDT is possible in a wide spectrum of clinical practices, and this article suggests a blueprint for assembly of such collaboration. Research strategies are needed to explain how MDTs improve clinical outcomes so that MDTs themselves can be improved.

Can sorafenib increase survival for recurrent hepatocellular carcinoma after liver transplantation? A pilot study.

Recurrence of hepatocellular carcinoma (HCC) remains a main detriment to long-term survival in liver transplants (LTx) for HCC. The study aims to review the use of sorafenib in recurrent HCC LTx in the Model End Stage Liver Disease era. Two hundred forty-seven patients with HCC LTx from 2002 to 2013 were included. Survival was calculated by the Kaplan-Meier (KM) method and Cox multivariate model. Twenty-two patients recurred (11%). By KM, overall survival was 27 months (standard deviation [SD], 3.2 months; median, 28.4 months). Mean time to recurrence was 16.9 months (SD, 2.8 months; median, 12 months). Nine patients were treated with sorafenib after recurrence. Median survival for sorafenib-treated patients was 42 months compared with a median of 16.2 months without sorafenib (-2 log likelihood ratio, P = 0.0582). By Cox, only sorafenib (P = 0.0233; hazard ratio, 8.528) and pathologic stage had a significant impact on survival. The recurrence rates of HCC LTx remain acceptable considering understaging and expansion of beyond Stage A. This pilot study of sorafenib in recurrent HCC demonstrates improved survival over historic controls. Many other factors affecting improved survival are explained. However, treatment remains palliative. Quality-of-life years and cost analysis need to be performed in this population.

Liver transplantation for hepatocellular carcinoma in Puerto Ricans: underutilization of a curative therapy.

OBJECTIVE: Hepatocellular carcinoma (HCC), the most common type of liver cancer, is becoming a healthcare burden for Puerto Rico and, in particular, for those clinics that specialize in liver disease. It is our hypothesis that liver transplantation, the most effective curative option for unresectable tumors, is underutilized. We describe in detail the outcomes of liver transplants for HCC in Puerto Ricans referred to a major liver transplant center in the USA. METHODS: Thirty-two Puerto Rican HCC patients receiving transplants (from January 1, 1997, through July of 2012) at Tampa General Hospital are described. Recurrence rates were calculated, and the Kaplan-Meier estimator was used for survival analysis. RESULTS: The proportion of transplants performed for HCC in our Puerto Rican patients was only 12% (p = 0.05). Disease-free survival at 1, 3, and 5 years was 93.7%, 83%, and 78.8%, respectively. Patient survival at 1, 3, and 5 years was 96.7%, 75%, and 67%, respectively. Sixty-nine percent of the 32 patients were alive at the mean follow-up of 56 months. The recurrence rate from 2002 to the present is 14%. CONCLUSION: This study provides the most comprehensive report detailing the relative benefits of utilizing liver transplantation as a curative option for Puerto Ricans with hepatocellular carcinoma. It also incorporates the first comprehensive review of the available literature of liver cancer in Puerto Rico. Survival and recurrence rates were comparable to published results. In Puerto Rico, liver transplantation for HCC patients has been underutilized. In order to improve outcomes over the next 2 decades, it is imperative that the healthcare system in Puerto Rico handle the burden of this disease using liver transplantation, locoregional therapies, and newer treatments for hepatitis C and HCC.

Obesity portends increased morbidity and earlier recurrence following liver transplantation for hepatocellular carcinoma.

BACKGROUND: Obesity has been associated with poor oncologic outcomes following pancreatoduodenectomy for pancreatic cancer. However, there is a paucity of evidence on the impact of obesity on postoperative complications, oncologic outcome and survival in patients with hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT). METHODS: From a database of over 1000 patients who underwent OLT during 1996-2008, 159 patients with a diagnosis of HCC were identified. Demographic data, body mass index (BMI), perioperative parameters, recurrence and survival were obtained. Complications were grouped according to Clavien-Dindo grading (Grades I-V). RESULTS: There were increased incidences of life-threatening complications in overweight (58%) and obese (70%) patients compared with the non-obese patient group (41%) (P < 0.05). Furthermore, the incidence of recurrence of HCC was doubled in the presence of overweight (15%) and obesity (15%) compared with non-obesity (7%) (P < 0.05). Time to recurrence also decreased significantly. Differences in mean ± standard deviation survival in the overweight (45 ± 3 months) and obese (41 ± 4 months) groups compared with the non-obese group (58 ± 6 months) did not reach statistical significance. CONCLUSIONS: These findings indicate that BMI is an important surrogate marker for obesity and portends an increased risk for complications and a poorer oncologic outcome following OLT for HCC.

