Predicting the Risk of Morbidity by GLIM-Based Nutritional Assessment and Body Composition Analysis in Oncologic Abdominal Surgery in the Context of Enhanced Recovery Programs : The PHase Angle Value in Abdominal Surgery (PHAVAS) Study.

BACKGROUND: Preoperative nutritional status and body structure affect short-term prognosis in patients undergoing major oncologic surgery. Bioimpedance vectorial analysis (BIVA) is a reliable tool to assess body composition. Low BIVA-derived phase angle (PA) indicates a decline of cell membrane integrity and function. The aim was to study the association between perioperative PA variations and postoperative morbidity following major oncologic upper-GI surgery. PATIENTS AND METHODS: Between 2019 and 2022 we prospectively performed BIVA in patients undergoing surgical resection for pancreatic, hepatic, and gastric malignancies on the day before surgery and on postoperative day (POD) 1. Malnutrition was defined as per the Global Leadership Initiative on Malnutrition criteria. The PA variation (ΔPA) between POD1 and preoperatively was considered as a marker for morbidity. Uni and multivariable logistic regression models were applied. RESULTS: Overall, 542 patients with a mean age of 64.6 years were analyzed, 279 (51.5%) underwent pancreatic, 201 (37.1%) underwent hepatobiliary, and 62 (11.4%) underwent gastric resections. The prevalence of preoperative malnutrition was 16.6%. The overall morbidity rate was 53.3%, 59% in those with ΔPA < -0.5 versus 46% when ΔPA ≥ -0.5. Age [odds ratio (OR) 1.11; 95% confidence interval (CI) (1.00; 1.22)], pancreatic resections [OR 2.27; 95% CI (1.24; 4.18)], estimated blood loss (OR 1.20; 95% CI (1.03; 1.39)], malnutrition [OR 1.77; 95% CI (1.27; 2.45)], and ΔPA [OR 1.59; 95% CI (1.54; 1.65)] were independently associated with postoperative complications in the multivariate analysis. CONCLUSIONS: Patients with preoperative malnutrition were significantly more likely to develop postoperative morbidity. Moreover, a decrease in PA on POD1 was independently associated with a 13% increase in the absolute risk of complications. Whether proactive interventions may reduce the downward shift of PA and the complication rate need further investigation.

Estimation of Right Atrial Pressure by Ultrasound-Assessed Jugular Vein Distensibility in Patients With Heart Failure.

BACKGROUND: Clinical evaluation of central venous pressure is difficult, depends on experience, and is often inaccurate in patients with chronic advanced heart failure. We assessed the ultrasound-assessed internal jugular vein (JV) distensibility by ultrasound as a noninvasive tool to identify patients with normal right atrial pressure (RAP ≤7 mm Hg) in this population. METHODS: We measured JV distensibility as the Valsalva-to-rest ratio of the vein diameter in a calibration cohort (N=100) and a validation cohort (N=101) of consecutive patients with chronic heart failure with reduced ejection fraction who underwent pulmonary artery catheterization for advanced heart failure therapies workup. RESULTS: A JV distensibility threshold of 1.6 was identified as the most accurate to discriminate between patients with RAP ≤7 versus >7 mm Hg (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.64-0.84]) and confirmed in the validation cohort (receiver operating characteristic, 0.82 [95% CI, 0.73-0.92]). A JV distensibility ratio >1.6 had predictive positive values of 0.86 and 0.94, respectively, to identify patients with RAP ≤7 mm Hg in the calibration and validation cohorts. Compared with patients from the calibration cohort with a high JV distensibility ratio (>1.6; n=42; median RAP, 4 mm Hg; pulmonary capillary wedge pressure, 11 mm Hg), those with a low JV distensibility ratio (≤1.6; n=58; median RAP, 8 mm Hg; pulmonary capillary wedge pressure, 22 mm Hg; P<0.0001 for both) were more likely to die or undergo a left ventricular assist device implant or heart transplantation (event rate at 2 years: 42.7% versus 18.2%; log-rank P=0.034). CONCLUSIONS: Ultrasound-assessed JV distensibility identifies patients with chronic advanced heart failure with normal RAP and better outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03874312.

