Systematic Review and Meta-Analysis of Clinical Outcomes after Enucleation of Pancreatic Metastases from Renal Cell Carcinoma.

INTRODUCTION: A systematic review and meta-analysis of the literature was carried out to determine the clinical and oncological outcome of patients who had enucleation of solitary pancreatic metastases from renal cell carcinoma. METHODS: Operative mortality, postoperative complications, observed survival, and disease-free survival were analyzed. The clinical outcomes of patients who had enucleation were compared to those of 947 patients collected from the literature who had standard or atypical pancreatic resection for the same disease using propensity score matching. RESULTS: There was no postoperative mortality in the 56 patients who had enucleation of pancreatic metastases from renal cell carcinoma. In 51 patients, postoperative complications could be analyzed. Ten patients (10/51 = 19.6%) had postoperative complications. Three patients (3/51 = 5.9%) had major complications (Clavien-Dindo III or more). Five-year observed survival rates and disease-free survival for patients with enucleation were 92% and 79%, respectively. These results compared favorably with those obtained in patients who had standard resection and other forms of atypical resection (also using propensity score matching). Patients who had partial pancreatic resection (atypical or not) with pancreatic-jejunal anastomosis had increased rates of postoperative complications and local recurrences. CONCLUSIONS: Enucleation of pancreatic metastases offers a valid solution in selected patients.

Surgical Resection Is Superior to TACE in the Treatment of HCC in a Well Selected Cohort of BCLC-B Elderly Patients-A Retrospective Observational Study.

Hepatocellular carcinoma (HCC) usually develops in cirrhotic liver, with high recurrence rates. However, considering its increasing detection in non-cirrhotic liver, the choice of treatment assumes particular relevance. This study aimed to investigate outcomes of patients among BCLC stages and enrolled for surgical resection (SR) according to a more complex evaluation, to establish its safety and efficacy. A total of 186 selected HCC patients (median age 73.2 yrs), submitted to SR between January 2005 and January 2021, were retrospectively analyzed. Of which, 166 were staged 0, A, B according to the BCLC system, while 20 with a single large tumor (>5 cm) were classified as stage AB. No perioperative mortality was recorded; complications occurred in 48 (25.80%) patients, and all but two were Clavien−Dindo grade I−II. Median follow-up was 9.2 years. Subsequently, 162 recurrent patients (87,1%) were selected for new treatments. Comparable overall survival rates (OS) were observed at 1, 3, 5, and 10 years in 0, A, B and AB stages (p = 0.2). Eventually, the BCLC-B group was matched to 40 BCLC-B patients treated (2015-2021) with TACE. Significant differences in baseline characteristics (p <0.0001) and in OS were observed at 1 and 3 years (p <0.0001); a significant difference was also observed in oncological outcomes, in terms of the absence, residual, or relapse of disease (p <0.05). Surgery might be a valid treatment in HCC for patients affected by chronic liver disease in a condition of compensation, up to BCLC-B stage. Surgical indication for liver resection in case of HCC should be extensively revised.

HCC in the Era of Direct-Acting Antiviral Agents (DAAs): Surgical and Other Curative or Palliative Strategies in the Elderly.