Early use of renal-sparing agents in liver transplantation: a closer look.

Renal dysfunction is a critical issue for liver transplant candidates and recipients. Acute nephrotoxicity and chronic nephrotoxicity, however, are the compromises for the potent immunosuppression provided by calcineurin inhibitors (CNIs). To maintain the graft and patient survival afforded by CNIs while minimizing renal dysfunction in liver transplant patients, the reduction, delay, or elimination of CNIs in immunosuppression regimens is being implemented more frequently by clinicians. The void left by standard-dose CNIs is being filled by nonnephrotoxic immunosuppressants such as mycophenolates and mammalian target of rapamycin inhibitors. The results of studies of renal-sparing regimens in liver transplant recipients have been inconsistent, and this may be explained upon a closer examination of several study-related factors, including the study design and the duration of follow-up.

Outcomes after transjugular intrahepatic portosystemic stent shunt: a "bridge" to nowhere.

BACKGROUND: Transjugular intrahepatic portosystemic stent shunt (TIPS) has become the modality of choice for complicated portal decompression. This study was undertaken to determine outcomes after TIPS and the usefulness of TIPS as a "bridge" to transplantation. METHODS: Patients undergoing TIPS from 2001 to 2010 at a teaching hospital with a transplant program were studied. The median data are presented. RESULTS: TIPS was undertaken in 256 patients. TIPS decreased portal vein-inferior vena cava (IVC) gradients from 17 to 5 mm Hg (P < .001). Reinterventions were undertaken in 54 patients (21%). Survival after TIPS was 26 months; liver transplantation was undertaken in 35 (14%) patients. CONCLUSIONS: TIPS effectively decompresses portal hypertension but leads to frequent reinterventions and short survival. After TIPS, liver transplantation is uncommonly undertaken. TIPS is a "bridge" to transplantation that is seldom "crossed," and TIPS continues to be plagued by frequent reinterventions. Outcomes after TIPS and the infrequency of transplantation after TIPS make it difficult to recommend on merit.

Important surgical considerations in the management of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumour thrombus.

UNLABELLED: What's known on the subject? and What does the study add? Historically, the surgical management of renal tumours with intravascular tumour thrombus has been associated with high morbidity and mortality. In addition, few cases are treated, and typically at tertiary care referral centres, hence little is known and published about the ideal surgical management of such complex cases. The present comprehensive review details how a multidisciplinary surgical approach to renal tumours with intravascular tumour thrombus can optimise patient outcomes. Similarly, we have developed a treatment algorithm in this review that can be used in the surgical planning of such cases. OBJECTIVES: To detail the perioperative and technical considerations essential to the surgical management of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumour thrombus, as historically patients with RCC and IVC tumour thrombus have had an adverse clinical outcome. • Recent surgical and perioperative advances have for the most part optimized the clinical outcome of such patients. MATERIALS AND METHODS: A comprehensive review of the scientific literature was conducted using MEDLINE from 1990 to present using as the keywords 'renal cell carcinoma' and 'IVC tumor thrombus'. • In all, 62 manuscripts were reviewed, 58 of which were in English. Of these, 25 peer-reviewed articles were deemed of scientific merit and were assessed in detail as part of this comprehensive review. • These articles consist of medium to large (≥25 patients) peer-reviewed studies containing contemporary data pertaining to the surgical management of RCC and IVC tumour thrombus. • Many of these studies highlight important surgical techniques and considerations in the management of such patients and report on their respective clinical outcomes. RESULTS: Careful preoperative planning is essential to optimising the outcomes within this patient cohort. High quality and detailed preoperative imaging studies help delineate the proximal extension of the IVC tumour thrombus and possible caval wall direct invasion while determining the potential necessity for intraoperative vascular bypass. • The surgical management of RCC and IVC tumour thrombus (particularly for level III or IV) often requires the commitment of a multidisciplinary surgical team to optimise patient surgical outcomes. • Despite significant improvements in surgical techniques and perioperative care, the 5-year overall survival remains only between 32% and 69%, highlighting the adverse prognosis of such locally advanced tumours. • Important prognostic factors within this patient cohort include pathological stage, nuclear grade, tumour histology, lymph node and distant metastatic status, preoperative performance status, Charlson comorbidity index, and nutritional status. CONCLUSIONS: The multidisciplinary surgical care of RCC and IVC tumour thrombus (particularly high level thrombi) is pivotal to optimising the surgical outcome of such patients. • Similarly, important preoperative, perioperative, and postoperative considerations can improve the surgical outcome of patients.

Factors contributing to health disparities in liver transplantation in a Hispanic population.