Prenatal use of indomethacin for preterm labor and renal function among very low birth weight infants.

BACKGROUND: Indomethacin is administered as a tocolytic agent for threatening preterm labor <28weeks of gestation. Only a few, not conclusive, studies have investigated its nephrotoxicity in very low birth weight (VLBW) infants. We investigated whether indomethacin increases the incidence of acute kidney injury (AKI) among VLBW infants. METHODS: This is a retrospective study including all VLBW infants born at our center between January 1, 2005, and December 31, 2013. Indomethacin was administered to women with preterm labor and intact membranes. Neonatal AKI was defined according to KDIGO classification. Univariate analyses were performed comparing VLBW infants exposed to and not exposed to indomethacin. In the multivariable model, the association of indomethacin and AKI was adjusted for patent ductus arteriosus, use of nephrotoxic medications, birth weight, and gestational age. RESULTS: Five hundred seventy-five VLBW infants were included, 49 (8.5%) of whom were exposed to indomethacin in utero. The univariate analysis showed that infants exposed to indomethacin had lower birth weight, lower gestational age, and higher incidence of AKI than infants not exposed. The multivariable model adjusted for confounding factors confirmed an increased risk of AKI in relation to gestational age at birth <27 weeks, but not to indomethacin. CONCLUSIONS: Our data suggest that extreme prematurity, but not the use of indomethacin, is associated with AKI.

Multidimensional evaluation of the learning curve for totally laparoscopic pancreaticoduodenectomy: a risk-adjusted cumulative summation analysis.

INTRODUCTION: Laparoscopic pancreaticoduodenectomy (LPD) is a challenging procedure. We investigated the learning curve (LC) for LPD with a multidimensional analysis. METHODS: Data of patients undergoing LPD between 2017 and 2021, operated by a single surgeon, were considered. A multidimensional assessment of the LC was performed through Cumulative Sum (CUSUM) and Risk-Adjusted (RA)-CUSUM analysis. RESULTS: 113 patients were selected. Rates of conversion, overall postoperative complication, severe complication and mortality were 4%, 53%, 29% and 4%, respectively. RA-CUSUM analysis showed a LC with three phases: competency (procedures 1-51), proficiency (procedures 52-94), and mastery (after procedure 94). Operative time was lower in both phase two (588.17 vs 541.13 min, p = 0.001) and three (534.72 vs 541.13 min, p = 0.004) with respect to phase one. Severe complication rate was lower in mastery as compared to competency phase (42% vs 6%, p = 0.005). During mastery phase a greater number of lymph nodes was harvested in comparison to proficiency phase. CONCLUSIONS: According to our LC analysis, 52 procedures were required to achieve technical competency in LPD. Mastery, which corresponded to a reduction in operative time and surgical failures, was acquired after 94 procedures.

Machine Learning Predictive Model to Guide Treatment Allocation for Recurrent Hepatocellular Carcinoma After Surgery.

