Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Transanal endoscopic microsurgery for rectal tumors: an option to radical surgery?

AIM: We present our experience in the treatment of rectal adenomas and selected cases of distal rectal cancer without evidence of nodal or distant metastasis (N0-M0) managed by transanal endoscopic microsurgery (TEM). This study examines our experience evaluating surgical morbidity, mortality and oncological outcome. METHODS: Eight hundred ten patients with rectal lesions (462 adenomas, 115 T1, 130 T2 and 103 T3) were enrolled. All patients staged preoperatively as T2 and T3 underwent preoperative high dose radiotherapy and since 1997 patients with less than 70 year old and good general conditions also preoperative chemotherapy. RESULTS: Minor complications were observed in 69 patients (8.5%) whereas major complications only in 5 patients (0.6%). Definitive histology confirmed adenomas in 431 cases (93%), while in 310 malignant lesions we had: 51 pT0 (14.7%), 127 pT1 (36.5%), 139 pT2 (39.9%) and 31 pT3 (8.9%). Sixteen (4.6%) patients (9 pT2 and 7 pT3) developed local recurrence whereas 6 (1.7%) patients distant metastasis. The survival rate at the end of follow-up was 100% for pT1 and 90% and 77% for pT2 and pT3 patients. CONCLUSION: TEM is safe and effective for rectal adenomas not removable endoscopically. T1 cancer may undergo local excision alone, while T2 and T3 lesions require preoperative radiochemotherapy. The results reported seems to be not very different in terms of local recurrence and survival rate to those after conventional surgery.

Laparoscopic adrenalectomy approaches: a 15-year experience in the search for a tailored procedure.

AIM: This study reports single-institution experience with anterior, flank lateral and submesocolic approaches in laparoscopic adrenalectomy (LA). METHODS: The study population was 267 patients who underwent LA from 1994 to 2008 at our institution. The choice of surgical route (anterior, anterior submesocolic or flank lateral) was based on patient characteristics (body-mass index, previous abdominal surgery) and lesion features (size, side, secreting mass, pheochromocytoma, suspected malignancy). The submesocolic approach, as described in 2005, was used for left-sided lesions ≤7-8 cm and in non-obese patients; the flank lateral approach was used in obese or previously operated patients. Of a total of 267 patients, 116 underwent right LA by the anterior and 4 by the flank lateral approach; 88 underwent left LA by the anterior, 37 by the submesocolic, and 22 by the flank lateral approach. RESULTS: The mean operating time was: 80.1 min (range, 65-125) for right anterior and 93 min (range, 96-145) for right flank lateral LA; 108 min (range, 80-305) for left anterior, 56.2 min (range, 38-105) for submesocolic, and 80.5 min (range, 54-125) for flank lateral LA. Major intraoperative complications requiring conversion to open surgery occurred in 7 patients: bleeding (5); splenic colonic flexure tear (1); and hypertension with severe arrhythmia in pheochromocytoma removal (1). There were no significant statistically differences in length of hospital stay or analgesic medications after anterior, flank lateral or submesocolic LA; the mean operating time was significantly shorter with use of the anterior and submesocolic approaches. CONCLUSION: In the authors' experience, tailoring the LA approach according to patient and lesion characteristics is both safe and effective. In selected cases, the operating time is shorter by the submesocolic appraoch. .

A flexible concept of fast track surgery for laparoscopic colorectal resections.

AIM: Laparoscopy per se improves the patient outcome allowing low pain, reduction of pulmonary dysfunction or less fatigue, better mood and psychological status on the operated on patient. In this study a series of laparoscopic colorectal resections underwent fast track in a "flexible" way. METHODS: From March 2006 to March 2009, 75 patients undergoing laparoscopic colectomy for cancer have been prospectively evaluated. There were 46 males and 29 females with 61.4 years mean age (26-87). The cohort was divided in three group, 25 patient each, on the basis of the fast track treatment used. In the series A fast track on the whole, in the B fast track partial and in the C fast track postoperatively only. RESULTS: Mean operating time was 81, 118, 142/76, 110, 151/83, 126, 145 minutes for right colectomy, left colectomy and rectal resection respectively in group A, B and C. The postoperative pain rating was less in the group A compared to B and C, with no differences concerning mobilization, flatus, resumption of solid feeding and mean postoperative hospital stay. CONCLUSION: Fast track management in laparoscopic colectomy is safe and effective, but it seems not essential in reducing the total hospital stay.