Hepatocellular carcinoma (HCC) accounts for 75-85% of primary liver malignancies, and elderlies have the highest incidence rates. Direct-acting antiviral agents (DAAs) have shown satisfying results in terms of HCV sustained viral response (SVR). However, data regarding HCC risk post-DAA-SVR is still conflicting. This study aims to consider HCC onset in moderate underlying liver disease. We conducted a retrospective study on 227 chronically infected patients (cHCV), treated with DAAs. Patients were divided into three groups: "de novo occurrent HCC", "recurrent HCC", and "without HCC". Fifty-six patients aged <65 years (yDAA) were studied separately. HCC patients aged ≥65 years (DAA-HCC) were compared to a historical group of 100 elderly HCC patients, treated with peginterferon (Peg-IFN) ± ribavirin antiviral agents, non-SVR (hHCC). The HCC prevalence in DAA patients was 32.75%: "de novo occurrent'' 18.13% and "recurrent'' 14.62%, despite 42.85% of them having no fibrosis to mild or moderate fibrosis (F0-F1-F2). yDAA showed 5.36% "de novo occurrent" HCC. Curative procedure rates were compared between DAA-HCC and hHCC at the first and at recurrent presentation (22 (39.29%) vs. 72 (72%); 17 (30.36%) vs. 70 (70%), respectively (p < 0.001)). No significant difference was found in 3-year OS (p = 0.6). However, in cause-specific mortality analysis, HCC-related death was higher in the DAA-treated group, whereas cirrhosis-related death was more common in the historical group (p = 0.0288), considering together the two causes of death. A more accurate patient stratification according to multifactorial and new diagnostic investigations identifying HCC risk might allow an improvement in management and access to curative therapies.

Balloon occluded TACE (B-TACE) vs DEM-TACE for HCC: a single center retrospective case control study.

BACKGROUND: To compare oncological results and safety profile of balloon micro-catheter trans-arterial chemoembolization (b-TACE) and drug-eluting-microsphere (DEM-TACE) in patients with hepatocellular-carcinoma (HCC). METHODS: This is a case-control, retrospective, single-center study. Between January-2015/March-2019, 149 patients (131 males [87.9%]) with 226 HCC were treated, 22 patients (35 HCC; 19 [86.4%] males) with b-TACE and 127 with DEM-TACE (191 HCC, 112 [88.2%] males). Embolization protocol was standardized (sequential 100 ± 25 and 200 ± 25 µm microspheres). Results were evaluated by modified-response-evaluation-criteria-in-solid-tumor [mRECIST] at 1, 3-6 and 9-12 months and time to recurrence after complete response [TTR] at 1 years. Cox's regression weighted with tumor dimensions was performed. Adverse events (AEs) were recorded. RESULTS: mRECIST oncological response at all time points (1, 3-6 and 9-12 months) for both treatments were similar, with the exception of Objective response rate at 9-12 months. Objective response at 1 and 3-6 months between b-TACE vs DEM-TACE [23/35 (65.7%) vs 119/191 (62.3%), 21/29 (72.4%) vs 78/136 (57.4%) (p > 0.05), respectively]. On the contrary, at 9-12 months, it was significantly higher in b-TACE subgroup than DEM-TACE (15/19 [78.9%] vs 48/89 [53.9%], p = 0.05). TTR for complete response at 1 year had a better trend for b-TACE vs DEM-TACE (278.0 days [196.0-342.0] vs 219.0 days [161.0-238.0], OR 0.68 [0.4-1.0], p = 0.10). The use of balloon micro-catheter reduced the relative risk of the event of recurrence by 0.63 [CI95% 0.38-1.04]; p = 0.07). No significant differences were found in AEs rate. CONCLUSION: b-TACE showed a trend of better oncological response over DEM-TACE with and longer TTR with a similar adverse events rate, in patients presenting with larger tumors.

Total Versus Completion Thyroidectomy: A Multidimensional Evaluation of Long-Term Vocal Alterations.