Importance: Clear indications on how to select retreatments for recurrent hepatocellular carcinoma (HCC) are still lacking. Objective: To create a machine learning predictive model of survival after HCC recurrence to allocate patients to their best potential treatment. Design, Setting, and Participants: Real-life data were obtained from an Italian registry of hepatocellular carcinoma between January 2008 and December 2019 after a median (IQR) follow-up of 27 (12-51) months. External validation was made on data derived by another Italian cohort and a Japanese cohort. Patients who experienced a recurrent HCC after a first surgical approach were included. Patients were profiled, and factors predicting survival after recurrence under different treatments that acted also as treatment effect modifiers were assessed. The model was then fitted individually to identify the best potential treatment. Analysis took place between January and April 2021. Exposures: Patients were enrolled if treated by reoperative hepatectomy or thermoablation, chemoembolization, or sorafenib. Main Outcomes and Measures: Survival after recurrence was the end point. Results: A total of 701 patients with recurrent HCC were enrolled (mean [SD] age, 71 [9] years; 151 [21.5%] female). Of those, 293 patients (41.8%) received reoperative hepatectomy or thermoablation, 188 (26.8%) received sorafenib, and 220 (31.4%) received chemoembolization. Treatment, age, cirrhosis, number, size, and lobar localization of the recurrent nodules, extrahepatic spread, and time to recurrence were all treatment effect modifiers and survival after recurrence predictors. The area under the receiver operating characteristic curve of the predictive model was 78.5% (95% CI, 71.7%-85.3%) at 5 years after recurrence. According to the model, 611 patients (87.2%) would have benefited from reoperative hepatectomy or thermoablation, 37 (5.2%) from sorafenib, and 53 (7.6%) from chemoembolization in terms of potential survival after recurrence. Compared with patients for which the best potential treatment was reoperative hepatectomy or thermoablation, sorafenib and chemoembolization would be the best potential treatment for older patients (median [IQR] age, 78.5 [75.2-83.4] years, 77.02 [73.89-80.46] years, and 71.59 [64.76-76.06] years for sorafenib, chemoembolization, and reoperative hepatectomy or thermoablation, respectively), with a lower median (IQR) number of multiple recurrent nodules (1.00 [1.00-2.00] for sorafenib, 1.00 [1.00-2.00] for chemoembolization, and 2.00 [1.00-3.00] for reoperative hepatectomy or thermoablation). Extrahepatic recurrence was observed in 43.2% (n = 16) for sorafenib as the best potential treatment vs 14.6% (n = 89) for reoperative hepatectomy or thermoablation as the best potential treatment and 0% for chemoembolization as the best potential treatment. Those profiles were used to constitute a patient-tailored algorithm for the best potential treatment allocation. Conclusions and Relevance: The herein presented algorithm should help in allocating patients with recurrent HCC to the best potential treatment according to their specific characteristics in a treatment hierarchy fashion.

Diversified Effects of Bile Contamination, Postoperative Infections, and Antimicrobial Resistance Level on the Oncologic Prognosis After Pancreatoduodenectomy for Ductal Adenocarcinoma.

BACKGROUND/AIM: Whether the presence of bacteria in the bile or postoperative infections sustained by microorganisms with different levels of drug-resistance are associated with changes in the oncologic prognosis of patients undergoing surgery for pancreatic cancer has not been thoroughly investigated. The aim was to study the association of bile contamination, postoperative infections, and multi-level resistance with long-term outcome. PATIENTS AND METHODS: Prospectively maintained databases were queried for patients who underwent pancreatoduodenectomy (PD). Patients who underwent preoperative biliary stenting prior to PD and an intraoperative bile culture were included. The levels of bacterial resistance of intraoperative bile cultures and of specimens of postoperative infections were stratified into multidrug sensitive (MDS), multidrug-resistant (MDR), and extensive drug-resistant (XDR). RESULTS: A total of 267 patients met the inclusion criteria. The Kaplan-Meier survival curves for overall survival (OS) of patients having no bacteriobilia or positive cultures with MDS versus MDR/XDR bacteria were not statistically different (log-rank=0.9). OS of patients stratified for no postoperative infection or infections by MDS was significantly better than those having MRD/XDR isolates (log-rank=0.04). A Cox multivariate model showed that having MRD/XDR postoperative infections was and independent variable for worse OS (HR=1.227; 95%CI=1.189-1.1918; p=0.036). CONCLUSION: Postoperative drug resistant infections are a significant risk factor for poor OS after pancreatoduodenectomy for ductal adenocarcinoma.

Hepatectomy Versus Sorafenib in Advanced Nonmetastatic Hepatocellular Carcinoma: A Real-life Multicentric Weighted Comparison.

