Alessio Fabozzi

Treatment of gastric cancer

The authors focused on the current surgical treatment of resectable gastric cancer, and significance of peri- and post-operative chemo or chemoradiation. Gastric cancer is the 4(th) most commonly diagnosed cancer and the second leading cause of cancer death worldwide. Surgery remains the only curative therapy, while perioperative and adjuvant chemotherapy, as well as chemoradiation, can improve outcome of resectable gastric cancer with extended lymph node dissection. More than half of radically resected gastric cancer patients relapse locally or with distant metastases, or receive the diagnosis of gastric cancer when tumor is disseminated; therefore, median survival rarely exceeds 12 mo, and 5-years survival is less than 10%. Cisplatin and fluoropyrimidine-based chemotherapy, with addition of trastuzumab in human epidermal growth factor receptor 2 positive patients, is the widely used treatment in stage IV patients fit for chemotherapy. Recent evidence supports the use of second-line chemotherapy after progression in patients with good performance status.

SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer

Purpose: Resistance to tyrosine kinase inhibitors (TKI) of EGF receptor (EGFR) is often related to activation of other signaling pathways and evolution through a mesenchymal phenotype. Experimental Design: Because the Hedgehog (Hh) pathway has emerged as an important mediator of epithelial-to-mesenchymal transition (EMT), we studied the activation of Hh signaling in models of EGFR-TKIs intrinsic or acquired resistance from both EGFR-mutated and wild-type (WT) non–small cell lung cancer (NSCLC) cell lines. Results: Activation of the Hh pathway was found in both models of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFR-TKIs. In EGFR-mutated HCC827-GR cells, we found SMO (the Hh receptor) gene amplification, MET activation, and the functional interaction of these two signaling pathways. In HCC827-GR cells, inhibition of SMO or downregulation of GLI1 (the most important Hh-induced transcription factor) expression in combination with MET inhibition exerted significant antitumor activity. In EGFR-WT NSCLC cell lines resistant to EGFR inhibitors, the combined inhibition of SMO and EGFR exerted a strong antiproliferative activity with a complete inhibition of PI3K/Akt and MAPK phosphorylation. In addition, the inhibition of SMO by the use of LDE225 sensitizes EGFR-WT NSCLC cells to standard chemotherapy. Conclusions:This result supports the role of the Hh pathway in mediating resistance to anti-EGFR-TKIs through the induction of EMT and suggests new opportunities to design new treatment strategies in lung cancer. Clin Cancer Res; 21(20); 4686–97. ©2015 AACR.

c-Met targeting in advanced gastric cancer: An open challenge

Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC) remains poor. Because of molecular heterogeneity, it is essential to classify tumors based on the underlying oncogenic pathways and to develop targeted therapies acting on individual tumors. High-quality research and advances in technology have contributed to the elucidation of molecular pathways underlying disease progression and have stimulated many clinical studies testing target therapies in an advanced disease setting. In particular, strong preclinical evidence for the aberrant activation of the HGF/c-Met signaling pathways in GC cancers exists. This review will cover the c-Met pathway, the mechanisms of c-Met activation and the different strategies of its inhibition. Next, we will focus on the current state of the art in the clinical evaluation of c-Met-targeted therapies and the description of ongoing randomized trials with the idea that in this disease, high quality translational research to identify and validate biomarkers is a priority task.

Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma and Child-Pugh A or B cirrhosis.

Sorafenib confers a survival benefit for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) A liver cirrhosis. At present, limited data exists with regard to the safety and efficacy of sorafenib in treating CP-B HCC patients. The present study describes the use of sorafenib in patients with HCC and CP-A or -B cirrhosis. Clinical data was obtained from patients with HCC who were treated with sorafenib at the Department of Clinical and Experimental Medicine, Second University of Naples (Naples, Italy) and were analyzed retrospectively in terms of tumor response, tolerance and survival. The treatment outcomes were analyzed according to the respective CP status. The adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 3.0, and the tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.2. In total, 26 patients received sorafenib at 400 mg twice daily. The median age was 69 years (range, 58–81 years) and the ratio of males to females was 18:8. Overall, 15 patients were infected with the hepatitis C virus (HCV), eight with HBV and three were co-infected with HCV/HBV. In total, 20 (77%) patients presented with an underlying CP-A (CP-A5 and CP-A6) cirrhosis and six (23%) with CP-B (CP-B7). Previous treatments included surgery (n=4), transarterial chemoembolization (n=5) and percutaneous ethanol injection or radiofrequency interstitial thermal ablation (n=12). A partial response was observed in three patients (12%), a stable disease lasting at least 12 weeks in 13 patients (50%) and a progression of disease in 10 patients (38%). The median overall survival (OS) time was 7.4 months [95% confidence interval (CI), 3.2–11.6) and the median progression-free survival (PFS) time was 3.7 months (95% CI, 1.9–5.5). The median OS and PFS times differed between patients with CP-A and CP-B, with a trend (P=0.06) toward a worse outcome in those with CP-B, although this was not statistically significant. The CP-A and CP-B groups experienced a similar incidence in the majority of AEs. A reduction in dose was required in 59% of the patients. The CP-A5, CP-A6 and CP-B7 patients tolerated sorafenib similarly, and derived comparable clinical and survival benefits.