BACKGROUND: Total thyroidectomy (TT) and completion thyroidectomy (CT) are two common surgical operations that are frequently followed by vocal symptoms despite preservation of the recurrent laryngeal nerve (RLN) and of the external branch of superior laryngeal nerve (EBSLN). The aim of this study was to analyze vocal alterations through endoscopic findings, videolaryngostroboscopy (VLS), acoustic vocal parameters and impact on patients' quality of life after surgery in the absence of laryngeal nerve injury. METHODS: We enrolled 198 patients who underwent thyroidectomy by the same surgeon. One hundred twenty-six patients underwent TT (group TT) while 72 underwent CT (group CT). All patients underwent preoperative VLS and Voice Handicap Index (VHI) assessment and postoperative VHI, VLS and Acoustic Voice Analysis with Multidimensional Voice Program Analysis 12 to 18 months after surgery. RESULTS: We observed a statistically significant higher rate of EBSLN injury in CT compared to TT. Even in the absence of RLN and EBSLN injury, patients who underwent TT and CT presented slightly worse acoustic vocal parameters and VHI scores compared to healthy controls. Interestingly, some acoustic vocal parameters and VHI scores were significantly worse in group CT compared to group TT. CONCLUSIONS: The higher rate of EBSLN injury in CT rather than in TT suggests a higher surgical risk in CT. The vocal parameters of loudness and self-perception of voice were significantly worse after CT, suggesting a larger trauma in patients' vocal outcome in CT if compared to TT, although these alterations were not reported as psychologically limiting daily life of patients. Nevertheless, the existence of multiple factors contributing to vocal alterations after thyroidectomy highlight the importance of a routine comprehensive functional voice analysis before and after surgery.

Gonioprobe, an Innovative Gamma-probe to Guide Parathyroid Radioguided Surgery: First Clinical Experiences with Navigator and Lock-ontarget Functions.

BACKGROUND: Radioguided surgery represents a validated technique for the detection and the excision of abnormal parathyroid glands responsible for primary hyperparathyroidism (PHPT). To date little attention has been paid as to how the characteristics of gamma-probes can influence surgical procedure and time, thus having an impact on postoperative morbidity, hospitalization and costs. METHODS: We designed a new prototype of gamma-probe, the Gonioprobe, and tested its clinical utility in the operating room. Gonioprobe, thanks to its 5 scintillating independent crystals, performs the dual function of Navigator and Lock-on-target. These characteristics allow the immediate guidance of the surgeon's hand towards the source with very high precision, and with a much higher spatial resolution than commercial probes. Gonioprobe was used during intervention to detect abnormal parathyroid tissue, and to ensure no radioactivity in surgery bed after adenoma removal. RESULTS: We tested our gamma-probe on parathyroid adenomas particularly difficult to identify at a visual inspection due to anatomy modifications from previous neck surgery and/or characterized by uncommon localization. Moreover, parathyroid adenomas were hardly removable due to the proximity to the esophagus, neck vessels and/or recurrent laryngeal nerve (RLN). An intraoperative nerve monitoring system was used to protect the recurrent laryngeal nerve from injuries. Parathyroid hormone (PTH) assay and frozen biopsy confirmed the successful excision of the adenomas. CONCLUSION: The intraoperative use of the innovative Gonioprobe along with the nerve monitoring system allowed an accurate and safe removal of parathyroid adenomas and offered a significant advantage by reducing surgical time and postoperative complications, as well as hospitalization and costs.

Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions.

In our study, we investigated the role of CD39 on tumor-infiltrating CD8+ T lymphocytes (CD8+ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T-cell exhaustion, we demonstrated a divergent functional activity in CD39+ CD8+ TILs. On the one hand, CD39+ CD8+ TILs (as compared to their CD39- counterparts) produced significantly lower IFN-γ and IL-2 amounts, expressed higher PD-1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD-1 expression. Therefore, CD39+ CD8+ TILs, including those co-expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A>G), as a genetic factor associated with CD39 expression in CD8+ TILs. Finally, we demonstrated that compounds inhibiting CD39-related ATPases improved CD39+ CD8+ T-cell effector function ex vivo, and that CD39+ CD8+ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39+ CD8+ T-cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8+ TILs.

Surgical-only treatment of pancreatic and extra-pancreatic metastases from renal cell carcinoma - quality of life and survival analysis.