OBJECTIVE: The aim of the study was to compare SURG vs SOR regarding the OS and progression-free survival (PFS) in a real-world clinical scenario. BACKGROUND DATA: The treatment for advanced nonmetastatic HCC belonging to the Barcelona Clinic Liver Cancer stage C (BCLC C) is still controversial. METHODS: BCLC C patients without extrahepatic spread and tumoral invasion of the main portal trunk were considered. Surgical patients were obtained from the HE.RC.O.LE.S. Register, whereas sorafenib patients were obtained from the ITA.LI.CA register The inverse probability weighting (IPW) method was adopted to balance the confounders between the 2 groups. RESULTS: Between 2008 and 2019, 478 patients were enrolled: 303 in SURG and 175 in SOR group. Eastern Cooperative Oncological Group Performance Status (ECOG-PS), presence of cirrhosis, steatosis, Child-Pugh grade, hepatitis B virus and hepatitis C virus, alcohol intake, collateral veins, bilobar disease, localization of the tumor thrombus, number of nodules, alpha-fetoprotein, age, and Charlson Comorbidity index were weighted by IPW to create two balanced pseudo-populations: SURG = 374 and SOR = 263. After IPW, 1-3-5 years OS was 83.6%, 68.1%, 55.9% for SURG, and 42.3%, 17.8%, 12.8% for SOR (P < 0.001). Similar trends were observed after subgrouping patients by ECOG-PS = 0 and ECOG-PS >0, and by the intrahepatic location of portal vein invasion. At Cox regression, sorafenib treatment (hazard ratio 4.436; 95% confidence interval 3.19-6.15; P < 0.001) and Charlson Index (hazard ratio 1.162; 95% confidence interval 1.06-1.27; P = 0.010) were the only independent predictors of mortality. PFS at 1-3-5 years were 65.9%, 40.3%, 24.3% for SURG and 21.6%, 3.5%, 2.9% for SOR (P = 0.007). CONCLUSIONS: In BCLC C patients without extrahepatic spread but with intrahepatic portal invasion, liver resection, if feasible, was followed by better OS and PFS compared with sorafenib.

Different antecedents and neonatal condition in neonatal arterial ischemic stroke and hypoxic-ischemic neonatal encephalopathy.

OBJECTIVE: To define similarities and differences between neonatal arterial ischemic stroke (NAIS) and hypoxic-ischemic neonatal encephalopathy (HINE). METHODS: A retrospective case-control study was conducted of neonates born at 35 weeks or more and weighing 1800 g or more at a tertiary care university hospital, between 2005 and 2016, with NAIS (group A), perinatal asphyxia (PA) with Stage II-III HINE (group B), and PA with or without Stage I HINE (group C). Ante- and intrapartum data, neonatal characteristics, and placental histopathology were compared. RESULTS: Eleven neonates were identified in group A, 10 in group B, and 227 in group C. Sentinel events occurred exclusively in groups B (80%) and C (41.4%). Umbilical cord blood gas values and Apgar score were worse in groups B and C compared to group A. No group A neonates required resuscitation at birth, whereas all group B and one-third of group C neonates did. Seizures developed only in neonates in groups A and B. One neonatal death occurred in group A. There were no significant differences in placental histopathology. CONCLUSION: NAIS and PA/HINE cases have different intrapartum and neonatal features. PA does not seem necessary for the occurrence of NAIS. More research is needed regarding associated placental abnormalities.

Risk factors for obstetric anal sphincter injury recurrence: A systematic review and meta-analysis.

BACKGROUND: Women with previous obstetric anal sphincter injuries (OASIs) are at a higher risk of recurrence in the subsequent pregnancy, which may lead to the development or worsening of anal incontinence. Due to a lack of evidence, few recommendations can be made about the factors that may affect the risk of OASI recurrence. OBJECTIVE: We sought to conduct a systematic review and meta-analysis to investigate potential risk factors for recurrent OASIs. SEARCH STRATEGY: Studies up to May 2019 were identified from PubMed, Scopus, Cochrane Library, and ISI Web of Science. SELECTION CRITERIA: Studies assessing the impact of risk factors on OASI recurrence in subsequent pregnancies were included. Reviews, letters to the editor, conference abstracts, book chapters, guidelines, Cochrane reviews, and expert opinions were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers. Odds ratio and standardized mean difference were chosen as effect measures. Pooled estimates were calculated using the random-effects model. MAIN RESULTS: The meta-analysis showed that maternal age, gestational age, occiput posterior presentation, oxytocin augmentation, operative delivery, and shoulder dystocia were associated with the risk of recurrent OASIs in the subsequent delivery. CONCLUSION: Prenatal and intrapartum risk factors are associated with recurrence of OASI. PROSPERO registration no. CRD42020178125.