Is laparoscopic fiberoptic choledochoscopy for common bile duct stones a fine option or a mandatory step?

BACKGROUND: Because choledochoscopy often is a challenging maneuver, it would be advantageous to define the real utility of its use. This study aimed to compare blind exploration of the common bile duct (CBD) with choledochoscopy-assisted CBD stone removal in terms of patient outcome and complication rate. METHODS: Two groups of patients were prospectively evaluated in a 4-year period. The study participants were 36 men and 27 women randomized to group A (n = 32) for a blind basket procedure or group B (n = 31) for a choledochoscopy-assisted procedure as the first step of laparoscopic CBD stone removal. Patients with preoperatively suspected CBD stones (n = 51) and those with unsuspected stones (n = 12) were included. The two groups did not differ significantly in terms of anagraphics, American Society of Anesthesiology (ASA) score, or previous surgery. All the procedures were performed by surgeons skilled in this surgical field. Choledochoscopy, when used, was always performed with the instrument connected to a camera monitor that had a wide vision, whether in a single-monitor, in a picture-in-picture manner, or with the use of an additional monitor. RESULTS: From March 2004 to April 2008, 63 patients undergoing CBD exploration for stone removal were enrolled in the study. Five of these patients had undergone previous endoscopic retrograde cholangiopancreatography (ERCP)/endoscopic sphincterotomy (ES). The mean operative time was 107 min for group A and 122 min for group B. The mean hospital stay was 3 days for group A and 3.6 days for group B. Clearance of CBD stones was achieved laparoscopically in 62 cases. One patient required open combined transduodenal papilloplasty and transcholedochotomy. In seven cases, blind basket exploration was unable to remove the stones according to the cholangiogram, so choledochoscopy was required. Six patients underwent a transversal coledocothomy for stone removal. A Kehr T-tube was placed in four of these patients. In four group A cases, the papilla was inadvertently passed during the procedure. In six group A cases, including the four aforementioned cases, a high level of amylases was found on postoperative day 1. At this writing, no late complications or stone recurrences have been observed in either group. CONCLUSIONS: The laparoscopic basket blind technique and choledochoscopy are safe and effective for CBD stone removal. However, the latter seems to be better in terms of a higher stone removal rate and fewer minor complications despite its longer operation time. In the authors' opinion, it may be preferable to reserve ERCP for very high-risk patients, taking into account that in addition to the related complications, it results in an approximate 10% rate of recurrent or persistent stones.

Electrothermal bipolar energy-based device in laparoscopic right colectomy: our experience.

AIM: Aim of the present study was to evaluate effectiveness of bipolar electrothermal energy in laparoscopic right colectomy, both for vascular pedicle ligature and dissecting manoeuvres. METHODS: Eighty-nine consecutive unselected patients underwent laparoscopic right colectomy between 2003 and 2006. All procedures were performed or supervised by the same surgical team (two staff of surgeons). Forty-four laparoscopic right colectomy were carried out with ultrasonic coagulating shears (UCS), (group 1) and forty-five by means of electrothermal bipolar atlas (EBA), (group 2). Intraoperative bleeding and postoperative blood loss, operating time, complication and hospital stay have been investigated within two groups. RESULTS: No mortality and no major intraoperative were reported in both series. A conversion to open surgery occurred in one case in both groups. A duodenal perforation occurred in UCS group as major postoperative complication. Comparing 1 and 2 series statistically significant differences were found concerning mean operating time (122.7 vs 98.4) and blood loss (220 vs 115 mL), with a P value <0.05. CONCLUSIONS: Both UCS and EBA devices were safe and effective in performing laparoscopic right colectomy. However, EBA did allow a statistically significant shorter operative time and bleeding/blood loss, tracing back its effectiveness in vessel sealing and dissection.