BACKGROUND: Treatment of pancreatic metastases (PM) from renal cell carcinoma (RCC) is still an issue between surgeons and oncologists, in the era of target-therapy. METHODS: Data from 26 patients undergoing resection of PM and extra-PM from RCC, with R0 intention were retrospectively analysed. No one received adjuvant chemotherapy. Patients were divided into two groups; Group A comprehends 14 patients who developed synchronous (5) or methacronous (9) extra-PM. Group B comprehends 12 patients that developed PM only. RESULTS: No intraoperative mortality was recorded. Complications occurred in 14 patients (53.8%), all but 2 (7.26%) were graded I and II according to Clavien-Dindo classification. Recurrences occurred in 8 patients (30.8%), of whom, 5 (62.5%) were submitted for further resections in other sites. Three-, five- and ten-year observed overall survival were respectively 88,5% [95%CI: 0,56 - 1,33], 76,9% [95%CI: 0,47 - 1,19] and 50% [95%CI: 0,20 - 1,03]. Disease-free survival was 65,4% [95%CI: 0,38 - 1,05], at 3 years, 57,7% [95%CI 0,323 - 0,952] at 5 years and 42,9% [95%CI 0,157 - 0,933], at 10 years. QoL analysis, through WHOQOL-BREF questionnaire, assessed at last available follow up revealed a mean score of 75,9 ± 11,6 on 100 points. CONCLUSION: Despite no significant differences in survival between patients affected by Pancreatic or Extra-Pancreatic metastases, PM patients seems to show better outcome when managed surgically. mRCC patients, eligible for radical metastasectomy, tend to have long survival rates, reduced recurrence rates and good QoL. STUDY REGISTRATION: This paper was registered retrospectively in ClinicalTrials.gov with Identification number: NCT03670992.

MicroRNA-203 impacts on the growth, aggressiveness and prognosis of hepatocellular carcinoma by targeting MAT2A and MAT2B genes.

Hepatocellular carcinoma (HCC) is characterized by the down-regulation of the liver-specific methyladenosyltransferase 1A (MAT1A) gene, encoding the S-adenosylmethionine synthesizing isozymes MATI/III, and the up-regulation of the widely expressed methyladenosyltransferase 2A (MAT2A), encoding MATII isozyme, and methyladenosyltransferase 2B (MAT2B), encoding a ß-subunit without catalytic action that regulates MATII enzymatic activity. Different observations showed hepatocarcinogenesis inhibition by miR-203. We found that miR-203 expression in HCCs is inversely correlated with HCC proliferation and aggressiveness markers, and with MAT2A and MAT2B levels. MiR-203 transfection in HepG2 and Huh7 liver cancer cells targeted the 3'-UTR of MAT2A and MAT2B, inhibiting MAT2A and MAT2B mRNA levels and MATα2 and MATß2 protein expression. These molecular events were paralleled by an increase in SAM content and were associated with growth restraint and apoptosis, inhibition of cell migration and invasiveness, and suppression of the expression of CD133 and LIN28B stemness markers. In contrast, MAT2B transfection in the same cell lines led to a rise of both MATß2 and MATα2 expression, associated with increases in cell growth, migration, invasion and overexpression of stemness markers and p-AKT. Altogether, our results indicate that the miR-203 oncosuppressor activity may at least partially depend on its inhibition of MAT2A and MAT2B and show, for the first time, an oncogenic activity of MAT2B linked to AKT activation.

Case-report: Metastases in a low-stage middle-graded HCC in cleared HCV infection, non-cirrhotic liver: Surgical therapy.

INTRODUCTION: Hepatocellular carcinoma (HCC) is rare in non-cirrhotic liver. Achievement of sustained virological response (SVR) reduces even more the risk. PRESENTATION OF CASE: Liver resection for small HCC was performed in cleared HCV infection non-cirrhotic 62-year-old man. Methacronous oligometastatic recurrences in intolerant to Nexavar® side-effects patient, were treated by multiple innovative microinvasive approaches: bilateral laparoscopic adrenalectomy, thoracic wall resection, laparoscopic sacrum cryoablation combined with hadron-therapy. DISCUSSION: Therapies allowed the patient to lead 6 years satisfying QoL with only a small residual presacral disease stable at 8 months. CONCLUSION: Microinvasive surgery may be a valid resource of therapy in indolent HCC limited distant recurrences.