Prospective Evaluation of Health Care Provider and Patient Assessments in Chemotherapy-Induced Peripheral Neurotoxicity.

BACKGROUND AND OBJECTIVE: There is no agreement on the gold standard for detection and grading of chemotherapy-induced peripheral neurotoxicity (CIPN) in clinical trials. The objective is to perform an observational prospective study to assess and compare patient-based and physician-based methods for detection and grading of CIPN. METHODS: Consecutive patients, aged 18 years or older, candidates for neurotoxic chemotherapy, were enrolled in the United States, European Union, or Australia. A trained investigator performed physician-based scales (Total Neuropathy Score-clinical [TNSc], used to calculate Total Neuropathy Score-nurse [TNSn]) and supervised the patient-completed questionnaire (Functional Assessment of Cancer Treatment/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX]). Evaluations were performed before and at the end of chemotherapy. On participants without neuropathy at baseline, we assessed the association between TNSc, TNSn, and FACT/GOG-NTX. Considering a previously established minimal clinically important difference (MCID) for FACT/GOG-NTX, we identified participants with and without a clinically important deterioration according to this scale. Then, we calculated the MCID for TNSc and TNSn as the difference in the mean change score of these scales between the 2 groups. RESULTS: Data from 254 participants were available: 180 (71%) had normal neurologic status at baseline. At the end of the study, 88% of participants developed any grade of neuropathy. TNSc, TNSn, and FACT/GOG-NTX showed good responsiveness (standardized mean change from baseline to end of chemotherapy >1 for all scales). On the 153 participants without neuropathy at baseline and treated with a known neurotoxic chemotherapy regimen, we verified a moderate correlation in both TNSc and TNSn scores with FACT/GOG-NTX (Spearman correlation index r = 0.6). On the same sample, considering as clinically important a change in the FACT/GOG-NTX score of at least 3.3 points, the MCID was 3.7 for TNSc and 2.8 for the TNSn. CONCLUSIONS: MCID for TNSc and TNSn were calculated and the TNSn can be considered a reliable alternative objective clinical assessment if a more extended neurologic examination is not possible. The FACT/GOG-NTX score can be reduced to 7 items and these items correlate well with the TNSc and TNSn. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a patient-completed questionnaire and nurse-assessed scale correlate with a physician-assessed scale.

Postpartum urinary retention: Absolute risk prediction model.

OBJECTIVES: To evaluate the incidence and assess clinical factors that can predict the occurrence of postpartum urinary retention (PPUR). PPUR is a puerperal condition defined as the inability to void over 6 hours after birth or after catheter removal in case of cesarean section, requiring catheterization. Lack of prompt diagnosis of this condition may lead to severe sequelae, including infection, chronic voiding difficulties, and renal failure. METHODS: This retrospective cohort study analyzed all deliveries from January 2011 to December 2017 in a single Italian university hospital. We used multivariate logistic regression to develop a predictive score for PPUR. RESULTS: By multivariate logistic regression, our analysis shows as minor (odds ratio [OR] < 2) risk factors for PPUR: non-Caucasian ethnicity (OR = 1.46, CI = 1.05-2.03), nulliparity (OR = 1.47, CI = 1.01-2.14), body mass index (BMI) at the end of the pregnancy <30 kg/m2 (OR = 1.54, CI = 1.10-2.17). On the other hand, epidural analgesia (OR = 3.93, CI = 2.96-5.22), meconium-stained amniotic fluid (OR = 2.07, CI = 1.54-2.77), nonoperative vaginal birth vs cesarean section (OR = 6.25, CI = 2.16-18.13), vacuum extraction vs cesarean section (OR = 8.80, CI = 2.86-27.01), pushing stage ≥60 minutes (OR = 3.00,CI = 2.26-3.97), and perineal tear (OR = 2.87, CI = 1.86-4.43) proved to be major (OR > 2) risk factors for PPUR. Using our final model (area under curve = 0.84), we created a nomogram for PPUR absolute risk calculation. Specifically, a 116-point cutoff might be used to identify high-risk patients who deserve more intensive micturition monitoring. CONCLUSIONS: Our study identified non-Caucasian ethnicity, nulliparity, and a BMI <30 kg/m2 at the end of the pregnancy as minor and epidural analgesia, meconium-stained amniotic fluid, vaginal nonoperative birth, vacuum extraction, pushing stage ≥60 minutes, and perineal tear as major independent risk factors for PPUR.

