Curvature-dimension inequalities and Li-Yau inequalities in sub-Riemannian spaces

In this paper we present a survey of the joint program with Fabrice Baudoin originated with the paper \cite{BG1}, and continued with the works \cite{BG2}, \cite{BBG}, \cite{BG3} and \cite{BBGM}, joint with Baudoin, Michel Bonnefont and Isidro Munive.Comment: arXiv admin note: substantial text overlap with arXiv:1101.359

Survivin depletion inhibits tumor growth and enhances chemosensitivity in hepatocellular carcinoma

Survivin is a member of the inhibitor of apoptosis family, which has been suggested to be crucial in the control of cell division and inhibition of apoptosis. Expression of this protein has been observed in transformed cell lines and human tumor tissues, including those from colorectal cancer, but not in terminally differentiated adult tissues. Survivin mRNA expression has frequently been detected in hepatocellular carcinoma (HCC) and its protein expression has been demonstrated to be highly correlated with proliferation index rather than apoptotic index. The present study aimed to analyze the effect of survivin on the tumorigenicity and chemosensitivity of HCC via the establishment of an HCC cell line (PLC/PRF/5) with the stable knockdown of the survivin gene (PLC-k3). This cell line displayed significantly lower rates of survival and proliferation in assays of cell viability and proliferation, respectively, compared with those of the control cell line (PLC-v). In addition, PLC-k3 cells were more sensitive to cisplatin treatment, resulting in S phase arrest. These findings were further confirmed by an in vivo experiment. The data of the present study suggest that survivin is critical in promoting cell proliferation but not in inhibition of apoptosis, and enhances the chemosensitivity of HCC. Thus, the suppression of survivin expression in combination with cisplatin may contribute to the development of more effective treatments for HCC.published_or_final_versio

Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease

Background The combination of bevacizumab (B) and erlotinib (E) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients. We aimed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment. Methods Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited. All patients received bevacizumab(B) at 10 mg/kg every 2 weeks with erlotinib(E) at 150 mg daily for a maximum of 6 cycles. Response assessments using both RECIST and modified RECIST criteria were performed after every 6 weeks. The primary endpoint was clinical benefit (CB) rate and a Simon two-stage design was employed. Results The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited. The median age was 47 years (range, 28-61) and all patients were in ECOG performance status 1. Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis. Among these 10 patients, none of the enrolled patients achieved response or stable disease. The median time-to-progression was 1.81 months (95 % confidence interval [C.I.], 1.08-1.74 months) and overall survival was 4.37 months (95 % C.I., 1.08-11.66 months). Rash (70 %), diarrhea (50 %) and malaise (40 %) were the most commonly encountered toxicities. Conclusion The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population. Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population. © 2012 The Author(s).published_or_final_versio

A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Methods Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design. Results Fifteen patients were enrolled at weekly doses of 500 U/kg (n = 3), 1000 U/kg (n = 3), 1600 U/kg (n = 3) and 2500 U/kg (n = 6). The median age was 57 years (33-74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600-2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for >8 weeks in 26.7% of the enrolled patients. Conclusion Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients.published_or_final_versio

Management of spontaneously ruptured hepatocellular carcinomas in the radiofrequency ablation era

Background and aim: Spontaneous rupture of hepatocellular carcinoma (HCC) carries a high mortality. The use of radiofrequency ablation (RFA) in recent years has enriched the armamentarium for hemostasis of spontaneously ruptured HCCs but its results have not been documented. This study investigated the prognosis and outcome of spontaneous rupture of HCC as well as the results of using RFA for hemostasis. Patients and method: From January 1991 to December 2010, 5283 patients were diagnosed with HCC at our hospital, and 189 of them had spontaneous rupture of HCCs. They were grouped under two periods: period 1, 1991-2000, n = 70; period 2, 2001-2010, n = 119. RFA was available in period 2 only. Results: Hepatitis B virus infection was predominant in both periods. Surgical hemostasis was mainly achieved by hepatic artery ligation in period 1 and by RFA in period 2. The 30-day hospital mortality after surgical treatment was 55.6% (n = 18) in period 1 and 19.2% (n = 26) in period 2 (p = 0.012). Multivariate analysis identified 4 independent factors for better overall survival, namely, hemostasis by transarterial chemoembolization (hazard ratio 0.516, 95% confidence interval 0.354-0.751), hemostasis by RFA (hazard ratio 0.431, 95% confidence interval 0.236-0.790), having surgery as a subsequent treatment (hazard ratio 0.305, 95% confidence interval 0.186-0.498), and a serum total bilirubin level <19 umol/L (hazard ratio 1.596, 95% confidence interval 1.137-2.241). Conclusion: The use of RFA for hemostasis during laparotomy greatly reduced the hospital mortality rate when compared with conventional hepatic artery ligation. © 2014 Cheung et al.published_or_final_versio

Survival analysis of transarterial radioembolization with yttrium-90 for hepatocellular carcinoma patients with HBV infection

