Morphological Factors Related to Nodal Metastases in Neuroendocrine Tumors of the Appendix: A Multicentric Retrospective Study.

OBJECTIVE: The aim of this study was to evaluate clinical and morphological features related to nodal involvement in appendiceal neuroendocrine tumors (NETs), to identify patients who should be referred for oncological radicalization with hemicolectomy. BACKGROUND: Appendiceal NETs are usually diagnosed accidentally after appendectomy; the indications for right hemicolectomy are currently based on several parameters (ie, tumor size, grading, proliferative index, localization, mesoappendiceal invasion, lymphovascular infiltration). Available guidelines are based on scarce evidence inferred by small, retrospective, single-institution studies, resulting in discordant recommendations. METHODS: A retrospective analysis of a prospectively collected database was performed. Patients who underwent surgical resection of appendiceal NETs at 11 tertiary Italian centers, from January 1990 to December 2015, were included. Clinical and morphological data were analyzed to identify factors related to nodal involvement. RESULTS: Four-hundred fifty-seven patients were evaluated, and 435 were finally included and analyzed. Of them, 21 had nodal involvement. Grading G2 [odds ratio (OR) 6.04], lymphovascular infiltration (OR 10.17), size (OR 18.50), and mesoappendiceal invasion (OR 3.63) were related to nodal disease. Receiver operating characteristic curve identified >15.5 mm as the best size cutoff value (area under the curve 0.747). On multivariate analysis, grading G2 (OR 6.98), lymphovascular infiltration (OR 8.63), and size >15.5 mm (OR 35.28) were independently related to nodal involvement. CONCLUSIONS: Tumor size >15.5 mm, grading G2, and presence of lymphovascular infiltration are factors independently related to nodal metastases in appendiceal NETs. Presence of ≥1 of these features should be considered an indication for oncological radicalization. Although these results represent the largest study currently available, prospective validation is needed.

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues.

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Gemcitabine mono-therapy versus gemcitabine plus targeted therapy in advanced pancreatic cancer: a meta-analysis of randomized phase III trials.

BACKGROUND: Prognosis of advanced pancreatic cancer is dismal and the novel targeted therapies, albeit successfully used to treat many advanced tumors, have shown modest results. We performed a meta-analysis in order to quantify the effect size on survival of adding targeted therapy to single agent gemcitabine. METHODS: Randomized phase III trials comparing gemcitabine mono-therapy versus gemcitabine plus a targeted agent in first-line treatment of advanced pancreatic cancer designed on survival as primary outcome were selected. Search was done through Medline and the registry of the NIH. Keywords used for searching were 'pancreas', 'pancreatic', 'gemcitabine'. Study quality was assessed with MERGE criteria. Findings were depicted in classical Forest plots. Publication bias was evaluated by the construction of funnel plot. RESULTS: Nine studies met the meta-analysis inclusion criteria including 4564 patients. The target therapies were: erlotinib, cetuximab, rigosertib, elpamotide, bevacizumab, aflibercept, axitinib, masitinib and ganitumab. There was no statistically significant heterogeneity among the nine trials (p = 0.77). The hazard ratio (HR) of the pooled analysis was 0.998 (CI 95%: 0.932-1.068). Subgroup meta-analysis was also performed in anti-EGFR and anti-angiogenesis trials: the pooled HR were 0.94 (CI 95%: 0.705-1.175) and 1.055 (CI 95%: 0.913-1.197), respectively. CONCLUSIONS: The present meta-analysis does not show significant improvements in survival for targeted drugs in advanced pancreatic cancer. The possible reason of these results could be linked to the biology of pancreatic cancer as well as to the absence of predictive factors.

Diabetes and Body Mass Index Are Associated with Neuropathy and Prognosis in Colon Cancer Patients Treated with Capecitabine and Oxaliplatin Adjuvant Chemotherapy.