Curative versus palliative treatments for recurrent hepatocellular carcinoma: a multicentric weighted comparison.

BACKGROUND: Management of recurrence after surgery for hepatocellular carcinoma (rHCC) is still a debate. The aim was to compare the Survival after Recurrence (SAR) of curative (surgery or thermoablation) versus palliative (TACE or Sorafenib) treatments for patients with rHCC. METHODS: This is a multicentric Italian study, which collected data between 2007 and 2018 from 16 centers. Selected patients were then divided according to treatment allocation in Curative (CUR) or Palliative (PAL) Group. Inverse Probability Weighting (IPW) was used to weight the groups. RESULTS: 1,560 patients were evaluated, of which 421 experienced recurrence and were then eligible: 156 in CUR group and 256 in PAL group. Tumor burden and liver function were weighted by IPW, and two pseudo-population were obtained (CUR = 397.5 and PAL = 415.38). SAR rates at 1, 3 and 5 years were respectively 98.3%, 76.7%, 63.8% for CUR and 91.7%, 64.2% and 48.9% for PAL (p = 0.007). Median DFS was 43 months (95%CI = 32-74) for CUR group, while it was 23 months (95%CI = 18-27) for PAL (p = 0.017). Being treated by palliative approach (HR = 1.75; 95%CI = 1.14-2.67; p = 0.01) and having a median size of the recurrent nodule>5 cm (HR = 1.875; 95%CI = 1.22-2.86; p = 0.004) were the only predictors of mortality after recurrence, while time to recurrence was the only protective factor (HR = 0.616; 95%CI = 0.54-0.69; p<0.001). CONCLUSION: Curative approaches may guarantee long-term survival in case of recurrence.

Performance of Comprehensive Complication Index and Clavien-Dindo Complication Scoring System in Liver Surgery for Hepatocellular Carcinoma.

BACKGROUND: We aimed to assess the ability of comprehensive complication index (CCI) and Clavien-Dindo complication (CDC) scale to predict excessive length of hospital stay (e-LOS) in patients undergoing liver resection for hepatocellular carcinoma. METHODS: Patients were identified from an Italian multi-institutional database and randomly selected to be included in either a derivation or validation set. Multivariate logistic regression models and ROC curve analysis including either CCI or CDC as predictors of e-LOS were fitted to compare predictive performance. E-LOS was defined as a LOS longer than the 75th percentile among patients with at least one complication. RESULTS: A total of 2669 patients were analyzed (1345 for derivation and 1324 for validation). The odds ratio (OR) was 5.590 (95%CI 4.201; 7.438) for CCI and 5.507 (4.152; 7.304) for CDC. The AUC was 0.964 for CCI and 0.893 for CDC in the derivation set and 0.962 vs. 0.890 in the validation set, respectively. In patients with at least two complications, the OR was 2.793 (1.896; 4.115) for CCI and 2.439 (1.666; 3.570) for CDC with an AUC of 0.850 and 0.673, respectively in the derivation cohort. The AUC was 0.806 for CCI and 0.658 for CDC in the validation set. CONCLUSIONS: When reporting postoperative morbidity in liver surgery, CCI is a preferable scale.

PKHhigh/CD133+/CD24- Renal Stem-Like Cells Isolated from Human Nephrospheres Exhibit In Vitro Multipotency.