Inhibition of HSF1 suppresses the growth of hepatocarcinoma cell lines in vitro and AKT-driven hepatocarcinogenesis in mice.

Upregulation of the heat shock transcription factor 1 (HSF1) has been described as a frequent event in many cancer types, but its oncogenic role in hepatocellular carcinoma (HCC) remains poorly delineated. In the present study, we assessed the function(s) of HSF1 in hepatocarcinogenesis via in vitro and in vivo approaches. In particular, we determined the importance of HSF1 on v-Akt murine thymoma viral oncogene homolog (AKT)-induced liver cancer development in mice. We found that knockdown of HSF1 activity via specific siRNA triggered growth restraint by suppressing cell proliferation and inducing massive cell apoptosis in human HCC cell lines. At the molecular level, HSF1 inhibition was accompanied by downregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade and related metabolic pathways. Most importantly, overexpression of a dominant negative form of HSF1 (HSF1dn) in the mouse liver via hydrodynamic gene delivery led to the inhibition of mouse hepatocarcinogenesis driven by overexpression of AKT. In human liver cancer specimens, we detected that HSF1 is progressively induced from human non-tumorous surrounding livers to HCC, reaching the highest expression in the tumors characterized by the poorest outcome (as defined by the length of patients' survival). In conclusion, HSF1 is an independent prognostic factor in liver cancer and might represent an innovative therapeutic target in HCC subsets characterized by activation of the AKT/mTOR pathway.

A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis.

Amplification and/or activation of the c-Myc proto-oncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c-Myc has been proven experimentally by the finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c-Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c-Myc-dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor, the unique member of mTORC1, strongly inhibits c-Myc liver tumor formation. Also, the p70 ribosomal S6 kinase/ribosomal protein S6 and eukaryotic translation initiation factor 4E-binding protein 1/eukaryotic translation initiation factor 4E signaling cascades downstream of mTORC1 are required for c-Myc-driven tumorigenesis. Intriguingly, microarray expression analysis revealed up-regulation of multiple amino acid transporters, including solute carrier family 1 member A5 (SLC1A5) and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c-Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1 as their inhibition suppressed mTORC1 in c-Myc tumor cells. In human hepatocellular carcinoma specimens, levels of c-Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6. CONCLUSION: Our current study indicates that an intact mTORC1 axis is required for c-Myc-driven hepatocarcinogenesis; thus, targeting the mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of hepatocellular carcinoma with activated c-Myc signaling. (Hepatology 2017;66:167-181).

Indications, technique, and results of robotic pancreatoduodenectomy.

Robotic assistance improves surgical dexterity in minimally invasive operations, especially when fine dissection and multiple sutures are required. As such, robotic assistance could be rewarding in the setting of robotic pancreatoduodenectomy (RPD). RPD was implemented at a high volume center with preemptive experience in advanced laparoscopy. Indications, surgical technique, and results of RPD are discussed against the background of current literature. RPD was performed in 112 consecutive patients. Conversion to open surgery was required in three patients, despite nine required segmental resection and reconstruction of the superior mesenteric/portal vein. No patient was converted to laparoscopy. A pancreato-jejunostomy was created in 106 patients (94.6 %), using either a duct-to-mucosa (n = 82; 73.2 %) or an invaginating (n = 24; 21.4 %) technique. Pancreato-gastrostomy was performed in one patient, the pancreatic duct was occluded in two patients, and a pancreatico-cutaneous fistula was created in three patients. Mean operative time was 526.3 ± 102.4 in the entire cohort and reduced significantly over the course of time. Experience was also associated with reduced rates of delayed gastric emptying and increased proportion of malignant tumor histology. Ninety day mortality was 3.6 %. Postoperative complications occurred in 83 patients (74.1 %) with a median comprehensive complication index of 20.9 (0-30.8). Clinically relevant pancreatic fistula occurred in 19.6 % of the patients. No grade C pancreatic fistula was noted in the last 72 consecutive patients. RPD is safely feasible in selected patients. Implementation of RPD requires sound experience with open pancreatoduodenectomy and advanced laparoscopic procedures, as well as specific training with the robotic platform.