Laparoscopic cecopexy for cecal volvulus after laparoscopy. Case report and a review of the literature.

Cecal volvulus is a rare cause of large bowel obstruction. Surgical therapy depends on visceral circulatory conditions at diagnosis. Possible options include endoscopic decompression, detorsion, cecopexy with or without cecostomy, right colectomy with immediate or delayed anastomosis. The present paper describes a case of cecal volvulus in a 40-year-old woman after laparoscopic removal of a pelvic mass successfully treated by laparoscopic cecopexy.

Sub-mesocolic access in laparoscopic left adrenalectomy.

BACKGROUND: This article reports an alternative laparoscopic access to left adrenal gland. METHODS: From January 1994 to August 2004, 209 laparoscopic adrenalectomies were performed in our Department. Indications were Conn adenoma (55 cases), incidentaloma (64), Cushing adenoma (45), pheochromocytoma (32), adreno-genital syndrome (two), mielolipoma (two), and metastatic mass(nine). Of 209, in 12 cases the left adrenalectomy was performed through a submesocolic access (seven pheochromocytoma, two incidentaloma, two Cushing adenoma, one Conn adenoma,). The identification and closure of the adrenal vein with minimal gland manipulation resulted the main benefit of this approach. Moreover, the adrenalectomy was performed with minimal anatomical dissection. RESULTS: No mortality or major complications occurred. During the operation, the blood pressure and cardiac rhythm were significantly more stable, in the group of patients who underwent a left adrenalectomy by the submesocolic approach compared to the anterior or flank lateral transperitoneal group. CONCLUSIONS: Left adrenal lesions, as selected cases of pheochromocytoma, can be safely treated by laparoscopic submesocolic access.

[Appendicectomy: laparoscopic or ''open approach''?]. / Appendicectomia: intervento laparoscopico o "a cielo aperto"?

AIM: The aim of our study was to evaluate the advantages and disadvantages of open appendectomy versus laparoscopic appendectomy in the surgical treatment of acute appendicitis. We have compared the following items: operating time, postoperative pain, length of hospital stay, postoperative complications and costs. METHODS: The study was conducted on 435 patients admitted in our Department from December 1993 to December 2003 with diagnosis of acute appendicitis: 339 (77.9%) cases were operated with laparoscopic approach (LA group) and 96 (22.1%) cases with open approach (OA group) according to personal experience of surgeons on laparoscopic technique and patient's anthropometrical conformation. RESULTS: Mean operative time in LA group was 50 minutes (range 25-195) and 65 minutes (range 35-160) for OA group. In 15 patients (4.4%), the operation had to be converted to open approach. The morbidity was observed in 4.4% of patients for the LA group and 14.6% for the OA group. Hospital stay was faster for patients having laparoscopic appendectomy (2.5 days vs 3.5 days). Pain in the 1st and 2nd postoperative days, evaluated on the use of pain medication, was less in patient in LA group whereas the costs were higher in the LA group than in OA group. CONCLUSIONS: In our experience the laparoscopic approach to acute appendicitis can be considered safe and effective with diagnostic and therapeutic value. It significantly offers all the advantages of mini-invasive surgery reported in literature.

Effect of trimetazidine on 99Tcm-tetrofosmin uptake in patients with coronary artery disease.

