[Show abstract][Hide abstract] ABSTRACT: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer (mCRC), but currently there are not valid predictors of response to this drug. In the control arms both of OPUS and PRIME studies Oxa seems more active in patients with mCRC with mutated (mt) KRAS than in those with wild type (wt) KRAS. Recently we have retrospectively confirmed this suggestion, therefore we have hypothesized that the mutational status of KRAS could influence the expression of ERCC1, one of the main mechanisms of Oxa resistance.
We used four cell lines of colorectal cancer: two KRAS wild type (wt) (HCT-8 and HT-29) and two KRAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test as well the ERCC1 levels before and after 24 h exposure to Oxa by Real-Time PCR. We silenced KRAS in a KRAS mt cell line (SW620LV) to evaluate the impact on Oxa sensitivity and ERCC1 levels. Lastly, ERCC1 was also silenced in order to confirm the importance of this protein as an Oxa resistance factor.
The KRAS mt cell lines resulted more sensitive to Oxa (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between KRAS mt and wt cell lines, however, after 24 h exposure to Oxa, only the wt KRAS lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). By silencing KRAS, sensitivity to Oxa was reduced in mt KRAS cell lines and this effect was associated with the acquisition of ability to induce ERCC1. Silencing of ERCC1, in turn, enhanced the sensitivity to Oxa in wt KRAS cell lines and restored sensitivity to Oxa in SW620LV cell line.
KRAS mutated cell lines were more sensitive to Oxa. This feature seems secondary to the inability of these cells to induce ERCC1 after exposure to Oxa. Thus, KRAS mutational status might be a predictor of response to Oxa in CRC surrogating the cell ability to induce ERCC1.
[Show abstract][Hide abstract] ABSTRACT: Gastric cancer represents one of the most common cancer worldwide. Unfortunately, the majority of patients still present in advanced stage and, despite advances in diagnostic and treatment strategies, outcome still remains poor with high mortality rate despite decreasing incidence. Although utility of classical chemotherapy agents has been widely explored, advances have been slow and the efficacy of these agents has reached a plateau of median overall survival not higher than 12 months. Therefore, researchers focused their attention on better understanding molecular biology of carcinogenesis and of acquisition of the cancer cell phenotype, as well on development of rationally designed drugs that would target specific molecular aberrancies in signal transduction pathways. These targets include cell surface receptors, circulating growth and angiogenic factors and other molecules involved in downstream intracellular signalling pathways, including receptor tyrosine kinases. Therapeutic advances in gastric cancer are not so encouraging when compared to other solid organ malignanciessuch as breast and colorectal cancer. This article reviews the role of targeted agents in gastric cancer as single-agent therapy or in combination regimens, including their rational and emerging mechanism of action, current and emerging data. We focused our attention mainly on published phase III studies, therefore cornerstone clinical trials with trastuzumab and bevacizumab have been largely discussed. Phase III studies presented in important international meetings are also reviewed as well phase II published studies and promising new therapies investigated in preclinical or phase I studies. Todate, only trastuzumab has shown significantly increased survival in combination with chemotherapy in first-line and ramucirumab as single agent in second-line treatment, but - despite other disappointing results - these are the proof of principle that targeting the proper molecular aberration is the best way for implementing outcome of therapy.
Current Medicinal Chemistry 11/2013; · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: In 2007, sorafenib was the first drug able to improve overall survival in patients with advanced hepatocellular carcinoma. AIM: In 2005 we designed a phase II study to assess safety and efficacy of sunitinib. METHODS: This is a single arm, open-label, single-centre phase II trial. Eligibility criteria were advanced hepatocellular carcinoma; no prior chemotherapy, performance status 0-1; and Child≤B8. The treatment schedule was 50mg each day orally, 4 weeks on, 2 weeks off. RESULTS: Between 10/2007 and 10/2010, 34 patients were enrolled. A significant worsening of liver functional reserve after sunitinib was observed. Grade 3/4 adverse effects occurred in 80% of patients and included fatigue (47%), nausea (15%), liver failure (15%), encephalopathy (12%) and upper gastrointestinal bleeding (12%). Six patients (18%) died within 60 days of enrolment. A partial response was observed in 4 patients (12%). Median time to tumour progression was 2.8 months and median overall survival was 5.8 months. CONCLUSION: A dose of 50mg/d induces a high rate of severe adverse events. Toxicity remains a key concern also at the dose of 37.5mg/d. However, sunitinib is able to induce a prolonged response in some patients. Positron Emission Tomography/Computed Tomography scans may select good responders.
Digestive and Liver Disease 02/2013; · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:In this study, we evaluated the possibility that KRAS mutational status might be predictive of oxaliplatin (OXA) efficacy. We also explored the role of excision repair cross complementing group-1 (ERCC-1).Methods:Ninety anti-epidermal growth factor receptor-naive advanced colorectal cancer patients were retrospectively analysed. In all patients KRAS mutational status was assessed. In 60 patients mRNA ERCC-1 expression was also investigated. Response rate (RR) and progression-free survival (PFS) after FOLFOX-6±bevacizumab were evaluated according to KRAS status and mRNA ERCC-1 expression.Results:Among 90 patients 47% wild-type (wt) and 53% mutated (mt) KRAS tumours were found. Response rate was 26% in the wt KRAS group, whereas it was 56% in the mt KRAS group; the difference is statistically significant in the total sample (P=0.008) and when only patients receiving FOLFOX-6±bevacizumab as first-line are considered (P=0.01). Progression-free survival was longer in mt than in wt KRAS patients over all patients (10 vs 8 months, respectively, P=0.001) and in those treated as first-line (10 vs 8 months, respectively, P=0.0069). Mt KRAS patients experienced a longer survival (24 vs 18 months; P=0.01). ERCC-1 mRNA expression was not found to correlate with FOLFOX activity in our analysis.Conclusion:Our results suggest that activating mutation of KRAS oncogene may predict response to OXA. Basal expression of ERCC-1 mRNA does not explain the high efficacy of FOLFOX-6 in mt KRAS patients.British Journal of Cancer advance online publication, 22 November 2012; doi:10.1038/bjc.2012.526 www.bjcancer.com.
British Journal of Cancer 11/2012; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is no agreement on which channel is involved in oxaliplatin neurotoxicity, most investigators favouring voltage-gated sodium channels. However, the small conductance Ca(++) activated K(+) channels, encoded by the SK1-3 genes, are also involved in membrane excitability, playing a role in after-hyperpolarization at the motor nerve terminal. As the SK3 gene is characterized in Caucasians by a highly polymorphic CAG motif within the exon 1, we hypothesize that SK3 gene polymorphism may influence the development of acute nerve hyperexcitability in oxaliplatin-treated patients.
Patients eligible for an oxaliplatin-containing regimen were enrolled. Detailed neurological examination, nerve conduction studies and needle electromyography were performed before and after oxaliplatin administration. DNA was extracted by polymerase chain reaction, and each allele was isolated and sequenced.
We evaluated 40 patients. After oxaliplatin administration, 28 patients developed symptoms of neurotoxicity, which were severe in 11. Patients were divided into three groups according to neurophysiological data: G0 (normal peripheral nerve excitability [PNE]), 16 patients; G1 (mild PNE), 15 patients; G2 (severe PNE), 9 patients. Genetic analysis showed different alleles ranging from 13 to 23 CAG repeats. Patients carrying alleles containing 13-15 CAG repeats experienced a significantly higher incidence of severe nerve hyperexcitability (chi-square 48.6; df 16; P = 0.0001).
The results suggest that OXA-neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene, which might modulate nerve after-hyperpolarization. The 13-14 CAG repeat allele could mark patients susceptible to acute OXA neurotoxicity.
Cancer Chemotherapy and Pharmacology 05/2011; 67(5):1179-87. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two cases of acute hepatitis occurring during treatment with anastrozole have previously been reported, but the underlying mechanisms of liver injury are still uncertain. We report the case of anastrozole-related acute hepatitis with some autoimmune features.
A 70-year-old woman developed acute hepatitis associated with serum antinuclear antibodies during anastrozole treatment; after drug withdrawal, liver function parameters rapidly improved and serum auto-antibodies were no longer detectable.
Anastrozole-induced hepatotoxicity is a very rare event. Drug-drug interactions or metabolically-mediated damage might be involved, with a possible role of individual susceptibility. Our report suggests that an immune-mediated mechanism may also be considered in anastrozole-related liver injury.
[Show abstract][Hide abstract] ABSTRACT: Gingival metastases are very rare and generally occur in disseminated tumors. We report a case of solitary gingival metastasis of lung cancer.
We report the case of a 74-year-old asymptomatic Caucasian woman affected by a rapidly growing, painless gingival swelling. Histopathologic examination of the excisional biopsy showed metastasis of poorly differentiated thyroid transcription factor 1-positive adenocarcinoma. A total-body computed tomographic scan revealed a tumor of the right lung lower lobe with ipsilateral, mediastinal lymph node swelling. Moreover, bone scintigraphy revealed no bone metastases. No other metastases were found, so we planned a multi-modal therapeutic approach with a curative intent. However, the tumor proved to be intrinsically resistant and highly aggressive.
The presentation of solitary gingival metastasis is exceptional. In view of its rapid clinical evolution, our case confirms that gingival metastasis is an important prognostic factor. This behavior raises the question whether the poor prognosis for patients with tumors with oral metastases depends on its diffuse spread or on its highly malignant nature.
[Show abstract][Hide abstract] ABSTRACT: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is very poor. The outcome of these patients is particularly bleak when the disease is complicated by portal vein tumor thrombosis (PVTT), since the increased portal pressure often causes serious gastrointestinal bleedings. Before the introduction of sorafenib (SOR), a tyrosine kinase inhibitor, no effective treatment was available for patients with advanced disease. SOR is now considered the standard treatment even for patients with tumor thrombosis, although the well-known interference between tyrosine kinase inhibitors and the coagulation pathway calls for caution against their use in this setting. Here, we report the case of a 74-year-old male patient with advanced HCC and PVTT treated with sunitinib (SUN), another multikinase inhibitor. During the third cycle, our patient experienced a life-threatening hematemesis with hemorrhagic shock that required intensive care treatment and SUN discontinuation. However, he completely recovered, and the PET/CT scan performed 1 year after the adverse effect demonstrated no evidence of the tumor together with portal vein recanalization. The short course of SUN causing both tumor response and gastrointestinal bleeding warrants further studies on the effectiveness of SUN in this setting as well as on the duration of treatment with multikinase inhibitors in patients with tumor thrombosis.
[Show abstract][Hide abstract] ABSTRACT: Renal cell carcinoma (RCC) is very resistant to both chemotherapy and radiotherapy. Localized disease can be cured by surgery but most patients are diagnosed when distant metastases are already present and about 30% of patients relapse after nephrectomy. Until 2 years ago, cytokine-based immunotherapy (interleukin-2 and interferon-alpha) was the only therapeutic option for advanced RCC patients. Fewer than 20% of patients benefit from this treatment, but some of these may experience very prolonged complete responses and progression-free intervals, suggesting a possibility of cure in a very few cases. Thanks to our expanding knowledge of the biology and pathogenesis of RCC, the treatment of this disease has recently undergone a major advance, through the development of potent angiogenesis inhibitors and targeted agents. Bevacizumab, an antibody directed against vascular endothelial growth factor (VEGF), has shown significant activity in combination with interferon-alpha (IFN-alpha). Sunitinib and sorafenib, multikinase inhibitors with proven antiangiogenic activity, have also been approved for the treatment of this tumor. Finally, temsirolimus and everolimus, which belong to the family of mammalian target of rapamycin (mTOR), have shown some activity in selected patients. The aim of this paper is to review clinical trials with these new agents, describing their activity and profiles of toxicity, and to evaluate potential future developmental strategies.
