Stefania Di Girolamo

Metronomic Capecitabine in Advanced Hepatocellular Carcinoma Patients: A Phase II Study

UNLABELLED Anti-angiogenic treatment with targeted agents is effective in advanced hepatocellular carcinoma (HCC). This trial evaluated the safety and efficacy of metronomic capecitabine in patients with HCC. METHODS This single-institution phase II trial included 59 previously untreated patients with advanced HCC and 31 patients resistant to or intolerant of sorafenib. The treatment schedule was capecitabine 500 mg twice daily until progression of disease, unacceptable toxicity level, or withdrawal of informed consent. Progression-free survival (PFS) was chosen as the primary endpoint. RESULTS A total of 59 previously untreated and 31 previously treated patients with HCC were enrolled. The first cohort achieved a median PFS of 6.03 months and an overall survival (OS) of 14.47 months. Two patients achieved a complete response, 1 patient achieved partial response, and in 30 patients, stable disease was the best outcome. The second cohort achieved a median PFS of 3.27 months and a median OS of 9.77 months. No complete or partial responses were observed, but 10 patients had stable disease. An unscheduled comparison of the first cohort of patients with 3,027 untreated patients with HCC from the Italian Liver Cancer (ITA.LI.CA) database was performed. One-to-one matching according to demographic/etiologic/oncologic features was possible for 50 patients. The median OS for these 50 capecitabine-treated patients was 15.6 months, compared with a median OS of 8.0 months for the matched untreated patients (p = .043). CONCLUSION Metronomic capecitabine is well tolerated by patients with advanced HCC and appears to have activity both in treatment-naive patients and in those previously treated with sorafenib.

Neoadjuvant Treatment in Rectal Cancer: Actual Status

Neoadjuvant (preoperative) concomitant chemoradiotherapy (CRT) has become a standard treatment of locally advanced rectal adenocarcinomas. The clinical stages II (cT3-4, N0, M0) and III (cT1-4, N+, M0) according to International Union Against Cancer (IUCC) are concerned. It can reduce tumor volume and subsequently lead to an increase in complete resections (R0 resections), shows less toxicity, and improves local control rate. The aim of this review is to summarize actual approaches, main problems, and discrepancies in the treatment of locally advanced rectal adenocarcinomas.

Adjuvant Systemic Chemotherapy After Putative Curative Resection of Colorectal Liver and Lung Metastases

OBJECTIVE Marginal statistical evidence of efficacy of adjuvant and/or perioperative chemotherapy after resection of colorectal metastases exists, but formal recommendations are still lacking. The present study evaluated the adjuvant systemic chemotherapy after the first resection of liver and lung colorectal cancer metastases. PATIENTS AND METHODS We retrospectively reviewed data of 181 consecutive unselected patients with R0 resection of colorectal metastases treated simultaneously at 2 institutions from 1997 to 2004. Patients > 75 years old, with an Eastern Cooperative Oncology Group Performance Status Score ≥ 2 or unfit for adjuvant chemotherapy were excluded from the analysis. The decision on chemotherapy after surgery was left to the patient in the absence of conclusive data on the efficacy of adjuvant chemotherapy in this setting. A total of 151 patients (131 with liver metastases, 20 with lung metastases), 78 of whom underwent adjuvant chemotherapy, were evaluable for disease-free survival (DFS) and overall survival. The main prognostic factors for DFS after resection of colorectal cancer metastases were investigated in univariate and multivariate analyses. RESULTS At the univariate analysis, the number of resected lesions, lesion volume, disease-free interval and adjuvant systemic chemotherapy were the only significant prognostic factors. At multivariate analysis, only adjuvant chemotherapy and disease-free interval were independent prognostic factors (hazard ratios 1.66 and 1.62, respectively). The median DFS of patients who underwent systemic adjuvant chemotherapy was 16 months compared with 9.7 months for patients with observation alone (hazard ratio 1.56). Estimated 5-year DFS was 17.4% and 10.5% for treated and untreated patients, respectively. CONCLUSION Adjuvant chemotherapy after metastasectomy in patients with colorectal cancer showed a significant benefit for DFS.

Durable complete response of hepatocellular carcinoma after metronomic capecitabine.

Background Hepatocellular carcinoma (HCC) is a highly vascular tumor which is poorly responsive to standard systemic chemotherapy. Recently, various antiangiogenic targeted agents have shown promising activity at different levels of evidence in patients with advanced HCC, suggesting that such treatments might be effective. Case report Since chemotherapy administered with metronomic schedules inhibits angiogenesis, we treated a 64-year-old man with advanced HCC with metronomic capecitabine. After only two months of treatment the HCC nodules disappeared on ultrasonography. This finding was confirmed by a computed tomography scan. After more than three years the patient is still in treatment with minimal toxicity and maintains a complete remission. Conclusions Our case report suggests that metronomic capecitabine may be effective in advanced HCC patients while being also well tolerated. This is important, given the frequent comorbidities of HCC patients. Free full text available at www.tumorionline.it

Antitumoral Efficacy of the Protease Inhibitor Gabexate Mesilate in Colon Cancer Cells Harbouring KRAS, BRAF and PIK3CA Mutations