OBJECTIVE: Among the challenges that Puerto Rico transplant patients face are a lack of social support that would enable them to move away from Puerto Rico, the difficulty of obtaining insurance coverage, and limitations imposed by language barriers. These factors may lead to reduced access to liver transplantation, which is a form of healthcare disparity. The objective of the study is to describe a group of Puerto Rican liver transplant candidates for the first time and to determine whether the above-named factors limit the possibilities of these candidates to be listed for transplant. METHODS: Using non-public databases from the referral and the transplant center, we performed a retrospective analysis of the medical records of patients who had been evaluated for liver transplant candidacy. Candidates (137) from the Liver Transplant Clinic at the University of Puerto Rico School of Medicine pre-evaluated for transplant candidacy during the period of 2002 to 2008 were selected. RESULTS: Records from 86 men and 51 women were reviewed. The most predominant etiologies of liver disease were hepatitis C virus (36%), a combination of etiologies (26%), alcoholic liver disease (16%), and cryptogenic cirrhosis (10%). While social support and history of psychiatric disorders did not affect listing, private insurance increased the odds of being enlisted for liver transplant (OR = 2.97) 195%CI: 1.067-8.242) (p<0.05). CONCLUSION: Access to private insurance increases the possibility of patient's being enlisted for liver transplantation. Recommendations for overcoming the gap in access to transplants by patients without private insurance are discussed.

Liver transplantation for hepatocellular carcinoma.

BACKGROUND: The treatment of hepatocellular carcinoma (HCC) is challenging, but transplantation of the liver has emerged as one of the options in the therapeutic armamentarium against this disease. METHODS: This article reviews the changing criteria for patient eligibility for liver transplantation for HCC and presents an initial evaluation of institutional treatment outcomes for this treatment modality. A method for evaluating prognosis is also described. RESULTS: Patients are considered for liver transplantation if they meet the Milan criteria for eligibility or a UCSF-attributed expansion of these criteria that includes the "rule of 7, " whereby the sum of the size of the largest nodule plus the total number of nodules cannot exceed 7. Preliminary institutional experience suggests a tumor recurrence rate of 11% in 91 patients with HCC who received liver transplants between 1996 and 2008. CONCLUSIONS: Liver transplantation offers an opportunity for long-term survival in patients with HCC and chronic cirrhosis whose tumor cannot be resected. Criteria for patient selection for this modality of treatment continue to be upgraded and refined.

Insertion of intracranial pressure monitors in fulminant hepatic failure patients: early experience using recombinant factor VII.

BACKGROUND: Cerebral edema contributes to the high morbidity and mortality of fulminant hepatic failure (FHF). OBJECTIVE: We report the results of our early experience with insertion of intraparenchymal intracranial pressure (ICP) monitors in these highly coagulopathic patients. METHODS: Eleven consecutive patients with FHF met the criteria for invasive ICP monitoring. Recombinant activated factor VII (rFVIIa) was administered at an average dose of 3 mg intravenous bolus (average, 36.7 microg/kg). We inserted the intraparenchymal ICP monitor within 15 minutes to 2 hours after rFVIIa administration, without waiting for the repeat coagulation results. Postprocedure computed tomographic scans of the brain were obtained in all patients. RESULTS: No hemorrhagic complications were detected on the immediate postprocedure computed tomographic scans. There were no thrombotic complications in this group of patients. CONCLUSION: In this group of patients with FHF, placement of an ICP monitor without hemorrhagic or thrombotic complications was feasible after administration of rFVIIa. This is a report of our early experience, and caution is advised. Further collaborative randomized studies are needed to prove the efficacy, optimal dosing, and cost effectiveness of rFVIIa for the placement of ICP monitors in this group of patients.

Outcome of liver transplantation in a Hispanic population: 100 liver transplants in Puerto Ricans.

BACKGROUND: The residents of Puerto Rico (PR) had limited access to liver transplantation (LTx) prior to 1996. LTx remains locally unavailable and success rates for LTx for patients from PR have never been published. The outcome of the first 100 LTx recipients from PR transplanted at our center is analyzed. METHODS: 100 consecutive patients transplanted between 3/1997 and 1/2005 were evaluated. RESULTS: Hepatitis C was the indication for LTx in 44%. Overall patient survival at 1, 3 and 5 yrs was: 94.0%, 81.4% and 75.7%, respectively, while for hepatitis C, it was 90%, 73% and 73%, respectively. At mean follow up of 44 mo., 80% of patients were alive (66% HCV were alive vs 91% non HCV, p < 0.01). CONCLUSIONS: Access to LTx in Puerto Rico has dramatically improved since 1996. The government-sponsored fund has provided access to indigent patients. Decreased survival in this minority population was not observed at 1, 3 and 5 years. Long-term survival was most affected by recurrence of HCV.