The mechanism upon which human kidneys undergo regeneration is debated, though different lineage-tracing mouse models have tried to explain the cellular types and the mechanisms involved. Different sources of human renal progenitors have been proposed, but it is difficult to argue whether these populations have the same capacities that have been described in mice. Using the nephrosphere (NS) model, we isolated the quiescent population of adult human renal stem-like PKHhigh/CD133+/CD24- cells (RSC). The aim of this study was to deepen the RSC in vitro multipotency capacity. RSC, not expressing endothelial markers, generated secondary nephrospheres containing CD31+/vWf+ cells and cytokeratin positive cells, indicating the coexistence of endothelial and epithelial commitment. RSC cultured on decellularized human renal scaffolds generated endothelial structures together with the proximal and distal tubular structures. CD31+ endothelial committed progenitors sorted from nephrospheres generated spheroids with endothelial-like sprouts in Matrigel. We also demonstrated the double commitment toward endothelial and epithelial lineages of single RSC. The ability of the plastic RSC population to recapitulate the development of tubular epithelial and endothelial renal lineages makes these cells a good tool for the creation of organoids with translational relevance for studying the parenchymal and endothelial cell interactions and developing new therapeutic strategies.

Treatment of hepatocellular carcinoma beyond the Milan criteria. A weighted comparative study of surgical resection versus chemoembolization.

BACKGROUND: Optimal treatment of hepatocellular carcinoma (HCC) beyond the Milan criteria (MC) is debated. The aim of the study was to assess overall-survival (OS) and disease-free-survival (DFS) for HCC beyond MC when treated by trans-arterial-chemoembolization (TACE) or surgical resection (SR). METHOD: between 2005 and 2015, all patients with a first diagnosis of HCC beyond MC(1 nodule>5 cm, or 3 nodules>3 cm without macrovascular invasion) were evaluated. Analyses were carried out through Kaplan-Meier, Cox models and the inverse probability weighting (IPW) method to reduce allocation bias. Sub-analyses have been performed for multinodular and single large tumors compared with a MC-IN cohort. RESULTS: 226 consecutive patients were evaluated: 118 in SR group and 108 in TACE group. After IPW, the two pseudo-populations were comparable for tumor burden and liver function. In the SR group, 1-5 years OS rates were 72.3% and 35% respectively and 92.7% and 39.3% for TACE (p = 0.500). The median DFS was 8 months (95%CI:8-9) for TACE, and 11 months (95%CI:9-12) for SR (p < 0.001). TACE was an independent predictor for recurrence (HR 1.5; 95%CI: 1.1-2.1; p = 0.015). Solitary tumors > 5 cm and multinodular disease had comparable OS and DFS as Milan-IN group (p > 0.05). CONCLUSION: Surgery allowed a better control than TACE in patient bearing HCC beyond MC. This translated into a significant benefit in terms of DFS but not OS.

Comparison of three therapeutic regimens for genotype-3 hepatitis C virus infection in a large real-life multicentre cohort.

BACKGROUND & AIMS: In the direct-acting antiviral era, treatment of genotype-3 HCV (HCV-GT3) is still challenging. Real-life comparisons between recommended regimens, sofosbuvir (SOF)+daclatasvir (DAC), SOF/velpatasvir (VEL), glecaprevir/pibrentasvir (GLE/PIB), are scarce. We aimed at filling this data gap. METHODS: Sustained virological response 12 weeks after treatment completion (SVR12) was assessed for all HCV-GT3 patients consecutively treated within the Lombardia web-based Navigatore HCV-Network; differences in SVR12 across regimens were evaluated by logistic regression. RESULTS: Of the 2082 subjects with HCV-GT3, 1544 were evaluable for comparisons between regimens: SOF + DAC (1023, 66.2%), SOF/VEL (369, 23.9%), GLE/PIB (152, 9.8%). Patients treated with former regimens were more frequently male, cirrhotic, HIV-positive, pretreated, used ribavirin in their regimen, and had lower baseline HCV-RNA. SVR12 was similar across groups: 94.8% in SOF + DAC, 97.6% in SOF/VEL, 96.7% in GLE/PIB (P = .065). At univariate analysis, SVR12 was associated with female gender (97.9% vs 94.8%, P = .007) and lower median pretreatment Log10 HCV-RNA (5.87 vs 6.20, P = .001). At multivariate logistic regression analysis, treatment with SOF/VEL was associated with a higher likelihood of SVR12 than SOF + DAC, but only in the absence of ribavirin (98% vs 90.3%). Female gender and lower pretreatment HCV-RNA were independently associated with SVR12. CONCLUSIONS: In a large real-life setting of HCV-GT3-infected patients with a high proportion of cirrhosis, the success rate was remarkable. The slight advantage of SOF/VEL on SOF + DAC was significant only without ribavirin. The current prescription shift towards novel regimens (ie SOF/VEL and GLE/PIB) in easier-to-treat patients allows ribavirin-free and shorter schedules without mining SVR12 in this <> genotype.