The employment of anti-epidermal growth factor receptor (EGFR) antibodies represents a backbone of the therapeutic options for the treatment of metastatic colorectal cancer (mCRC). However, this therapy is poorly effective or ineffective in unselected patients. Mutations in KRAS, BRAF and PIK3CA genes have recently emerged as the best predictive factors of low/absent response to EGFR-targeted therapy. Due to the need for efficacious treatment options for mCRC patients bearing these mutations, in this short report we examined the antitumoral activity of the protease inhibitor gabexate mesilate, alone and in combination with the anti-EGFR monoclonal antibody cetuximab, in a panel of human CRC cell lines harbouring a different expression pattern of wild-type/mutated KRAS, BRAF and PIK3CA genes. Results obtained showed that gabexate mesilate significantly inhibited the growth, invasive potential and tumour-induced angiogenesis in all the CRC cells employed in this study (including those ones harbouring dual KRAS/PIK3CA or BRAF/PIK3CA mutation), while cetuximab affected these parameters only in CRC cells with KRAS, BRAF and PIK3CA wild-type. Notably, the antitumoral efficacy of gabexate mesilate and cetuximab in combination was found to be not superior than that observed with gabexate mesilate as single agent. Overall, these preliminary findings suggest that gabexate mesilate could represent a promising therapeutic option for mCRC patients, particularly for those harbouring KRAS, BRAF and PIK3CA mutations, either as mono-therapy or in addition to standard chemotherapy regimens. Further studies to better elucidate gabexate mesilate mechanism of action in CRC cells are therefore warranted.

Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients

Sorafenib is the standard treatment of advanced hepatocarcinoma (HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine‐kinase (TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK‐related pathways and by inhibiting angiogenesis.

Fulminant hepatitis in a patient with hepatocellular carcinoma related to nonalcoholic steatohepatitis treated with sorafenib.

Background Endometriosis and infertility have been shown to be related to one another. The mechanisms that explain this phenomenon are not fully understood. One of the possible mechanisms of infertility in endometriosis patients is failure of implantation of the embryo in the endometrium. This may be caused by high levels of methylation of HOXA10 gene in patients with endometriosis, resulting a decrease in the expression of genes that play a role in this endometrial receptivity. Objective To determine the methylation profile of HOXA10 gene on eutopic endometrium in endometriosis patients with infertility. Methods This is a cross-sectional study conducted at Cipto Mangunkusumo General Hospital from July 2015 to July 2016. The subjects of research were cystic ovarian endometriosis patients with infertility, confirmed histopathologically and non-endometriosis-fertile patients. The methylation status of HOXA 10 gene in both groups was examined and compared. Statistical analysis is Mann-Whitney U-test, a two-tailed p value less than 0.05 was considered significant. Results There were six endometriosis patients and six controls. Six samples on endometriosis group showed the following percentage rate of methylation: 63.29%, 55.28%, 33.92%, 43.27%, 77.20% and 65.94%. Meanwhile, four samples in the control group did not undergo methylation at all and two other samples methylated at low levels equal to 15.24% and 16.48%. Methylation status between these two groups is statistically different with p 0.03. Conclusions In patients with endometriosis-associated infertility, HOXA10 gene in eutopic endometrium has a higher methylation level.We describe a case of acute liver failure in a patient with advanced hepatocellular carcinoma related to nonalcoholic steatohepatitis during sorafenib treatment. A 74-year-old man with diabetes mellitus and hypertension was diagnosed with hepatocellular carcinoma associated with fatty liver. Three weeks after sorafenib therapy, at Eastern Cooperative Oncology Group performance status 3, he developed jaundice, general weakness, flapping tremor, nausea, and anorexia. Sorafenib was stopped: laboratory tests showed a relevant elevation of transaminases suggesting diagnosis of acute hepatitis. During hospital admission, the patient died of liver failure. Sorafenib is the first successful target therapy effective for advanced hepatocellular carcinoma. The most common adverse events are fatigue, hand-foot skin reaction, skin rash/desquamation, diarrhea, and hypertension, whereas liver dysfunction is uncommon. To our knowledge, this is the first patient reported in the literature with hepatocellular carcinoma related to nonalcoholic steatohepatitis who died of rapid worsening of liver function during sorafenib treatment.

Occupational exposure to asbestos and cholangiocarcinoma: findings from an explorative case-control analysis

Objectives Alongside to respiratory cancers, exposure to asbestos has been associated with gastrointestinal cancers. An association between exposure to amphibole fibres and their presence in hepatic tissue has been reported. We conducted a case-control analysis to explore the association between occupational exposure to asbestos and cholangiocarcinoma. Methods We used historical data from 155 consecutive patients referred to our centre for diagnosis and treatment of cholangiocarcinoma in 2007–2011 (69 affected by Intrahepatic Cholangiocarcinoma (ICC) and 86 by Extrahepatic Cholangiocarcinoma (ECC)). When feasible, cases were individually matched (ratio up to 1:4) by calendar period of birth (5-year interval), sex and provenience to historical population controls (originally sampled to study other occupational diseases, not related to asbestos). Occupational exposure to asbestos was assessed by industrial hygienists considering life-prevalent job titles. Separate conditional logistic regression models were conducted for ICC and ECC, adjusting for smoking status and socioeconomic class. Results We matched 149 controls to 49 cases of ICC and 212 controls to 59 cases of ECC (47 cases were not matched mainly due to provenience). We found an increased risk of ICC in workers exposed to asbestos (adjusted OR 4.73, 95% CI 1.54 to 14.54); conversely, no clear evidence of increased risk was found for ECC (adjusted OR 1.84, 95% CI 0.66 to 5.08). Sensitivity analysis conducted using only patients from our city district (conducted to minimise referral bias) produced confirmatory figures. Conclusions Findings from our exploratory study support the hypothesis that intrahepatic cholangiocarcinoma could arise from chronic irritation and inflammation caused by deposition of asbestos fibres.