Search

ImportanceCurrent third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients.ObjectiveTo compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC.Design, Setting, and ParticipantsThis phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug–free interval of 4 or more months during second-line therapy were included.InterventionsPatients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone.Main Outcomes and MeasuresThe primary end point was progression-free survival (PFS). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients.ResultsOf 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 [61.3%] male; median age, 65 years [range, 39-81 years]) and 31 received trifluridine-tipiracil alone (17 [54.8%] male; median age, 66 years [range, 32-82 years]). The primary end point was met. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio [HR], 0.48; 95% CI, 0.28-0.82; P = .007). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA; in 15 of 23 patients (65.2%) whose tumors were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months (95% CI, 3.7-9.2 months). Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response.Conclusions and RelevanceIn this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. The findings support the clinical utility of liquid biopsy–guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC.Trial RegistrationClinicalTrials.gov Identifier: NCT05468892

Supplemental material, sj-pptx-1-tam-10.1177_17588359221096878 for Comprehensive genome profiling by next generation sequencing of circulating tumor DNA in solid tumors: a single academic institution experience by Vincenza Caputo, Vincenzo De Falco, Anna Ventriglia, Vincenzo Famiglietti, Erika Martinelli, Floriana Morgillo, Giulia Martini, Carminia Maria Della Corte, Davide Ciardiello, Luca Poliero, Ferdinando De Vita, Michele Orditura, Morena Fasano, Renato Franco, Michele Caraglia, Arianna Avitabile, Roberto Scalamogna, Beatrice Marchi, Fortunato Ciardiello, Teresa Troiani and Stefania Napolitano in Therapeutic Advances in Medical Oncology

Supplemental material, sj-pptx-5-tam-10.1177_17588359221096878 for Comprehensive genome profiling by next generation sequencing of circulating tumor DNA in solid tumors: a single academic institution experience by Vincenza Caputo, Vincenzo De Falco, Anna Ventriglia, Vincenzo Famiglietti, Erika Martinelli, Floriana Morgillo, Giulia Martini, Carminia Maria Della Corte, Davide Ciardiello, Luca Poliero, Ferdinando De Vita, Michele Orditura, Morena Fasano, Renato Franco, Michele Caraglia, Arianna Avitabile, Roberto Scalamogna, Beatrice Marchi, Fortunato Ciardiello, Teresa Troiani and Stefania Napolitano in Therapeutic Advances in Medical Oncology

Supplemental material, sj-pptx-3-tam-10.1177_17588359221096878 for Comprehensive genome profiling by next generation sequencing of circulating tumor DNA in solid tumors: a single academic institution experience by Vincenza Caputo, Vincenzo De Falco, Anna Ventriglia, Vincenzo Famiglietti, Erika Martinelli, Floriana Morgillo, Giulia Martini, Carminia Maria Della Corte, Davide Ciardiello, Luca Poliero, Ferdinando De Vita, Michele Orditura, Morena Fasano, Renato Franco, Michele Caraglia, Arianna Avitabile, Roberto Scalamogna, Beatrice Marchi, Fortunato Ciardiello, Teresa Troiani and Stefania Napolitano in Therapeutic Advances in Medical Oncology

Supplemental material, sj-pptx-4-tam-10.1177_17588359221096878 for Comprehensive genome profiling by next generation sequencing of circulating tumor DNA in solid tumors: a single academic institution experience by Vincenza Caputo, Vincenzo De Falco, Anna Ventriglia, Vincenzo Famiglietti, Erika Martinelli, Floriana Morgillo, Giulia Martini, Carminia Maria Della Corte, Davide Ciardiello, Luca Poliero, Ferdinando De Vita, Michele Orditura, Morena Fasano, Renato Franco, Michele Caraglia, Arianna Avitabile, Roberto Scalamogna, Beatrice Marchi, Fortunato Ciardiello, Teresa Troiani and Stefania Napolitano in Therapeutic Advances in Medical Oncology

Oncological outcome depends not only on tumor behaviour but also on nutritional and immune-inflammatory host status. Data in gastric cancer are limited. The main aim of this study was to prospectively assess Naples prognostic score (NPS) in gastric cancer patients. NPS was also compared with prognostic nutritional index (PNI), controlling nutritional status (CONUT) score and systemic inflammation score (SIS).Overall survival (OS) and complication rates of 415 patients undergoing gastric cancer surgery from January 2000 to December 2015 were calculated. Disease-free survival (DFS) rates were assessed in 307 radically resected patients. MaxStat analysis was used to identify the best cut-off values. NPS scores were divided into 3 groups (NPS 0-3). The receiver-operating-characteristic (ROC) curve for censored survival data was used to compare the prognostic performance of scoring systems.NPS positively correlated with current scoring systems (p0.001) and advanced tumor stages (p0.001). Patients with elevated NPS scores experienced more postoperative complications (all patients: p=0.003; radically resected patients: p=0.010). NPS1 and NPS2 patients had a higher hazard ratio (HR) than NPS0 patients for OS (NPS1 HR 2.04, NPS2 HR 4.27; p0.001) and DFS (NPS1 HR 1.70, NPS2 HR 4.98; p0.001). Among the different scoring systems, only NPS was selected as an independent significant predictor for OS (p=0.024) and DFS (p=0.009). NPS was assigned the best prognostic performance by ROC analysis, equalling TNM staging system, and correctly identified highrisk patients.NPS is an easy to calculate prognostic score strongly associated with outcome in patients undergoing gastric cancer surgery.Gastric cancers, Immune-nutritional and inflammatory host status, Naples prognostic score.In molte neoplasie umane è stato dimostrato che il decorso della malattia oncologica non dipende solo dallo stadio del tumore ma anche dalle condizioni del paziente, in particolare lo stato nutrizionale, immunologico ed infiammatorio. Nel cancro dello stomaco, comunque, le esperienze sono ancora limitate. Lo scopo principale di questo studio è stato di valutare prospetticamente un nuovo sistema prognostico (definito Naples Prognostic Score – NPS), e di confrontarlo con precedenti sistemi già studiati come il PNI (Prognostic Nutritional Index), il CONUT (Controlling Nutritional Status), e il Systemic Inflammation Score (SIS).Sono state calcolate le percentuali di sopravvivenza globale (OS) e di complicanze in 415 pazienti sottoposti a chirurgia per tumore dello stomaco dal gennaio 2000 al dicembre 2015. Le percentuali di sopravvivenza libera da malattia (DFS) sono state valutate in 307 pazienti sottoposti a chirurgia potenzialmente curativa. Il sistema statistico MaxStat è stato utilizzato per identificare i migliori valori soglia dei differenti biomarcatori, ed i punteggi dell’NPS sono stati divisi in 3 gruppi (NPS 0-3). L’efficacia prognostica dei differenti sistemi di punteggio considerati è stata investigata mediante una sofisticata tecnica statistica costituita dalla Receiver- Operating-Characteristic (ROC) Curve per i dati di sopravvivenza censurati.Il nuovo sistema prognostico NPS ha dimostrato possedere una positiva correlazione statistica con i precedenti sistemi (p0,001), e gli stadi avanzati del tumore (p0,001). Nei pazienti con punteggi più alti di NPS sono state osservate un maggior numero di complicanze postoperatorie (tutti i pazienti: p = 0,003; pazienti trattati radicalmente: p = 0,010). Rispetto ai pazienti con un punteggio uguale a 0 di NPS, i pazienti con valori di NPS uguali a 1 o 2 hanno mostrato un rischio maggiore (HR) di presentare una sopravvivenza globale minore (NPS1 HR 2,04, NPS2 HR 4,27; p0,001), ed un più breve decorso libero da recidiva neoplastica (NPS1 HR 1,70, NPS2 HR 4,98; p0,001). Tra i diversi sistemi di punteggio, solo l’NPS è stato selezionato come un fattore prognostico significativamente indipendente per OS (p = 0.024) e DFS (p = 0.009). L’analisi ROC ha evidenziato che l’NPS ha dimostrato possedere, tra i quattro sistemi analizzati, la migliore capacità prognostica nell’identificare i pazienti ad alto rischio di recidiva neoplastica, ed ha quasi eguagliato l’attuale sistema di stadiazione TNM.Il Naples Prognostic Score è un sistema prognostico facile da calcolare, ed appare essere positivamente correlato ai risultati oncologici nei pazienti sottoposti a chirurgia per cancro dello stomaco.

Additional file 1.

To determine the maximum tolerated dose of oxaliplatin (L-OHP) given as a two-hour infusion followed by raltitrexed (Tomudex [TOM]) administered as a 15-min infusion on day 1, and bolus 5-fluorouracil (5-FU) modulated by a fixed dose of levo-folinic acid (LFA) 250 mg/m2 on day 2, recycling every two weeks, and to have preliminary evidence of activity of this combination in pretreated advanced colorectal cancer patients.Fifty-two patients with advanced colorectal carcinoma previously treated with one (25 cases) or two or more lines of chemotherapy, including irinotecan (26 cases), and/or modulated 5-FU (40 cases) entered this study. Starting doses of L-OHP, TOM, and 5-FU were 85, 2.5 and 750 mg/m2, respectively.Seven dose levels were tested. Neutropenia was the main dose limiting toxicity of the dose escalation (8 of 13 cases). The recommended doses were 130 mg/m2 of L-OHP, and 3.0 mg/m2 of TOM on day 1, followed by 250 mg/m2 of LFA, and 1050 mg/m2 of 5-FU on day 2, every two weeks. Severe diarrhoea and stomatitis were rarely reported. Most patients complained of mild peripheral sensitive aeurotoxicity, which was related to the cumulative dose of L-OHP. Twelve patients were considered as having a major responses (one complete), and an additional eight patients showed a minor response; the median time to treatment failure was twenty-four weeks.With this regimen it is possible to give full doses of all three cytotoxic drugs every two weeks. Its activity and its manageable toxicity profile deserve further evaluation in pretreated advanced colorectal cancer patients.

BackgroundPenile cancer (PC) is an extremely rare malignancy, and the patients at advanced stages have currently limited treatment options with disappointing results. Immune checkpoint inhibitors anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are currently changing the treatment of several tumors. Furthermore, the microsatellite instability (MSI) and the deficient mismatch repair system (dMMR) proteins represent predictive biomarkers for response to immune checkpoint therapy. Until present, few data have been reported related to PD-L1 expression and MSI in PC. The main aim of our study was the evaluation of PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) in immune cells and the analysis of dMMR/MSI status in a large series of PCs.MethodsA series of 72 PC, including 65 usual squamous cell carcinoma (USCC), 1 verrucous, 4 basaloid, 1 warty, and 1 mixed (warty-basaloid), was collected. Immunohistochemistry (IHC) was performed to assess PD-L1 expression using two different anti-PD-L1 antibodies (clone SP263 and SP142 Ventana) and MMR proteins expression using anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 antibodies. PCR analysis was performed for the detection of MSI status.ResultsOf the 72 PC cases analyzed by IHC, 45 (62.5%) cases were TC positive and 57 (79%) cases were combined positive score (CPS) using PDL1 SP263. In our cohort, TILs were present in 62 out of 72 cases (86.1%), 47 (75.8%) out of 62 cases showed positivity to PDL1 clone SP142. In our series, 59 cases (82%) had pMMR, 12 cases (16.7%) had lo-paMMR, and only 1 case (1.3%) had MMR. PCR results showed that only one case lo-paMMR was MSI-H, and the case dMMR by IHC not confirmed MSI status.ConclusionOur findings showed that PD-L1 expression and MSI status represent frequent biological events in this tumor suggesting a rationale for a new frontier in the treatment of patients with PC based on the immune checkpoint inhibitors.

Gastric cancer (GC) is recognized as one of the most common deadly malignancies worldwide and about 40–50% of patients present at diagnosis with an unresectable disease due to a locally advanced or already metastatic condition. Recently, therapeutic options for management of metastatic GC (mGC) have been approved allowing a potential improvement of patient cancer treatment response and also an establishment of a continuum of care for this aggressive disease. This report is the result of a literature review by an expert panel. The aim of this document is to provide evidence, wherever it is lacking, to provide expert opinion directed at strategic management of mGC, and in particular aspect at practical management where appropriate guidelines are not available. Treatment landscape with new therapeutic strategies for third line and beyond, role of imaging, prognostic factors, symptoms, and markers as well as the importance of multidisciplinary approach particularly the nutritional aspects are discussed.

The amplification and expression of ERBB2 have been linked with prognosis and response to therapy with the anti-HER-2-humanised monoclonal antibody, trastuzumab, in patients with advanced metastatic breast cancer. However, one of the major clinical problems encountered with trastuzumab treatment is that metastatic breast cancer patients, who initially responded to trastuzumab, showed disease progression within 1 year from treatment initiation. Several studies have already reported or speculated on potential mechanisms of resistance to trastuzumab. Despite these important leads, there is/are no biomarker(s) that can reliably predict lack of benefit from trastuzumab, which in turn can be used for subsequent clinical trial development and/or individual therapeutic decisions.

CoronaVirus disease-2019 has changed the delivery of health care worldwide and the pandemic has challenged oncologists to reorganize cancer care. Recently, progress has been made in the field of precision medicine to provide to patients with cancer the best therapeutic choice for their individual needs. In this context, the Foundation Medicine (FMI)-Liquid@Home project has emerged as a key weapon to deal with the new pandemic situation. FoundationOne Liquid Assay (F1L) is a next-generation sequences-based liquid biopsy service, able to detect 324 molecular alterations and genomic signatures, from May 2020 available at patients’ home (FMI-Liquid@Home). We analyzed time and costs saving for patients with cancer, their caregivers and National Healthcare System (NHS) with FMI-Liquid@Home versus F1L performed at our Department. Different variables have been evaluated. Between May 2020 and August 2021, 218 FMI-Liquid@Home were performed for patients with cancer in Italy. Among these, our Department performed 153 FMI-Liquid@Home with the success rate of 98% (vs. 95% for F1L in the hospital). Time saving for patients and their caregivers was 494.86 and 427.36 hours, respectively, and costs saving was 13 548.70€. Moreover, for working people these savings were 1084.71 hours and 31 239.65€, respectively. In addition, the total gain for the hospital was 163.5 hours and 6785€, whereas for NHS was 1084.71 hours and 51 573.60€, respectively. FMI-Liquid@Home service appears to be useful and convenient allowing time and costs saving for patients, caregivers, and NHS. Born during the COVID-19 pandemic, it could be integrated in oncological daily routine in the future. Therefore, additional studies are needed to better understand the overall gain and how to integrate this service in different countries.

Pancreatic ductal adenocarcinoma (PDAC) is currently the most deadly cancer. Although characterized by 5–20% of neoplastic cells in the highly fibrotic stroma, immunotherapy is not a valid option in PDAC treatment. As CXCR4-CXCL12 regulates tumor invasion and T-cell access and PD-1/PD-L1 controls immune tolerance, 76 PDACs were evaluated for CXCR4-CXCL12-CXCR7 and PD-1/PD-L1 in the epithelial and stromal component. Neoplastic CXCR4 and CXCL12 discriminated PDACs for recurrence-free survival (RFS), while CXCL12 and CXCR7 discriminated patients for cancer-specific survival (CSS). Interestingly, among patients with radical resection (R0), high tumor CXCR4 clustered patients with worse RFS, high CXCL12 identified poor prognostic patients for both RFS and CSS, while stromal lymphocytic-monocytic PD-L1 associated with improved RFS and CSS. PD-1 was only sporadically expressed (

Background: Neoangiogenesis has proven to be a relevant pathogenetic mechanism in gastric cancer (GC) and lymphatic spread represents an important well-known prognostic factor. Vascular endothelial growth factor C (VEGF-C) plays a key role in lymphangiogenesis and its blood levels in GC patients are easily measurable. This analysis aimed to investigate the prognostic role of preoperative VEGF-C blood levels.Methods: VEGF-C serum levels were determined by enzyme-linked immunoadsorbent assay (ELISA) in 186 patients observed at our institution from January 2004 until December 2009 and 82 healthy subjects. Statistical analyses were performed using SPSS 21.0.Results: VEGF-C levels were significantly higher in GC patients (median: 287.4 pg/mL; range, 76.2-865.2 pg/mL) than in the control group (median VEGF-C: 31 pg/mL; range, 12-97 pg/mL). A significant correlation between VEGF-C levels, T, N and tumor stage has been described. The median overall survival (OS) was statistically significantly higher in pts with low serum VEGF-C levels [median: not reached (NR) vs. 26 months; P

BackgroundChemotherapy with carboplatin, paclitaxel, and bevacizumab is the standard therapy for patients with advanced stage ovarian cancer wild-type BRCA after primary surgery. The most frequent side effects of bevacizumab in this setting are hypertension, thrombosis, hemorrhage, and proteinuria, while arthralgia has been poorly described.ObjectiveTo examine the incidence, duration, and reversibility of arthralgia.Patients and methodsA retrospective analysis was performed to describe the occurrence and outcome of arthralgia in 114 patients with advanced ovarian cancer, given first-line treatment with a combination of carboplatin, paclitaxel, and bevacizumab. Statistical analysis was performed to investigate a possible prognostic role of arthralgia, with progression-free survival as endpoint.Results47 of 114 patients (41%) developed arthralgia during therapy. All patients had grade 1 or grade 2 arthralgia. Toxicity persisted after the end of bevacizumab in 17/47 patients (36%). Median progression-free survival for patients without arthralgia was 18 months (95% CI 14 to 24) compared with 29 months (95% CI 21 to not reached) for patients experiencing arthralgia (p=0.03). In order to avoid possible biases related to treatment duration, a multivariable Cox proportional hazards model including toxicity as a time dependent variable and age, stage, and residual disease after primary surgery was performed. In this model no variable showed a statistically significant association with progression-free survival.ConclusionA high incidence of arthralgia (41%) was found and although rogression-free survival was worse for those patients who developed arthralgia, this was not maintained on multivariate analysis. Guidelines for treatment of this adverse event are needed.

Background: Recently, new evidence of the next-generation sequencing (NGS) liquid biopsy utility in clinical practice has been developed. This assay is emerging as a new promising tool to use as a noninvasive biomarker for cancer mutation profiling. Additional data supporting the clinical validity of cell free DNA (cfDNA) based testing is necessary to inform optimal use of these assays in the clinic. Materials and methods: A total of 398 cancer patients were analyzed by FoundationOne Liquid Analysis (F1LA), a genomic profiling assay and by standard NGS diagnostic ThermoFisher platform. The association between diagnostic technique was evaluated using a Poisson regression model. FoundationOne Liquid (F1L) and FoundationOne Liquid CDx (F1LCDx) detect 70 and 324 cancer-related genes alterations, respectively, including genomic signatures tumor fraction, blood tumor mutational burden (only for the 324 genes version), and microsatellite instability high status. Both assays used a single DNA extraction method to obtain cfDNA. The real-life clinical impact and feasibility of F1L and F1LCDx were evaluated across different solid tumors in our department. Results: Between 1 January 2019 and 28 February 2021, 398 samples of different tumor types from 398 patients were analyzed (overall success rate: 92%, in FoundationOne Liquid CDx Analysis success rate: 97%). Most frequent molecular alterations were TP53 (74), APC (40), DNMT3A (39), KRAS (23). The comprehensive clinical impact of F1LA compared with standard diagnostic was 64.7% versus 22.1% [risk ratio (RR) = 2.94; p Conclusions: Although additional studies are needed to better select patients and setting, NGS F1LA is a useful, noninvasive, and repeatable assay to guide therapeutic choice in oncology. It provides a snapshot of cancer heterogeneity profile that could be incorporated in routinely clinical practice.

Despite recent progresses, locally advanced gastric cancer remains a daunting challenge to embrace. Perioperative chemotherapy and D2-gastrectomy depict multimodal treatment of gastric cancer in Europe, shows better results than curative surgery alone in terms of downstaging, micrometastases elimination, and improved long-term survival. Unfortunately, preoperative chemotherapy is useless in about 50% of cases of non-responder patients, in which no effect is registered. Tumor regression grade (TRG) is directly related to chemotherapy effectiveness, but its understanding is achieved only after surgical operation, accordingly, preoperative chemotherapy is given indiscriminately. Conversely, Naples Prognostic Score (NPS), related to patient immune-nutritional status and easily obtained before taking any therapeutic decision, appeared an independent prognostic variable of TRG. NPS was calculated in 59 consecutive surgically treated gastric cancer patients after neoadjuvant FLOT4-based chemotherapy. 42.2% of positive responses were observed: all normal NPS and half mild/moderate NPS showed significant responses to chemotherapy with TRG 1–3, while only 20% of the worst NPS showed some related benefits. Evaluation of NPS in gastric cancer patients undergoing multimodal treatment may be useful both in selecting patients who will benefit from preoperative chemotherapy and for changing immune-nutritional conditions in order to improve patient’s reaction against the tumor.

Background Pioglitazone, a synthetic peroxisome proliferator activated receptor (PPAR-γ) ligand, is known as an antidiabetic drug included in the thiazolidinediones (TZDs) class. It regulates the lipid and glucose cell metabolism and recently a role in the inhibition of numerous cancer cell processes has been described. Methods In our work we investigate the anti-tumor effects of pioglitazone in in vitro models of non small cell lung cancer (NSCLC) and also, we generated ex-vivo three-dimensional (3D) cultures from human lung adenocarcinoma (ADK) as a model to test drug efficacy observed in vitro. The inhibitory effect of pioglitazone on cell proliferation, apoptosis and cell invasion in a panel of human NSCLC cell lines was evaluated by multiple assays. Results Pioglitazone reduced proliferative and invasive abilities with an IC50 ranging between 5 and 10 μM and induced apoptosis of NSCLC cells. mRNA microarray expression profiling showed a down regulation of MAPK, Myc and Ras genes after treatment with pioglitazone; altered gene expression was confirmed by protein analysis in a dose-related reduction of survivin and phosphorylated proteins levels of MAPK pathway. Interestingly mRNA microarray analysis showed also that pioglitazone affects TGFβ pathway, which is important in the epithelial-to-mesenchimal transition (EMT) process, by down-regulating TGFβR1 and SMAD3 mRNA expression. In addition, extracellular acidification rate (ECAR) and a proportional reduction of markers of altered glucose metabolism in treated cells demonstrated also cell bioenergetics modulation by pioglitazone. Conclusions Data indicate that PPAR-γ agonists represent an attractive treatment tool and by suppression of cell growth (in vitro and ex vivo models) and of invasion via blockade of MAPK cascade and TGFβ/SMADs signaling, respectively, and its role in cancer bioenergetics and metabolism indicate that PPAR-γ agonists represent an attractive treatment tool for NSCLC.

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. 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 nonfunctional; 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. (c) 2016 Published by Elsevier Ltd on behalf of IJS Publishing Group Limited.

Poly-ADP-ribosepolymerase inhibitors (PARPis) are the most active and interesting therapies approved for the treatment of epithelial ovarian cancer. They have changed the clinical management of a disease characterized, in almost half of cases, by extreme genetic complexity and alteration of DNA damage repair pathways, particularly homologous recombination (HR) deficiency. In this review, we provide an updated overview of the available results of recent clinical trials on the three Food and Drug Administrationand European Medicines Agency approved PARPis in ovarian cancer: olaparib, niraparib, and rucaparib. Furthermore, we anticipate the future perspective of combination regimens with antiangiogenic, immunocheckpoint inhibitors, and other biological agents as strategies to overcome resistance mechanisms, potentiate the therapeutic efficacy, and expand their clinical use in non-HR deficient tumors.

Triple-negative breast cancer (TNBC) accounts for 15–20% of diagnosed breast tumours, with higher incidence in young and African-American women, and it is frequently associated with BRCA germline mutations. Chemotherapy is the only well-established therapeutic option in both early- and advanced-stages of the disease. TNBC tumours relapse earlier after standard anthracycline- and/or taxane-based chemotherapy treatments, generally within 1–3 years after the diagnosis, and often develop visceral metastases, representing the subtype with a worse prognosis among all breast cancers. In the present review, we will provide an updated overview of the available results of recent clinical trials for this disease and we will describe the implications of the known molecular pathways representing novel targets for development of future therapies for TNBC patients. Over the past decade, the advent of gene expression micro-array technology has led to the identification of different actionable targets including various genomic alterations, androgen receptor, PARP, PI3K, VEGF and other proteins of the angiogenic pathway. Thus, novel targeted drugs have been tested in clinical trials reporting promising results in specific TNBC molecular subgroups. Although cytotoxic chemotherapy remains the mainstay of treatment for TNBC patients, the identification of novel ‘drugable’ targets and pathways for developing personalized treatments represents a promising investigational approach in the management of the TNBC subtype.

Objective: We built and externally validated a nomogram for predicting the overall survival (OS) probability of advanced gastric cancer patients receiving second-line treatment. Methods: The nomogram was developed on a set of 320 Italian patients and validated on two independent sets (295 Italian and 172 Korean patients). Putative prognostic variables were selected using a random forest model and included in the multivariable Cox model. The nomogram’s performance was evaluated by calibration plot and C index. Results: ECOG performance status, neutrophils to lymphocytes ratio, and peritoneal involvement were selected and included into the multivariable model. The C index was 0.72 (95% CI 0.68–0.75) in the development set, 0.69 (95% CI 0.65–0.73) in the Italian validation set, but only 0.57 (95% CI 0.52–0.62) in the Korean set. While Italian calibrations were quite good, the Korean one was poor. Regarding 6-month OS predictions, calibration was best in both Caucasian cohorts and worst the in Asian one. Conclusions: Our nomogram may be a useful tool to predict 3- or 6-month OS in Caucasian gastric cancer patients eligible for second-line therapy. Based on three easy-to-collect variables, the Gastric Life nomogram may help clinicians improve patient selection for second-line treatments and assist in clinical trial enrollment.

Background Pancreatic neuroendocrine tumors (pNETs) are uncommon entities. pNETs are often small, slow growing, clinically silent neoplasms. However, they have an almost unpredictable biological behaviour with a not negligible malignant potential. Surgery still represents the treatment of choice, but the high morbidity associated to the enucleation or the formal pancreatectomy should be considered in the decision of the proper treatment. Management of these neoplasms is still debated, and indications for a conservative observational approach and for parenchyma sparing resections are not yet standardized. Method We review the state of art on the indications for the conservative management of pNETs. Searches on MEDLINE database were performed to identify articles reporting prognostic systems, biochemical screening, observational management, medical treatment and surgical strategies for pNETs. Discussion Currently, an accurate ‘wait-and-see' policy is recommended by the European Neuroendocrine Tumor Society (ENETS) only for non-functioning pNETs (NF-pNETs) A biochemical screening, based on sampling of serum levels of pancreatic polypeptide (PP) and chromogranin A, can address to early conservative surgery for MEN-1 associated NF-pNETs The subtotal (80%) distal pancreatectomy first proposed by Thompson, often with the enucleation of possible pancreatic head tumors, still represents a good compromise between oncological radicality and prevention of pancreatic endocrine/exocrine insufficiency caused by standard radical resections for the treatment of inherited syndromes associated with NF-pNETs >2 cm and symptomatic F-pNETs of any size. Conclusion More studies are needed to further clarify and predict the biologic behaviour of pNETs and increase the indications for conservative observational management and parenchyma sparing pancreas resections.

Background Systemic inflammation and immune response play a crucial role in tumor growth, and the neutrophil to lymphocyte ratio (NLR) may be a simple way to assess the host inflammatory response. The NLR has been shown to be a prognostic indicator in many human tumors; in early colon cancers, it has been evaluated only in a few studies and its role remains controversial. Methods We analyzed data from 503 colon cancer patients. The best cutoff value for NLR was defined by receiver operating characteristic curve analysis. We grouped 276 Dukes A/B colon cancers, not receiving adjuvant chemotherapy, into low ( 2.36) NLR and subjected to further analyses related to disease-free survival (DFS). A propensity score-matched analysis and the inverse probability of treatment weighting (IPTW) were performed to avoid confounding bias. Results The NLR correlated with tumor stage and oncologic outcome. The best NLR cutoff value was identical in the whole cohort and in Dukes A/B patients. Low NLR patients had a significantly better DFS rate than high NLR patients (hazard ratio [HR], 0.27; P = .0001); along with elevated carcinoembryonic antigen levels and Dukes B stage, high NLR was an independent prognostic factor of worse prognosis (HR, 2.86; P = .0033). Even in Dukes A patients, NLR discriminated between relapsing and nonrelapsing patients. Propensity score and IPTW analyses confirmed such results, thus excluding possible misinterpretation. Conclusion Preoperative NLR, an inexpensive and readily available biomarker, can predict tumor relapse and should be assessed for implementation of tailored therapy in early stage colon cancer.

The incidence of esophagogastric junction adenocarcinoma (AEG) is increasing worldwide. Barrett’s esophagus (BE) associated with dysplasia is the main risk factor for the development of cancer. Currently, screening programs to individuate and eradicate BE represent the best way to reduce AEG cancer. Several endoscopic approaches are here discussed. Surgical strategies for different types of AEG cancer are now fairly standardized, and multidisciplinary strategies using chemotherapy or chemoradiotherapy may improve the outcome of these patients. Here we briefly discuss the keypoints, main topics, and critical issues, according to accumulating evidence and taking into account our own experience.

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.

The best choice of chemotherapy regimen for patients with metastatic gastric cancer is still debated. Although several studies support a superior efficacy of a triplet chemotherapy regimen over a doublet-based regimen, the magnitude of this benefit appears small and accompanied by an increased toxicity. Based on this background, we evaluated the outcome of patients with HER2-negative metastatic gastric cancer (mGC) who received in the clinical practice a triplet or doublet regimen as first-line therapy. A total of 165 patients (pts) with HER2-negative mGC treated outside of clinical trials at our department with FOLFOX-4 or ECX from 2012 and 2015 were included in our retrospective analysis: FOLFOX-4: 86 pts; ECX: 79 pts. Median progression-free survival (PFS) was 5.1 months for FOLFOX-4 and 5.6 months for ECX regimen, respectively. Median overall survival (OS) was 10.3 months for FOLFOX-4 and 10.9 months for ECX regimens. Toxicity: grade 3–4 vomiting (12.6%), neutropenia (31.6%), mucositis (11.3%) and fatigue (22.7%) occurred more frequently in ECX regimen, while grade 3–4 peripheral neuropathy was more common with FOLFOX-4 (19.7%). Both evaluated regimens are active and safe in the palliation of HER2-negative mGC in the first-line setting: Three-drug chemotherapy regimen appear more active but offer only a slight improvement in OS with an increased G3–G4 toxicity. Our data suggest that a doublet therapy should be preferred in the clinical practice, preferentially reserving a three-drug combination to pts with bulky disease and/or to pts with initially unresectable locally advanced disease.

Summary Background Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m 2 intravenously; cisplatin 60 mg/m 2 intravenously; capecitabine 625 mg/m 2 orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. Findings Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6–12·0) for patients in the rilotumumab group and 9·4 months (5·3–13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7–10·2) in the rilotumumab group compared with 10·7 months (9·6–12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10–1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression. Interpretation Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma. Funding Amgen.

NTRODUCTION: Circulating tumor cells are thought to play a crucial role in the development of distant metastases. Their detection in the blood of colorectal cancer patients may be linked to poor outcome, but current evidence is controversial. MATERIALS AND METHODS: Pre- and postoperative flow cytometric analysis of blood samples was carried out in 76 colorectal cancer patients undergoing surgical resection. The EpCAM/CD326 epithelial surface antigen was used to identify circulating tumor cells. RESULTS: Fifty-four (71%) patients showed circulating tumor cells preoperatively, and all metastatic patients showed high levels of circulating tumor cells. Surgical resection resulted in a significant decrease in the levels of circulating tumor cells. Among 69 patients undergoing radical surgery, 16 had high postoperative levels of circulating tumor cells, and 12 (75%) experienced tumor recurrence. High postoperative level of circulating tumor cells was the only independent variable related to cancer relapse. In patients without circulating tumor cells, the progression-free survival rate increased from 16 to 86%, with a reduction in the risk of tumor relapse greater than 90%. CONCLUSIONS: High postoperative levels of circulating tumor cells accurately predicted tumor recurrence, suggesting that assessment of circulating tumor cells could optimize tailored management of colorectal cancer patients.

Targeted agents have dramatically improved and enriched the therapeutical choices for patients with metastatic colorectal cancer (mCRC). By better understanding the role of the angiogenic pathway in colorectal cancer (CRC), new therapies have been developed. Bevacizumab, the first anti-angiogenetic agent approved for the treatment of mCRC provide a proof of concept since it has improved the progression-free survival and overall survival when combined with cytotoxic chemotherapy.This review is focused on the most recent findings on the VEGF signaling pathway and new therapeutic drugs explored in clinical trials.Despite the advantage offered by bevacizumab, the median overall survival of mCRC patient exceeds 21 months; thus, investigational efforts are needed. Several antiangiogenic agents for the treatment of mCRC are being tested in preclinical and clinical Phase I/II trials. Unfortunately a discrete number of Phase III trials produced negative results. Recently aflibercept and regorafenib, two new antiangiogenic drugs, have been approved as the new-targeted agents for the treatment of mCRC, according to the positive findings from the VELOUR and the CORRECT studies. In order to maximize clinical impact it will be important to validate predictive biomarkers and best combination treatments to offer for mCRC patients; further research and intense investigation is still required.

Axitinib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with Sunitinib or cytokine. The present study is an Italian Multi-Institutional Retrospective Analysis that evaluated the outcomes of Axitinib, in second-line treatment of mRCC. The medical records of 62 patients treated with Axitinib, were retrospectively reviewed. The Progression Free Survival (PFS), the Overall Survival (OS), the Objective Response Rate (ORR), the Disease Control Rate (DCR), and the safety profile of axitinib and sunitinib–axitinib sequence, were the primary endpoint. The mPFS was 5.83 months (95% CI 3.93–7.73 months). When patients was stratified by Heng score, mPFS was 5.73, 5.83, 10.03 months according to poor, intermediate, and favorable risk group, respectively. The mOS from the start of axitinib was 13.3 months (95% CI 8.6–17.9 months); the observed ORR and DCR were 25 and 71%, respectively. When stratified patients by subgroups defined by duration of prior therapy with Sunitinib (≤ vs. >median duration), there was a statistically significant difference in mPFS with 8.9 (95% CI 4.39–13.40 months) vs. 5.46 months (95% CI 4.04–6.88 months) for patients with a median duration of Sunitinib >13.2 months. DCR and ORR to previous Sunitinib treatment was associated with longer statistically mPFS, 7.23 (95% CI 3.95–10.51 months, p = 0.01) and 8.67 (95% CI 4.0–13.33 months, p = 0.008) vs. 2.97 (95% CI 0.65–5.27 months, p = 0.01) and 2.97 months (95% CI 0.66–5.28 months, p = 0.01), respectively. Overall Axitinib at standard schedule of 5 mg bid, was well-tolerated. The most common adverse events of all grades were fatig (25.6%), hypertension (22.6%), gastro-intestinal disorders (25.9%), and hypothyroidism (16.1%). The sequence Sunitinib–Axitinib was well-tolerated without worsening in side effects, with a median OS of 34.7 months (95% CI 18.4–51.0 months). Our results are consistent with the available literature; this retrospective analysis confirms that Axitinib is effective and safe in routine clinical practice.

Cystic peritoneal mesothelioma is commonly regarded as a benign neoplasm at its first manifestation. It can only seldom show malignant transformation, and only after repeated postoperative recurrences.We hereby represent a unique case of peritoneal cystic mesothelioma, malignant since its first presentation. We observed a 73 year-old man presenting with intermittent abdominal pain and periumbilical swelling. At surgery, we found an extensive, oval-shaped, multi-lobed cystic formation that was surgically removed.Histopathology was consistent with a malignant peritoneal cystic mesothelioma. In agreement with oncologists, we decided not to give any further therapy because of the few possibilities offered by systemic chemotherapy and the paucity of published data from the literature. We planned periodical follow-up including US scan every six and CTscan every 12 months.Several cases of malignant transformation occurring after repeated recurrences of peritoneal mesothelioma have been reported. To our knowledge, this is the first case showing "ab initio" histological features of malignancy, typical of an active, proliferating and infiltrating lesion. In addition, advanced age and male gender of our patient are extremely peculiarOur observation suggests the possibility, although very rare, that peritoneal cystic mesothelioma may present as malignant since its first manifestation.Peritoneal cystic mesothelioma.Il mesotelioma peritoneale cistico è un tumore raro. Si tratta di un tumore benigno, che tuttavia va incontro a recidive locali post-chirurgiche in oltre il 50% dei casi. È proprio a seguito di recidive ricorrenti che si possono determinare trasformazioni maligne di questa neoplasia, come descritto in Letteratura. Nel Giugno del 2004 un paziente di 73 anni è giunto presso la nostra struttura con una tumefazione addominale causa di dolore gravativo: si trattava di una massa di 16 cm, la cui struttura, agli esami strumentali (ecografia, TC con m.d.c. e RMN), appariva pluricistica. Attraverso una laparotomia mediana si è provveduto alla sua rimozione e il paziente è stato dimesso in VIII giornata post-operatoria senza complicanze. L’esame istologico, corredato da studio immunoistochimico e di microscopia elettronica, ha consentito di porre diagnosi di mesotelioma peritoneale pluricistico in trasformazione maligna. D’accordo con gli oncologi, in considerazione della scarsa efficacia dei trattamenti adiuvanti e della scarsità dei dati riportati in Letteratura sull’argomento, si è deciso di sottoporre il paziente unicamente ad uno stretto follow-up, con esecuzione di ecografia addominale ogni sei mesi e TC addominale ogni anno. Ad oggi, dieci anni dopo il trattamento, il paziente, di 83 anni, gode di un discreto stato di salute e non si sono verificate riprese o recidive di malattia, né locali, né a distanza. Oltre al fatto di essere risultato maligno alla sua prima manifestazione e non dopo ripetute recidive, il caso presenta altre particolarità: il mesotelioma peritoneale cistico, infatti, solitamente colpisce soggetti di sesso femminile (con un rapporto F:M di 4,5:1) ad un’età media di 60 anni, mentre il caso descritto riguarda un soggetto di sesso maschile di 73 anni. La nostra osservazione dimostra la possibilità che il mesotelioma peritoneale vada incontro a trasformazioni maligne già alla sua prima manifestazione e non esclusivamente dopo ripetute recidive locali, come è invece documentato in Letteratura; dimostra inoltre che la radicalità della rimozione chirurgica, senza la rottura della capsula di rivestimento, quando la patologia è ancora localizzata, garantisce la possibilità che non si verifichino recidive.

Treatment of colorectal cancer (CRC) has changed dramatically over the past decade, mainly due to the advent of molecularly targeted agents. In particular, an improved understanding of the role of the angiogenesis pathway in CRC has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic CRC (mCRC) and at present is the only antiangiogenesis agent approved for the treatment of this cancer.In this review, the authors outline the most recent data on the VEGF signaling pathway and on new therapeutic reagents that target it, provide insight into their mechanisms, and describe results from recent clinical trials.In the new decade of 'modern therapy', an increasing number of antiangiogenic agents for the treatment of mCRC are being tested in preclinical models, and dozens of studies on these drugs are ongoing. Presently, eight novel antiangiogenic agents are in Phase III trials and a wide range of other candidates are being tested in Phase I/II trials. Given the preliminary positive results of two recent Phase III trials, aflibercept and regorafenib, probably, will be new-targeted agents approved for the treatment of mCRC. Furthermore, the list of potentially approved agents seems to increase in the next years and to maximize their potential clinical impact, is critically important to introduce efficient molecular diagnostic methodologies into the drug development process to indentify the subset of patients who would benefit most from their use.