Joint model robustness compared with the time-varying covariate Cox model to evaluate the association between a longitudinal marker and a time-to-event endpoint.

BACKGROUND: The recent progress in medical research generates an increasing interest in the use of longitudinal biomarkers for characterizing the occurrence of an outcome. The present work is motivated by a study, where the objective was to explore the potential of the long pentraxin 3 (PTX3) as a prognostic marker of Acute Graft-versus-Host Disease (GvHD) after haematopoietic stem cell transplantation. Time-varying covariate Cox model was commonly used, despite its limiting assumptions that marker values are constant in time and measured without error. A joint model has been developed as a viable alternative; however, the approach is computationally intensive and requires additional strong assumptions, in which the impacts of their misspecification were not sufficiently studied. METHODS: We conduct an extensive simulation to clarify relevant assumptions for the understanding of joint models and assessment of its robustness under key model misspecifications. Further, we characterize the extent of bias introduced by the limiting assumptions of the time-varying covariate Cox model and compare its performance with a joint model in various contexts. We then present results of the two approaches to evaluate the potential of PTX3 as a prognostic marker of GvHD after haematopoietic stem cell transplantation. RESULTS: Overall, we illustrate that a joint model provides an unbiased estimate of the association between a longitudinal marker and the hazard of an event in the presence of measurement error, showing improvement over the time-varying Cox model. However, a joint model is severely biased when the baseline hazard or the shape of the longitudinal trajectories are misspecified. Both the Cox model and the joint model correctly specified indicated PTX3 as a potential prognostic marker of GvHD, with the joint model providing a higher hazard ratio estimate. CONCLUSIONS: Joint models are beneficial to investigate the capability of the longitudinal marker to characterize time-to-event endpoint. However, the benefits are strictly linked to the correct specification of the longitudinal marker trajectory and the baseline hazard function, indicating a careful consideration of assumptions to avoid biased estimates.

Long-term outcomes and five-year recurrence-free survival curves after native-tissue prolapse repair.

OBJECTIVE: To evaluate the long-term objective and subjective outcomes to build recurrence-free survival curves after mesh-free uterosacral ligament suspension and to evaluate the long-term impact of prognostic factors on outcome measures. METHODS: A retrospective study analyzed 5-year follow-up after repair of primary prolapse through high uterosacral ligament suspension. Bulging symptoms and post-operative prolapse stage II or above were considered subjective and objective recurrences, respectively. The cumulative proportion of relapse-free patients in time was analyzed by Kaplan-Meier curves. RESULTS: A total of 353 women were analyzed. Five-year recurrence rates were 15.0% for objective recurrence, 13.0% for subjective recurrence, and 4.0% for the combined objective and subjective recurrences. Premenopausal status was shown to be a risk factor for anatomic (P=0.022), symptomatic (P=0.001), and combined (P=0.047) recurrence. Conversely, anterior repair was shown to be a protective factor for symptomatic (P=0.012) and combined (P=0.002) recurrence. Most of the recurrences occurred within 2 years after surgery. CONCLUSION: Long-term outcomes after high uterosacral ligament suspension were satisfactory. Premenopausal status and lack of anterior repair represented risk factors for recurrence in the long term.