BACKGROUND: There are few background data on the impact of clinical factors on neurotoxicity and prognosis in patients treated with adjuvant capecitabine and oxaliplatin (CAPOX) chemotherapy. METHODS: 102 stage II high-risk and stage III colorectal cancer patients were treated for 6 months with adjuvant CAPOX, then they were followed up. Associations between clinical variables, metabolic syndrome components, smoking and neurotoxicity were evaluated by the x03C7;2 test. The Kaplan-Meier product limit method was applied to graph disease-free survival (DFS). Univariate analysis was done with the log-rank test. Cox's proportional hazards regression was used to analyze the effect of several risk factors on DFS. RESULTS: Significant associations were found between diabetes (p < 0.001), BMI (p = 0.01) and the occurrence of chronic neurotoxicity. After a median follow-up of 46 months, 14 patients (13.7%) had suffered recurrence. An analysis of the prognostic factors for DFS showed that prognosis is unfavorable for patients with high lymph-nodal involvement (HR: 5.23, p = 0.0007), diabetes (HR: 4.86; p = 0.03) and a BMI ≥25 (HR: 3.69, p = 0.002). DISCUSSION: Common mediators in diabetes and obesity could be involved in peripheral neuropathy and in stimulating micro-metastases. Further studies are necessary to explain this interesting connection between diabetes, obesity and colon cancer.

Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor.

PURPOSE: To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment. METHODS: A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety. RESULTS: Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events. CONCLUSIONS: HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials.

Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment.

Lenvatinib is an emerging multi-kinase inhibitor with a preferential anti-angiogenic activity, which has shown efficacy in the treatment of renal cell carcinoma, differentiated thyroid cancer and hepatocellular carcinoma. It inhibits vascular endothelial growth factor receptor family (VEGFR1-3), fibroblast growth factor receptor family (FGFR1-4), platelet-derived growth factor receptor-alpha (PDGFRα), tyrosine-kinase receptor (KIT) and rearranged during transfection receptor (RET). In this review we have evaluated the development from bench to bedside of lenvatinib. PubMed, MEDLINE and clinicaltrials.gov are the sources of data. Furthermore, the preclinical in vitro and in vivo data, as well as efficacy and toxicity results of lenvatinib in the clinic, are presented and discussed. Treatment with lenvatinib causes side effects (hypertension, proteinuria, fatigue and diarrhea), which are predominantly related to the inhibition of angiogenesis. For these reasons, the identification of biomarkers of efficacy and resistance to lenvatinib is a key challenge in order to select responsive patients. This review provides an overview on lenvatinib's clinical use, perspectives and indications for future development.

Folfiri-Aflibercept vs. Folfiri-Bevacizumab as Second Line Treatment of RAS Mutated Metastatic Colorectal Cancer in Real Practice.

Background: There are no clinical studies comparing the efficacy of bevacizumab vs.aflibercept in association with folfiri in RAS mutated (RAS-M) metastatic colorectal cancer patients (mCRC) pretreated with folfox and bevacizumab. Patients and Methods: Consecutive RAS-M unresectable mCRC patients progressing to first-line folfox/bevacizumab were treated with 12 cycles of folfiri/bevacizumab (arm A) or folfiri/aflibercept (arm B) at Oncologist discretion. Differences in overall survival between the two schedules were analyzed. Responses and toxicities were described with RECIST and NCI-CTC v4.0, respectively. Results: Seventy-four patients were treated from January 2014 to January 2018; 31 with arm A, 43 with arm B. Among clinical factors there was a predominance of more extended disease (>2 metastatic sites) in arm B (26/43 [60.5%] vs. 10/31 [32.2%] arm A; p = 0.0414). Fifty-nine patients were evaluable for response: arm A, 5 PR (Partial Response), 15 SD (Stable Disease), 8 PD (Progressive Disease); arm B, 5 PR, 16 SD, 10 PD. There were no grade 4 toxic events. Duration of first-line chemotherapy was significantly shorter in patients treated in arm B (12 pts <6 months, 16 pts ≥6, and <12, 15 pts ≥12) vs. arm A (1 pts <6 months, 14 pts ≥6, and <12, 16 pts ≥12) (p = 0.0210); these patients were excluded from survival analysis to avoid prognostic interferences. No maintenance treatment with aflibercept was done in arm B while in arm A bevacizumab with or without fluorouracil and folinic acid were allowed. Median OS were 8.9 months in arm A vs. 12.1 months in arm B (+3.2 months; p = 0.9331, HR: 1.02; 95% CI: 0.57-1.84). Six-months survivals were 65% in arm A and 80% in arm B. Conclusions: Folfiri/bevacizumab and folfiri/aflibercept are equally effective second-line therapies in RAS-M mCRC patients. Although not significant, folfiri/aflibercept was associated with a lower risk of death particularly during the 6-months induction phase.