Pancreatic neuroendocrine tumors: Nosography, management and treatment.

Pancreatic neuroendocrine tumors (pNETs) represent about 7% of all NETs, 8.7% of gastroenteropancreatic NETs (GEP-NETs) and 1-2% of all pancreatic neoplasms. In the last two decades, the increased diagnosis of pNETs has generated great interest and the development of different classifications, grading and staging systems. Recently, several trials were performed in order to improve the knowledge of biomarkers and imaging and to provide an early diagnosis, but their role is still under debate. Nowadays, surgery represents the only curative approach for pNETs. Approximately 90% of pNETs are silent and non-functional; therefore, most patients are diagnosed in late stage and present metastatic (60%) or locally unresectable advanced disease (21%) with a poor prognosis. Not many therapeutic options are available for pNETs, with different treatments for G1-G2 and G3 tumors, because these diseases are still rare and trials are made up of few series of patients. At present, medical treatments is controversial. On these bases, we believe that a multidisciplinary team composed of surgeons, oncologists, endocrinologists, radiation oncologists, radiologists, pathologists and medicals nuclear is required. This paper presents a review of present state-of-the-art in the field of pNETs.

Effect of preoperative chemoradiotherapy on outcome of patients with locally advanced esophagogastric junction adenocarcinoma—a pilot study

BACKGROUND To date, few studies of preoperative chemotherapy or chemoradiotherapy (crt) in gastroesophageal junction (gej) cancer have been statistically powered; indeed, gej tumours have thus far been grouped with esophageal or gastric cancer in phase iii trials, thereby generating conflicting results. METHODS We studied 41 patients affected by locally advanced Siewert type i and ii gej adenocarcinoma who were treated with a neoadjuvant crt regimen [folfox4 (leucovorin-5-fluorouracil-oxaliplatin) for 4 cycles, and concurrent computed tomography-based three-dimensional conformal radiotherapy delivered using 5 daily fractions of 1.8 Gy per week for a total dose of 45 Gy], followed by surgery. Completeness of tumour resection (performed approximately 6 weeks after completion of crt), clinical and pathologic response rates, and safety and outcome of the treatment were the main endpoints of the study. RESULTS All 41 patients completed preoperative treatment. Combined therapy was well tolerated, with no treatment-related deaths. Dose reduction was necessary in 8 patients (19.5%). After crt, 78% of the patients showed a partial clinical response, 17% were stable, and 5% experienced disease progression. Pathology examination of surgical specimens demonstrated a 10% complete response rate. The median and mean survival times were 26 and 36 months respectively (95% confidence interval: 14 to 37 months and 30 to 41 months respectively). On multivariate analysis, TNM staging and clinical response were demonstrated to be the only independent variables related to long-term survival. CONCLUSIONS In our experience, preoperative chemoradiotherapy with folfox4 is feasible in locally advanced gej adenocarcinoma, but shows mild efficacy, as suggested by the low rate of pathologic complete response.

Serum insulin-like growth factor 1 correlates with the risk of nodal metastasis in endocrine-positive breast cancer

Increased insulin-like growth factor (igf) signalling has been observed in breast cancer, including endocrine-responsive cancers, and has been linked to disease progression and recurrence. In particular, igf-1 has the ability to induce and promote lymphangiogenesis through the induction of vascular endothelial growth factor C (vegfc). In the present study, we analyzed serum and tumour samples from 60 patients with endocrine-positive breast cancer to determine the expression and the possible relationship of circulating igf-1, igf binding protein 3 (igfbp3), and vegfc with the presence of lymphatic metastasis and other immunohistochemical parameters. The analysis revealed a clear and significant correlation between high basal levels of igf-1, igfbp3, and vegfc and lymph node metastasis in endocrine-responsive breast cancer. In addition, expression of those molecules was significantly higher in breast cancer patients than in healthy control subjects. Those findings may enable more accurate prediction of prognosis in patients with breast cancer.