Introduction: For patients with resectable hepatocellular carcinoma (HCC), hepatectomy remains one of the best treatment options to provide long-term survival. However, more than 50% of the patients have unresectable disease upon diagnosis even though there are no distant metastases. Transarterial chemoembolization (TACE) is a well-established treatment option that offers a palliative survival benefit for this group of patients. A better treatment for unresectable HCC has been sought after. There is some evidence that transarterial radioembolization (TARE) with the agent yttrium-90 produces encouraging outcomes, especially in patients with portal vein tumor thrombus. This study aims to analyze the outcomes of TARE at our center. Methods: From August 2009 to April 2013, 16 patients underwent TARE at our center. Sixteen patients with similar tumor characteristics were selected to undergo TACE alone for comparison. A retrospective analysis of the prospectively collected data of the patients was conducted. Only patients with newly diagnosed primary tumors were included in this study. Results: The median survival for patients having TARE was 19.9 versus 14.0 months in the TACE group (P=0.615). There was no difference in terms of tumor response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) (P=0.632). The 1-, 2- and 3-year survival rates in the TARE group were 80.0%, 30.5% and 20.3% respectively. The 1-year survival in the TACE group was 58.3% (P=0.615). For patients who had major vascular invasion (eight in each group), the 1- and 2-year survival rates in the TARE group were 62.5% and 15.6% respectively, while the 1-year survival in the TACE group was 35.0% (P=0.664). Conclusions: The two groups showed similar results in terms of tumor response and overall survival benefit. TARE might provide a survival benefit for patients with major vessel invasion.published_or_final_versio

Tolerance of high-intensity focused ultrasound ablation in patients with hepatocellular carcinoma

BACKGROUND: High-intensity focused ultrasound (HIFU) ablation is a relatively new, noninvasive way of ablation for treating hepatocellular carcinoma (HCC). Emerging evidence has shown that it is effective for the treatment of HCC, even in patients with poor liver function. There is currently no data on the safety limit of HIFU ablation in patients with cirrhosis. However, this information is vital for the selection of appropriate patients for the procedure. We analyzed HCC patients who had undergone HIFU ablation and determined the lower limit of liver function and other patient factors with which HCC patients can tolerate this treatment modality. METHODS: Preoperative variables of 100 patients who underwent HIFU ablation for HCC were analyzed to identify the risk factors in HIFU intolerance in terms of stress-induced complications. Factors that may contribute to postablation complications were compared. RESULTS: Thirteen (13 %) patients developed a total of 18 complications. Morbidity was mainly due to skin and subcutaneous tissue injuries (n = 9). Five patients had first-degree skin burn, one had second-degree skin burn, and three had third-degree skin burn. Four complications were grade 3a in the Clavien classification and 14 were below this grade. Univariate analysis showed that age (p = 0.022) was the only independent factor in HIFU intolerance. CONCLUSIONS: HIFU ablation is generally well tolerated in HCC patients with cirrhosis. It is safe for Child-Pugh A and B patients and selected Child-Pugh C patients. With this new modality, HCC patients who were deemed unsalvageable by other surgical means in the past because of simultaneous Child-Pugh B or C disease now have a new hope.published_or_final_versio

Long Term Survival Analysis of Hepatectomy for Neuroendocrine Tumour Liver Metastases

Background. Liver is the commonest site for metastasis in patients with neuroendocrine tumour (NET). A vast majority of treatment strategies including liver directed nonsurgical therapy, liver directed surgical therapy, and nonliver directed therapy have been proposed. In this study we aim to investigate the outcome of liver resection in neuroendocrine tumour liver metastases (NELM). Method. 293 patients had hepatectomy for liver metastasis in our hospital between June 1996 and December 2010. Twelve patients were diagnosed to have NET in their final pathology and their data were reviewed. Results. The median ages of the patients were 48.5 years (range 20-71 years). Eight of the patients received major hepatectomy. Four patients received minor hepatectomy. The median operation time was 418 minutes (range 195-660 minutes). The median tumor size was 8.75 cm (range 0.9-21 cm). There was no hospital mortality. The overall one-year and three-year survivals were 91.7% and 55.6%. The one-year and three-year disease-free survivals were 33.3% and 16.7%. Conclusion. Hepatectomy is an effective and safe treatment for NELM. Reasonable outcome on long term overall survival and disease-free survival can be achieved in this group of patients with a low morbidity rate. © 2014 Tan To Cheung et al.published_or_final_versio

Polynomial Growth Harmonic Functions on Finitely Generated Abelian Groups

In the present paper, we develop geometric analytic techniques on Cayley graphs of finitely generated abelian groups to study the polynomial growth harmonic functions. We develop a geometric analytic proof of the classical Heilbronn theorem and the recent Nayar theorem on polynomial growth harmonic functions on lattices \mathds{Z}^n that does not use a representation formula for harmonic functions. We also calculate the precise dimension of the space of polynomial growth harmonic functions on finitely generated abelian groups. While the Cayley graph not only depends on the abelian group, but also on the choice of a generating set, we find that this dimension depends only on the group itself.Comment: 15 pages, to appear in Ann. Global Anal. Geo