Therapeutic sequences in patients with grade 1-2 neuroendocrine tumors (NET): an observational multicenter study from the ELIOS group.

PURPOSE: Many different treatments are suggested by guidelines to treat grade 1-2 (G1-G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1-G2 NET. METHODS: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation. RESULTS: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1-G2 gastroenteropancreatic, lung and unknown primary NET, unresectable or persistent/relapsing after surgery, treated with ≥2 systemic treatments, were included. Four main therapeutic sequences were identified in 99 patients: (A) somatostatin analogs (SSA) standard dose to SSA high dose (n = 36), (B) SSA to everolimus (n = 31), (C) SSA to chemotherapy (n = 17), (D) SSA to peptide receptor radionuclide therapy (PRRT) (n = 15). Median PFS of the second-line treatment was not reached in sequence A, 33 months in sequence B, 20 months in sequence C, 30 months in sequence D (p = 0.16). Both total number and severity of side effects were significantly higher in sequences B and C than A and D (p = 0.04), as well as the rate of dose reduction/discontinuation (p = 0.03). CONCLUSIONS: SSA followed by SSA high dose, everolimus, chemotherapy or PRRT represent the main therapeutic sequences in G1-G2 NET. Median PFS was not significantly different between sequences. However, the sequences with SSA high dose or PRRT seem to be better tolerated than sequences with everolimus or chemotherapy.

Funds Reimbursement of High-Cost Drugs in Gastrointestinal Oncology: An Italian Real Practice 1 Year Experience at the National Cancer Institute of Naples.

Introduction: The therapeutic scenario of Oncology is enriching of innovative agents which are determining an increase in public expenditure because of their high cost. In Italy, a web-based government Registry is used to monitor the clinical use of these drugs and, in later phases, to obtain funds reimbursement according to specific economic agreements with companies. Methods: A health policy expert Pharmacist was included in the multidisciplinary team of the Department of Abdominal Oncology of the National Cancer Institute (NCI) of Naples "G. Pascale Foundation" in order to improve the management of the Registry for oncologic drugs monitoring. Pharmacist activities were: basal data registration, prescription appropriateness, drug request, response monitoring, toxicity reporting, follow-up, reimbursement request. These activities were conducted in strict interrelation with clinicians. The source of data were medical records and a web-based national reimbursement platform. The analysis of the economic impact of this strategy was descriptive and it was indicated as resources recovery comparing 2 years: 2015 vs. 2016. The currency reference used was the Euro (€). Results: A total of 932 patients were followed-up and registered, 365 treatments are ongoing at the Department of Abdominal Oncology (NCI of Naples, Italy). The most prescribed biologic drug in advanced gastrointestinal cancers was bevacizumab. Compared to the year 2015, in 2016 we recorded a strong increase of reimbursements: EUR 881.712,42 vs. EUR 214.554,98. Conclusions: We suggest that the reimbursement process can be improved when a health policy reimbursement professional Pharmacist is integrated in the multidisciplinary team along with clinicians.

Obesity and Cancer: Biological Links and Treatment Implications.

Obesity is an epidemic disease and correlates with cardiovascular diseases increasing the overall mortality. However, it has been recently demonstrated that cancer is an unexpected consequence of obesity. In most of the studies, it is evaluated with body mass index (BMI): high BMI increases cancer risk and reduces survival of many solid tumors. The main biologic and clinic topics regarding obese cancer patients are here presented and discussed. Hyperinsulinemia and Insulin-like Growth Factors (IGFs) are among the most important links between cancer and obesity. However, adipose tissue (AT) also produces sex hormones, pro-inflammatory cytokines and hypoxia which in turn promote initiation and progression of tumors. One of the major clinic concern about obese cancer patients is the risk of chemotherapy-related toxicity. Previous studies showed that obese patients do not experience significant increased toxicity compared to non-obese patients. Thus, the increasing incidence and scientific knowledge of obesity should prompt the researchers to study for personalization of therapy in obese patients with cancer rather than for the simple chemotherapy "depotentiation". It has been demonstrated that weight loss reduces cancer risk and can ameliorate compliance to therapy. Thus, social politics as well as therapies against obesity may impact on cancer risk, treatment and survival.

Biotherapies in Solid Tumors: Are Negative Results Still of Low Priority for Publication?

In 2005, we performed the largest survey on clinical trials of biotherapies for all solid tumors and found indirect evidence of a publication bias: editors of medical journals were more prone to publish positive results independently from the quality of the studies. We collected data from 2003 to 2015 in 487 studies, and the publication bias previously described was not found in the years between 2010 and 2015: this could be related to changes and/or innovations in the guidelines and editorial policies of oncology journals occurred over the last years.

First Biologic Drug in the Treatment of RAS Wild-Type Metastatic Colorectal Cancer: Anti-EGFR or Bevacizumab? Results From a Meta-Analysis.

Introduction: We performed a meta-analysis in order to analyze and quantify the effect on survival of starting therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC) patients with anti-EGFR agents or bevacizumab. Patients and Methods: Randomized, phase II or III, clinical trials reporting overall survival (OS) in RAS wt mCRC patients treated with first-line chemotherapy (CT) associated with bevacizumab or anti-EGFR agents were selected. The primary end-point of this meta-analysis was OS; findings were depicted in classical Forest plots. Results: Seven studies met the criteria for meta-analysis including 3,805 patients. The pooled second-line cross-over rate to bevacizumab was 36.6%, to anti-EGFR 33.2%. Only one study was selected reporting comparison between CT vs. CT plus bevacizumab in RAS wt patients with a HR of 1.13 in favor of CT (CI: 0.89-1.43, p = 0.317). The pooled HRs were 0.89 (95% CI: 0.79-1.00) for CT plus anti-EGFR vs. CT and 0.81 (95% CI: 0.71-0.92) in favor of CT plus anti-EGFR vs. CT plus bevacizumab. Subgroup analysis showed a positive prognostic impact of starting CT plus anti-EGFR in left colon cancer (pooled HR: 0.70; CI: 0.54-0.85) while a positive trend of starting CT plus bevacizumab was observed in right colon cancer (pooled HR: 1.29; CI: 0.81-1.77). Conclusions: This meta-analysis shows that starting therapy in RAS wt mCRC patients with an anti-EGFR agent improves OS when the primary tumor location is in the left colon but a strong limitation of previous studies is the very low rate of biologic drug therapy cross-over.

Integration of stereotactic radiotherapy in the treatment of metastatic colorectal cancer patients: a real practice study with long-term outcome and prognostic factors.

BACKGROUND: There are very few clinical or prognostic studies on the role of SRT (Stereotactic Radiation Therapy) in the continuum of care of metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients affected by oligo-mCRC were treated with SRT before or after front-line standard treatments. SRT was delivered according to a risk-adapted protocol. Total body CT (Computed Tomography) scan was done before therapy and every three months thereafter. The radiologic responses to therapy were evaluated by RECIST (Response Evaluation Criteria In Solid Tumors). FDG-PET (FluoroDeoxyGlucose - Positron Emission Tomography) was done before and after SRT; metabolic responses were evaluated by using the EORTC (European Organization for Research and Treatment of Cancer) criteria. The Kaplan-Meier product limit method was applied to graph Overall Survival (OS) and Progression-Free Survival (PFS). RESULTS: Forty-seven patients were included. Twenty-one patients had disease limited to lungs, 9 to lung and liver, 7 only to liver, 10 to multiple sites. The median prescription SRT dose was 60 Gy per organ in 3 fractions (median biological effective dose of 180 Gy). The reduction of delta SUVmax (maximum Standardized Uptake Value) correlated with the local control (p<0.001) and two-years survival (p=0.003). At univariate analysis, localization of primary tumor, site of metastases, KRAS (Kirsten RAt Sarcoma) oncogene mutational status, response to first-line chemotherapy, response to SRT and number of treated lesions predicted both PFS and OS. DISCUSSION: This real practice experience suggests that further studies are needed to analyze the promising role of SRT in the multidisciplinary management of mCRC.

Nab-Paclitaxel and Gemcitabine in Advanced Pancreatic Cancer: The One-year Experience of the National Cancer Institute of Naples.

BACKGROUND: Pancreas adenocarcinoma is the sixth cause of cancer-related death worldwide with an increasing mortality in the Western countries. Recently, the association between nab-paclitaxel (nab-P) and gemcitabine (GEM) has significantly improved progression-free and overall survival. PATIENTS AND METHODS: Patients affected by metastatic pancreas adenocarcinoma were treated at the Department of Abdominal Oncology of the National Cancer Institute of Naples from July 2015 to July 2016 with nab-P at 125 mg per square meter of body-surface area followed by GEM at 1,000 mg per square meter on days 1, 8 and 15 every 4 weeks. Computed tomography (CT) was performed every three months of therapy. Toxicity was graded with National Cancer Institute-Common Toxicity Criteria (NCI-CTC) v4.0. Objective responses were evaluated with Response Evaluation Criteria in Solid Tumors (RECIST). Analysis of time-to-progression is only descriptive. Pain was evaluated with a visual analogue scale (VAS). RESULTS: Twenty-three patients were treated. Median age was 67 years (range=45-81); 8 patients were ≥70 years old. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 2 in 8 patients, 1 in 10 and 0 in 5. Twelve patients presented with diffuse hepatic metastases, 4 with carcinosis, 7 with more than one organ involvement. Nab-P was reduced at 100 mg per square meter in all patients. The most common G3/G4 adverse events were neutropenia (13.0% G4, 8.6% G3; none was febrile), neuropathy (30.4% G3) and asthenia (G3 17.3%). The disease control rate was 43.4% (partial response+stable disease (PR+SD) 10/23). The median time-to-progression was 7.9 months (95% confidence interval (CI)=5.8-11.2). After three months of therapy the PS improved in 14 patients, as well as pain in 18 patients. CONCLUSION: We present an experience with nab-P and GEM association in a series with poor PS and highly metastatic disease relatively to a previous randomized study. The schedule is feasible, with nab-P at 100 mg per square meter achieving a good disease control rate, as well as a clinical benefit.

Serum and tissue markers in colorectal cancer: State of art.

Colorectal cancer (CRC) represents one of the most commonly diagnosed cancers worldwide. It is the second leading cause of cancer death in Western Countries. In the last decade, the survival of patients with metastatic CRC has improved dramatically. Due to the advent of new drugs (irinotecan and oxaliplatin) and target therapies (i.e. bevacizumab, cetuximab, panitumab, aflibercept and regorafenib), the median overall survival has risen from about 12 mo in the mid nineties to 30 mo recently. Molecular studies have recently widened the opportunity for testing new possible markers, but actually, only few markers can be recommended for practical use in clinic. In the next future, the hope is to have a complete panel of clinical biomarkers to use in every setting of CRC disease, and at the same time: 1) to receive information about prognostic significance by their expression and 2) to be oriented in the choice of the adequate treatment. Moreover, molecular analyses have shown that the natural history of all CRCs is not the same. Individual patients with same stage tumors may have different long-term prognosis and response to therapy. In addition, some prognostic variables are likely to be more important than others. Here we review the role of serum and tissue markers according to the recently published English literature. This paper is an extension of the article "Biological and clinical markers in colorectal cancer: state of art" by Cappellani A published in Jan 2010.

Use of Complementary and Alternative Medicine (CAM) in cancer patients: An Italian multicenter survey.

INTRODUCTION: Complementary and Alternative Medicine (CAM) include a wide range of products (herbs, vitamins, minerals, and probiotics) and medical practices, developed outside of the mainstream Western medicine. Patients with cancer are more likely to resort to CAM first or then in their disease history; the potential side effects as well as the costs of such practices are largely underestimated. PATIENTS AND METHOD: We conducted a descriptive survey in five Italian hospitals involving 468 patients with different malignancies. The survey consisted of a forty-two question questionnaire, patients were eligible if they were Italian-speaking and receiving an anticancer treatment at the time of the survey or had received an anticancer treatment no more than three years before participating in the survey. RESULTS: Of our patients, 48.9% said they use or have recently used CAM. The univariate analysis showed that female gender, high education, receiving treatment in a highly specialized institute and receiving chemotherapy are associated with CAM use; at the multivariate analysis high education (Odds Ratio, (OR): 1.96 95% Confidence Interval, CI, 1.27-3.05) and receiving treatment in a specialized cancer center (OR: 2.75 95% CI, 1.53-4.94) were confirmed as risk factors for CAM use. CONCLUSION: Roughly half of our patients receiving treatment for cancer use CAM. It is necessary that health professional explore the use of CAM with their cancer patients, educate them about potentially beneficial therapies in light of the limited available evidence of effectiveness, and work towards an integrated model of health-care provision.

Antiangiogenic Therapy in Pancreatic Neuroendocrine Tumors.

In recent years, many progresses have been pursued in the management of advanced pancreatic neuroendocrine tumor (pNET); most of them were prompted by increasing knowledge of biology of these neoplasms, including the identification of promising biological targets for therapy. PNETs belong to a group of rare neoplastic diseases. They originate from neuroendocrine system cells and are very heterogeneous regarding anatomic localization and aggressiveness. Recently, many efforts have been particularly focused on the identification of pathologic pathways and innovative drugs in order to treat patients with unresectable, metastatic disease, in progressive well-differentiated pNETs. Chemotherapy remains the mainstay of treatment of poorly-differentiated pNETs. The positive results obtained by sunitinib, a multi-targeted tyrosine kinase receptor inhibitor of vascular endothelial growth factor receptor (VEGFR) 1-3, platelet-derived growth factor receptor (PDGFR), c-kit, RET, colony stimulating factor-1 receptor (CSF-1R) and Fms-like tyrosine kinase 3 (FLT3), with direct antitumor and antiangiogenic effects, have highlighted the importance of tumor angiogenesis inhibition in controlling these tumors. Angiogenesis is a crucial process during tumor progression and plays a key role in development of metastasis. The role of angiogenesis in the malignant spread of pNET cells is finally supported by in vivo studies conducted on the RIP1-Tag2 mouse model. In this mini-review, we focus on the two pharmaceuticals that have given the most interesting results in clinical trials: bevacizumab and sunitinib. These drugs are changing the management of advanced pNETs.

Prospective Evaluation of Cetuximab-Mediated Antibody-Dependent Cell Cytotoxicity in Metastatic Colorectal Cancer Patients Predicts Treatment Efficacy.

Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcγ receptors on immune cells. Although SNPs in genes encoding Fcγ receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer, a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic colorectal cancer (mCRC) patients at diagnosis in a study that assessed FcγR status and cetuximab-mediated ADCC. Patients carrying the FcγRIIa H alleles 131H/Hand 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P= 0.013). Patients carrying FcγRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P= 0.001). Progression-free survival of patients with an FcγRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P= 0.05), whereas no significant difference was observed for overall survival. Twenty-eight of 50 mCRC patients with wild-type KRAS received cetuximab. The average ADCC-mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response, 21% in patients with stable disease and 9% in patients with progressive disease. To characterize basal natural killer (NK) activity, cytotoxicity was evaluated in 39 of 96 mCRC patients. Patients who responded to first-line treatment had higher NK-cell cytotoxicity. Thus, although limited to this cohort of patients, in vitro cetuximab-mediated ADCC correlated with FcγR polymorphisms and predicted cetuximab responsiveness.

CXCR4-CXCL12-CXCR7, TLR2-TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients.

A neoadjuvant clinical trial was previously conducted in patients with resectable colorectal cancer liver metastases (CRLM). At a median follow up of 28 months, 20/33 patients were dead of disease, 8 were alive with disease and 5 were alive with no evidence of disease. To shed further insight into biological features accounting for different outcomes, the expression of CXCR4-CXCL12-CXCR7, TLR2-TLR4, and the programmed death receptor-1 (PD-1)/programmed death-1 ligand (PD-L1) was evaluated in excised liver metastases. Expression profiles were assessed through qPCR in metastatic and unaffected liver tissue of 33 CRLM neoadjuvant-treated patients. CXCR4 and CXCR7, TLR2/TLR4, and PD-1/PD-L1 mRNA were significantly overexpressed in metastatic compared to unaffected liver tissues. CXCR4 protein was negative/low in 10/31, and high in 21/31, CXCR7 was negative/low in 16/31 and high in 15/31, CXCL12 was negative/low in 14/31 and high in 17/31 CRLM. PD-1 was negative in 19/30 and positive in 11/30, PD-L1 was negative/low in 24/30 and high in 6/30 CRLM. Stromal PD-L1 expression, affected the progression-free survival (PFS) in the CRLM population. Patients overexpressing CXCR4 experienced a worse PFS and cancer specific survival (CSS) (p = 0.001 and p = 0.0008); in these patients, KRAS mutation identified a subgroup with a significantly worse CSS (p < 0.01). Thus, CXCR4 and PD-L1 expression discriminate patients with the worse PFS within the CRLM evaluated patients. Within the CXCR4 high expressing patients carrying Mut-KRAS in CRLM identifies the worst prognostic group. Thus, CXCR4 targeting plus anti-PD-1 therapy should be explored to improve the prognosis of Mut-KRAS-high CXCR4-CRLMs.

Everolimus and pancreatic neuroendocrine tumors (PNETs): Activity, resistance and how to overcome it.

Neuroendocrine tumors (NET) are rare malignancies, with the most common site of origin being from the gastrointestinal tract, particularly the pancreas, small bowel and appendix. Pancreatic neuroendocrine tumors (PNETs) can be functional, hormone secreting tumors, and can have distinctive symptoms leading to the diagnosis. In contrast nonfunctional tumors, the majority of PNETs, usually present later either incidentally or due to tumor bulk symptoms. Currently Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is the most promising drug for patients with unresectable, metastatic disease, in progressive well-differentiated PNETs and many studies are ongoing to demonstrate its effects on the other neuroendocrine histotipes. Food and Drug Administration (FDA) and European Medicines Agency (EMA) registered Everolimus in advanced/metastatic breast cancer, in advanced/metastatic renal cell carcinoma and in well/moderately differentiated pancreatic neuroendocrine tumors. Nevertheless only a subset of patients respond to the therapy due to the development of drug resistance. Thus the powerful Everolimus antitumor activity have prompted extensive efforts to overcome drug resistance and to maximize clinical benefit. In this review we aim to summarize current knowledge on mechanisms of Everolimus and other mTOR inhibitors molecules resistance with the intent to overcome it.