Critical appraisal of the use of regorafenib in the management of colorectal cancer

The lack of valid clinical management options for patients affected by metastatic colorectal cancer, which has progressed after all approved standard treatments, has lead to research into new active molecules. Regorafenib is an oral small-molecule multi kinase inhibitor, binding to several intracellular kinases, with powerful inhibitory activity against vascular endothelial growth factor receptors (VEGFR-1,VEGFR-2, and VEGFR-3), platelet-derived growth factor receptor, fibroblast growth factor receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. The antitumor activity of regorafenib has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in several cancer models, particularly colorectal cancer and gastrointestinal stromal tumors. The most frequent adverse events of grade 3 or higher related to regorafenib were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Only a few Phase I–II trials, and most recently a Phase III trial in pretreated colorectal cancer, have been carried out to date. Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy. At this point in time, regorafenib is the first small-molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients.

BRAF Test and Cytological Diagnosis with a Single Fine Needle Cytology Sample

Objective: Recently, fine needle cytology (FNC) of the thyroid has been combined with biomolecular analysis. In particular, there has been detailed study of the V600E-BRAF mutation. The aim of our study is to demonstrate that with a single thyroid sample it is possible to obtain enough cellular material for both cytological diagnosis and a V600E-BRAF molecular test. Study Design: FNC was carried out under ultrasound guidance aided by an echographist and cytopathologist. We acquired one biopsy for each nodule with a 23-gauge needle without suction. The preparations were smeared by the pathologist onto one glass slide, air dried and stained with Diff-Quick. Cell adequacy was evaluated for each patient. The needle was washed by aspirating 2 ml of physiologic solution which was collected into a tube. The material was collected for molecular testing. Results: The following cytological diagnoses were made: not neoplastic, Tir2 (n = 227); indeterminate, Tir3 (n = 15); suspicious, Tir4 (n = 4), and malignancy, Tir5 (n = 12). The V600E-BRAF mutation was found in 0 of 227 Tir2 specimens, 2 of 15 (13.3%) Tir3 specimens, 2 of 4 (50%) Tir4 specimens and 9 of 12 (75%) Tir5 specimens. Conclusions: Our data showed that, in a routine clinical setting, FNC specimens can be handled properly to provide both morphological and molecular information. In fact, our tests show that with a single specimen it is possible to set up a slide for the cytological diagnosis and to obtain enough residual cellular material for DNA extraction (>70 ng) and for the identification of the V600E-BRAF mutation.

Reactivation of hepatitis B virus in cancer patients treated with chemotherapy for solid tumors. Is the prophylaxis really required

BACKGROUND Reactivation of hepatitis B virus during cancer chemotherapy for non-hematological tumors is not fully clear. AIM To evaluate the risk of hepatitis B virus reactivation in carriers of hepatitis B virus cancer patients treated with chemotherapy for solid tumors. METHODS Two hundred sixty-seven patients with solid tumors were consecutively enrolled: 13 (4.8%) were hepatitis B s-antigen positive, of whom 6 were documented inactive carriers and 7 had chronic liver disease. Thirty-two patients (12%) were hepatitis B s-antigen negative/hepatitis B c-antibody positive. Hepatitis B virus inactive carriers were followed every 3 months by alanine aminotransferases, hepatitis B virus-DNA; whereas hepatitis B virus occult carriers were followed every 3 months by alanine aminotransferases and hepatitis B s-antigen. RESULTS None of the 38 total patients with inactive or occult B infection who did not receive prophylaxis presented hepatitis B virus reactivation during the follow-up period. CONCLUSION This study suggests that, in hepatitis B s-antigen negative patients who undergo chemotherapy for solid tumors, hepatitis B and c-antibody screening results are not relevant to clinical decision and can be avoided. Larger studies are needed to establish whether the risk of reactivation of HBV during chemotherapy is negligible in this subset of patients and they could not be monitored for HBV reactivation.