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease.

Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14-3-3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells.

The learning curve in robotic distal pancreatectomy.

No data are available on the learning curve in robotic distal pancreatectomy (RADP). The learning curve in RADP was assessed in 55 consecutive patients using the cumulative sum method, based on operative time. Data were extracted from a prospectively maintained database and analyzed retrospectively considering all events occurring within 90 days of surgery. No operation was converted to laparoscopic or open surgery and no patient died. Post-operative complications occurred in 34 patients (61.8%), being of Clavien-Dindo grade I-II in 32 patients (58.1%), including pancreatic fistula in 29 patients (52.7%). No grade C pancreatic fistula occurred. Four patients received blood transfusions (7.2%), three were readmitted (5.4%) and one required repeat surgery (1.8%). Based on the reduction of operative times (421.1 ± 20.5 vs 248.9 ± 9.3 min; p < 0.0001), completion of the learning curve was achieved after ten operations. Operative time of the first 10 operations was associated with a positive slope (0.47 + 1.78* case number; R (2) 0.97; p < 0.0001*), while that of the following 45 procedures showed a negative slope (23.52 - 0.39* case number; R (2) 0.97; p < 0.0001*). After completion of the learning curve, more patients had a malignant histology (0 vs 35.6%; p = 0.002), accounting for both higher lymph node yields (11.1 ± 12.2 vs 20.9 ± 18.5) (p = 0.04) and lower rate of spleen preservation (90 vs 55.6%) (p = 0.04). RADP was safely feasible in selected patients and the learning curve was completed after ten operations. Improvement in clinical outcome was not demonstrated, probably because of the limited occurrence of outcome comparators.

Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue.

UNLABELLED: Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T-bethigh IFN-γ- "T-helper (Th)1-suppressing" phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon-gamma (IFN-γ; T-bet+IFN-γ+), thus becoming "Th1-like" cells. OX40-expressing and Th1-suppressing Tregs were enriched in the Helios-positive subset, carrying highly demethylated Treg cell-specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2-like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-γ, ultimately leading to complete, full Th1-like Treg differentiation. CONCLUSION: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ.

Elderly and very elderly patients with hepatocellular carcinoma. Strategy for a first line treatment.

AIM: Health-status of elderly patients with hepatocellular carcinoma (HCC) may limit surgical approach; other options are thus auspicable. METHODS: The authors reviewed 98 selected patients, aged 65 to 90 years, with 149 HCC treated between 2002 and 2011. According to the extent of malignancy, health status and treatment, patients were divided into 3 groups. Sixty-one, submitted to major and minor curative resections, were in group A and B while group C included 37 patients, unsuitable for high-risk procedures and percutaneous ablation, submitted to intraoperative-radiofrequency ablation (IRFA) alone or combined with minor resections. Assessment of safety and therapeutic efficacy of this managment was evaluated. RESULTS: A postoperative mortality rate of 1,02% and an overall survival rate at 5 years of 62.3% were observed. Indeeed matched post-operative morbidity and mortality rates of A, B, C groups were 45%, 8%, 16.21% (p < 0.004) and 9 %, 0%, 0% (p= 0.112 ) respectively. 3 years overall-survival was not statistically different (p= 0.585). However 5 years survival rate and disease-free-survival rate were significantly higher in patients of group A and B (p= 0.003; p< 0.001). CONCLUSION: Treatment strategies to minimize treatment-related morbidity and mortality have resulted satisfactory for early and late outcomes of an heterogeneous group of elderly patients with HCC.

Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone (FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation (BDL). AIMS: To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models. METHODS: Evaluation of FSH receptor (FSHR), FSH, phospho-extracellular-regulated kinase (pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen (PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD (LCDE) with or without transient silencing of the FSH gene. RESULTS: Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway. CONCLUSION: These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD.