Sorafenib treatment during partial hepatectomy reduces tumorgenesis in an inflammation-associated liver cancer model.

The long-term prognosis after resection of hepatocellular carcinoma (HCC), which is one of the treatment options for early-stage HCC, remains unsatisfactory as a result of a high incidence of disease recurrence. Recent studies performed in murine models revealed a link between liver regeneration under chronic inflammation and hepatic tumorigenesis. Sorafenib is a potent drug for advanced HCC with multikinase inhibition activity. We propose that inhibition of signal transduction pathways which are activated during hepatectomy, using Sorafenib, will reduce accelerated tumorigenesis. To test this hypothesis, we studied the Mdr2-knockout (KO) mouse strain, a model of inflammation-associated cancer, which underwent partial hepatectomy (PHx) at three months of age, with or without Sorafenib.Here we show that Sorafenib treatment during PHx inhibited different signal transduction pathways at the multikinase levels, but did not result in increased morbidity or mortality. At the early stages after PHx, Sorafenib treatment had no effect on the course of proliferation, apoptosis and DNA repair in the regenerating liver, but resulted in decreased stellate cells activation and inflammatory response. Finally, we show that Sorafenib treatment during PHx at three months of age resulted in decreased fibrosis and tumor formation at 8.5 months.In conclusion our study indicates that short-term Sorafenib treatment during PHx is safe and effective in inhibiting inflammation-associated cancer, and is therefore a potential strategy for recurrence prevention in patients with early-stage HCC treated with PHx.

Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer.

Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signaling pathways. In breast cancer cell lines and xenograft models activated STAT3 participates in breast tumorigenesis, while studies in humans have demonstrated that phosphorylated (tyrosine705)-STAT3 is a marker of good prognosis in breast cancer. In order to resolve this paradox we hypothesized that in clinic, phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy; therefore the goal of this study was to determine the usefulness of phospho-STAT3 status as a predictor of benefit from adjuvant chemotherapy in breast cancer patients. Immunohistochemical analysis of phospho-STAT3 was performed on a tissue microarray of breast cancer specimens. The expression pattern of phospho-STAT3 was retrospectively correlated with pathological parameters and overall survival in patients who were or were not treated with adjuvant chemotherapy. Of 375 tissue specimens interpretable for phospho-STAT3, 134 (36 %) exhibited positive phospho-STAT3 nuclear expression. Among 234 patients who received adjuvant therapy, those with tumors displaying positive phospho-STAT3 nuclear expression had a better ten-year rate of overall survival than patients with tumors displaying negative phospho-STAT3 nuclear expression (P = 0.001). Among patients who did not received adjuvant chemotherapy, positive phospho-STAT3 nuclear status was not correlated with increased overall survival (P = 0.54). Positive phospho-STAT3 was correlated with improved overall survival only among patients who received adjuvant chemotherapy in a multivariate analysis adjusted for stage, grade, hormonal status, Her2 status, and age, irrespective of the chemotherapy regimen received (hazard ratio for death, 0.35 [95 % CI 0.188-0.667]; P = 0.001). These findings support the role of phospho-STAT3 as a marker of favorable outcome in breast cancer patients treated with adjuvant chemotherapy. Whether phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy has to be validated on prospective, randomized, controlled studies.

Long-term outcome of continuous 5-fluorouracil/cisplatin-based chemotherapy followed by chemoradiation in patients with resected gastric cancer.

Despite substantial developments in gastric cancer treatment, the majority of patients relapse after definitive surgery. We have previously described well-tolerated adjuvant regimen that includes a combination of bolus 5-fluorouracil, continuous 5-fluorouracil, and cisplatin followed by chemoradiation after 3 months of chemotherapy. The aim of this study was to evaluate long-term outcomes of patients treated with this regimen and to determine whether expressions of the excision repair cross-complementing (ERCC1) and thymidylate synthase (TS) predict clinical outcome in those patients. The study population consisted of 36 advanced gastric cancer patients. Patients were treated with six cycles of continuous 5-fluorouracil (600 mg/m(2)) for 24 h, push 5-fluorouracil (400 mg/m(2)), and leucoverin (LCV) (200 mg/m(2)) on day 1-2 every 2 weeks, cisplatin (60 mg/m(2)) on day 1 every 4 weeks followed by combined modality therapy using 45 Gy at 1.8 Gy per day concomitant with weekly bolus 5-fluorouracil (600 mg/m(2)) and LCV (50 mg). After median follow-up of 48.9 months, the median disease-free survival was 45 months and the overall survival was 66.4 months. Sixteen patients (44 %) were alive and disease-free. There was no significant correlation between ERCC1 expression and TS expression pattern and time to relapse (P = 0.302 and P = 0.707, respectively). In conclusion, long-term follow-up demonstrates that postoperative chemoradiation with combination of bolus 5-fluorouracil, continuous 5-fluorouracil, and cisplatin is a feasible approach.

Renal tubular acidosis secondary to capecitabine, oxaliplatin, and cetuximab treatment in a patient with metastatic colon carcinoma: a case report and review of the literature.

We report a case of renal tubular acidosis (RTA) secondary to capecitabine, oxaliplatin, and cetuximab administration in a 63-year-old woman with liver metastasis from colon carcinoma who had partial treatment response. On day 5 posttreatment, she arrived to the emergency room with severe weakness, and blood tests demonstrated hypokalemia with metabolic acidosis. Urine potassium levels were elevated, and the transtubular potassium gradient (TTKG) was 6.6, consistent with hypokalemic RTA with associated Fanconi syndrome, which presented as hyperphosphaturia, uricaciduria, and loss of protein and sugar in the urine. She was treated with intravenously administered potassium and fluids. RTA is one type of nephrotoxicity induced by chemotherapy, and it is reversible in mild cases when appropriately treated. The mechanism of RTA induced by chemotherapy in cancer patients has not yet been clearly elucidated. Oncologists should therefore be aware of the potential for RTA to occur after capecitabine, oxaliplatin, and cetuximab treatment, especially in the context of other predisposing factors.