[Show abstract][Hide abstract] ABSTRACT: The indications for liver transplantation among patients with post-hepatitis B virus (HBV)-related cirrhosis have changed over the past 35 years. We reviewed the long-term results of 47 patients treated with liver transplantation for HBV-related cirrhosis. Patients were classified into 3 groups according to the perioperative regimen. In the initial experience, no immunoprophylaxis was adopted (no-IP; n=5). From 1988-1996, an immunoprophylaxis scheme was adopted (HBIg; n=16). From 1997-2007, we adopted the combination of lamivudine and HBIg (LAM-HBIg; n=26). We calculated the prevalence of serological reinfection and patient survival at 1 to 20 years, using the 3 regimens. The recurrence rate was 75% in the group of untreated patients; 30% in the HBIg group; and 9% in the LAM-HBIg group. The overall survival was 67% at 5 years, and 64% at 10 and 20 years. The long-term survival for each of the 3 therapeutic approaches, namely, for the patients who did not receive any treatment, for the HBIg group, and for the LAM-HBIg group, were 20%, 50%, and 84%, respectively. We suggest to use the LAM-HBIg combination.
[Show abstract][Hide abstract] ABSTRACT: We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m(-2), day 1; folinic acid, 200 mg m(-2); and 5-fluorouracil: as a 400 mg m(-2) bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m(-2), from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times.
British Journal of Cancer 11/2007; 97(8):1035-9. · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In advanced gastric cancer few data are available on the efficacy or safety of new drug combination regimens after progression following first-line chemotherapy.
Patients with histologically confirmed advanced gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than 2, progressing after first-line chemotherapy, were eligible. Patients were treated with docetaxel 75 mg/m(2) on day 1 and oxaliplatin 80 mg/m(2) on day 2, every 3 weeks, until progression or unacceptable toxicity.
Between May 2002 and April 2005, 38 patients were enrolled. Men accounted for 73.7% of the patients and the median age was 59 years. The primary tumor was not resected in 47.4% of the patients; the peritoneum was the most frequent metastatic site (60.5%). The first-line treatment was cisplatin, epirubicin, and infusional 5-fluorouracil (ECF) in 81.5% of the patients and cisplatin and infusional 5-fluorouracil (CF) in 15.7%. The median number of cycles was 4.3. The treatment was well tolerated, with no toxic deaths. National Cancer Institute (NCI) grade III-IV neutropenia was frequent (26.3%), but no febrile neutropenia was reported. Severe asthenia (15.7%) and severe nausea (15.7%) required dose reductions in 2 patients and treatment discontinuation in another. The overall response rate was 10.5%, and 18 patients (47.3%) experienced disease stabilization (7 of them with significant clinical benefit). Median time to progression was 4.0 months (range, 2-8 months) and median overall survival was 8.1 months (range, 3-26 months). Thirteen patients (34.2%) also received third-line chemotherapy, with an irinotecan-containing regimen, and their median overall survival was higher than that of the other patients (16.3 vs 6.0 months)
The combination of oxaliplatin and docetaxel shows only marginal activity as second-line treatment, but it has a good tolerability profile. This suggests that there is room for optimizing the schedule as well as for planning sequential treatments in gastric cancer.
Gastric Cancer 02/2007; 10(2):104-11. · 4.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several schedules of 5-fluorouracil (FU) and irinotecan (IRI) have been shown to improve overall survival in advanced colorectal cancer (CRC). Preclinical evidence suggests that the sequential administration of IRI and FU produces synergistic activity, although their clinical use has not been fully optimised. We investigated the interaction between short-term exposure to SN-38, the active metabolite of IRI, and prolonged exposure to FU in human CRC HT-29 cells and observed that the synergism of action between the two agents can be increased by extending the time of cell exposure to FU and reducing the interval between administration of the two agents. Based on these findings, we performed a phase I trial in 25 advanced CRC patients using a modified IRI/FU regimen as first-line therapy and evaluated three dose levels of IRI (150-300 mg/m(2)) and two of continuous infusion of FU (800-1000 mg/m(2)) in a 3-weekly schedule. The most severe grade III-IV toxicities were neutropoenia in four cycles and diarrhoea in three. One patient achieved complete response (4%), 12 a partial response (48%), the overall response rate was 52% (+/-20, 95% CI); seven of 25 patients had stable disease (28%), the overall disease control was 80% (+/-16, 95% CI). This modified IRI/FU schedule is feasible and exhibits potentially interesting clinical activity.
British Journal of Cancer 02/2007; 96(1):21-8. · 4.82 Impact Factor