Myocardial uptake of 99Tcm-tetrofosmin in vivo is determined by a combination of flow and metabolic status of myocytes. The accumulation of tetrofosmin in the mitochondria is related to their ability to transduce metabolic energy into electronegative membrane potential. Trimetazidine (TMZ), an anti-ischaemic drug, appears to have a metabolic cytoprotective effect related to mitochondrial function, since it does not induce systemic or coronary haemodynamic changes. In this study, we evaluated the effects of TMZ on tetrofosmin uptake in hypoperfused myocardial regions in patients with coronary artery disease (CAD). Twenty-two patients, 14 with previous myocardial infarction (group A) and eight with a history of angina (group B), with angiographically documented CAD were studied. All patients underwent two tetrofosmin SPET studies at rest, before (baseline) and 1 week after TMZ administration (post-TMZ). On quantitative analysis, 131 segments showed less tetrofosmin uptake at baseline. In these segments, tetrofosmin uptake was 51 +/- 13% at baseline and 55 +/- 15% post-TMZ (P < 0.001 vs control). In the 86 hypoperfused segments of group A, tetrofosmin uptake was 48 +/- 14% at baseline and 52 +/- 17% post-TMZ (P < 0.001 vs control). In the 45 hypoperfused segments of group B, tetrofosmin uptake was 56 +/- 9% at baseline and 60 +/- 10% post-TMZ (P < 0.001 vs control). In the remaining 309 segments, no significant difference in tetrofosmin uptake before and after TMZ was observed. In conclusion, our results suggest that TMZ administration may increase myocardial uptake of tetrofosmin in hypoperfused regions at rest in patients with CAD, based on its metabolic effect.

Left ventricular function and exercise tolerance in patients with type II diabetes mellitus.

BACKGROUND: Left ventricular (LV) preload changes may alter exercise tolerance (ET), probably lessening activation of the Maestrini-Starling mechanism. Reduced LV filling (pre-load) during the diastolic phase, usually impaired in diabetic patients, could affect ventricular function. HYPOTHESIS: To evaluate the relationship between some echocardiographic LV function indices and ET, 24 patients (age 43-75 years, mean 54 +/- 13 years, Group A) with type II diabetes mellitus (DM), not suffering from other pathologies, and for whom the ergometric stress test (EST) resulted in an early interruption because of muscular fatigue and/or dyspnea, and 14 patients (age 38-70 years, mean 53 +/- 12 years, Group B) with type II DM and maximal ergometric stress test, used as control group, were studied. METHODS: The EST was performed by increasing the load by 25 W every 2 min; its duration was used as an ET index and correlated with clinical parameters of LV function obtained with M-mode, two-dimensional, and Doppler echocardiography. RESULTS: No patients in either Group A or Group B showed a high systolic blood pressure value at rest and/or an LV hypertrophy and/or an alteration of systolic functional indices. In neither group was there significant correlation between ET and duration of DM, basal heart rate, basal and max systolic blood pressure, and EF values. Linear regression analysis showed a significant correlation between Doppler parameters of the diastolic function and ET index in Group A, while there was no significant correlation in Group B. CONCLUSION: From these data we can deduce that in absence of left systolic ventricular dysfunction the impairment of LV relaxation in DM can influence exercise tolerance, probably by limiting activation of the contractile reserve.

Evaluation of the cardiomyopathy in Becker muscular dystrophy.

To evaluate the features and the course of cardiomyopathy in Becker muscular dystrophy, 68 patients--identified by clinical assessment and by reduced dystrophin labeling and/or DNA analysis--were followed in the years 1976-1993, for periods ranging from 3 to 18 years (mean 8). Patients periodically underwent clinical, electrocardiographic, echocardiographic, nuclear, and radiological assessments. Preclinical cardiac involvement was found in 67.4% of patients under 16 years of age, decreasing to 30% in patients older than 40. Clinically evident cardiomyopathy was found in 15% of patients under 16 years of age, increasing to 73% in patients older than 40. A real, dilated cardiomyopathy is the most frequent type of myocardial involvement after the age of 20. Results show that the severity of cardiac involvement can be unrelated to the severity of skeletal muscle damage and confirm that cardiac dysfunction is a primary feature of Becker muscular dystrophy.