INTRODUCTION: Chemotherapy-induced neutropenia, the depth and length of which are correlated to the risk of febrile neutropenia (FN) and neutropenia sepsis, remains a serious problem in medical oncology. Granulocyte colony-stimulating factors (G-CSF) stimulate the proliferation and survival of neutrophils and their precursors, thereby reducing the incidence, duration and severity of neutropenic events across a broad range of malignancies and regimens, often enabling the delivery of full chemotherapy dose intensity. AREAS COVERED: In this review, areas covered include the physiologic role of G-CSF in granulopoiesis, as well as a related biological model of bone marrow kinetics after chemotherapy. Information relating to the application of clinical guidelines for optimization of prophylaxis of FN in adult cancer patients was critically summarized. The literature and pharmacological data were obtained through an electronic search. EXPERT OPINION: There are relevant physiological and clinical evidences for the use of G-CSF to prevent FN and to ameliorate the myelotoxicities of cancer chemotherapy. In particular, biological models are in favor of the prophylactic rather than therapeutic use of G-CSF therapy. Use of a single dose of pegfilgrastim per cycle in appropriate patients provides a more convenient and potentially more effective strategy for assisting neutrophil recovery. While biosimilars may cost less, future developments in their regulation will need to address multiple issues. In the interim, physicians should remember that small differences in biochemical and biophysical characteristics might translate into differences in potency and immunogenic potential.

In the last decade dramatic improvements have been obtained in the treatment of metastatic colorectal cancer. Thanks to the introduction in the clinical practice of new drugs such as Irinotecan and Oxaliplatin, and modern biological drugs such as Bevacizumab and Cetuximab, the response rate, progression-free and overall survival are about 50-60%, 9-11 and 20-24 months respectively. Despite this progress, many questions remain unsolved especially those related to the optimal duration of treatment and the role of maintenance therapy. To treat until progression (or unacceptable toxicity) is the classical way but in the common clinical practice is frequent to perform an induction therapy (until the maximum response is obtained) followed by a complete stop and restart on progression, or by a maintenance without the drug/s responsible of the major cumulative toxicities. The following report focus on the role of different strategies respect to the classic "treatment until progression".

Capecitabine is an orally administered fluoropyrimidine carbamate which has been developed as a prodrug of 5-FU with the goal to improve its tolerability and intratumoral drug concentration. The review aims to provide an evidence-based update of clinical trials investigating the clinical efficacy, adverse-event profile, dosage and administration of this drug, alone or in combination with conventional chemotherapeutics and/or new target-oriented drugs, in the management of colorectal cancer patients. © 2010 Elsevier Ltd.

Renal cell carcinoma (RCC) is a frequent adult malignancy comprising different subtypes, with clear cell renal cell carcinoma (CCRCC) the most common. CCRCC is associated with the loss of function of the von Hippel-Lindau (VHL) gene. pVHL, the product of the VHL gene, is a component of an E3 ubiquitin ligase complex which targets proteins for degradation. In the absence of functional pVHL, a series of proteins accumulate in the cells, including hypoxic-inducible factor-1a (HIF-1a) and the products of the target genes of pVHL, such as vascular endothelial growth factor (VEGF). The activation of this pathway explains the use of both VEGF and VEGF-receptor inhibitors (bevacizumab, sunitinib and sorafenib) in the therapy of advanced CCRCC. In addition, mammalian target of rapamycin (mTOR), an intracellular serine/threonine kinase, is also implicated in HIF-1a regulation, thus reinforcing the rationale for using mTOR inhibitors (rapamycin) in CCRCC. Proteomic technologies have been applied to human renal cancer to detect biomarkers able to guide physicians for diagnostic and prognostic purposes. Among others, vimentin, heat shock protein 27 (Hsp27), annexin IV and serum amyloid alpha-1 (SAA-1) have been identified as reliable markers of RCC that are potentially useful in the clinical setting. Renal cell carcinoma (RCC) is a frequent adult malignancy comprising different subtypes, with clear cell renal cell carcinoma (CCRCC) the most common. CCRCC is associated with the loss of function of the von Hippel-Lindau (VHL) gene. pVHL, the product of the VHL gene, is a component of an E3 ubiquitin ligase complex which targets proteins for degradation. In the absence of functional pVHL, a series of proteins accumulate in the cells, including hypoxic-inducible factor-1α (HIF-1α) and the products of the target genes of pVHL, such as vascular endothelial growth factor (VEGF). The activation of this pathway explains the use of both VEGF and VEGF-receptor inhibitors (bevacizumab, sunitinib and sorafenib) in the therapy of advanced CCRCC. In addition, mammalian target of rapamycin (mTOR), an intracellular serine/threonine kinase, is also implicated in HIF-1α regulation, thus reinforcing the rationale for using mTOR inhibitors (rapamycin) in CCRCC. Proteomic technologies have been applied to human renal cancer to detect biomarkers able to guide physicians for diagnostic and prognostic purposes. Among others, vimentin, heat shock protein 27 (Hsp27), annexin IV and serum amyloid alpha-1 (SAA-1) have been identified as reliable markers of RCC that are potentially useful in the clinical setting. © 2011 Società Italiana di Nefrologia.

Summary The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR is the first molecular target against which monoclonal antibodies (mAb) have been developed for cancer therapy. Here we review the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy. The efficacy of EGFR-specific mAb in cancer occurs thanks to inhibition of EGFR-generated signalling; furthermore, the effects of antibodies on the immune system seem to play an important role in determining the overall anti-tumour response. In this review, attention is focused on cetuximab and panitumumab, two mAb introduced recently into clinical practice for treatment of metastatic colorectal and head and neck cancer which target the external part of EGFR.

BACKGROUND: Gastric cancer still represents a leading cause of death worldwide. Several cytotoxic agents have demonstrated activity and combination regimens improve progression-free survival, overall survival and quality of life. Nevertheless, now there is no standard therapy for advanced gastric cancer patients. OBJECTIVE: To evaluate the role of new investigational agents. METHODS: We analysed Phase I, II and III studies that evaluated tailored drugs directed against the epidermal growth factor receptor (EGFR), the c-erbB2, the vascular endothelial growth factor (VEGF), the vascular endothelial growth factor receptor (VEGFR), the matrix metalloproteinases (MMP) and the mammalian target of rapamycin (mTOR). CONCLUSION: Data from Phase II trials indicate the potential of improved efficacy of chemotherapy when administered in combination with bevacizumab and cetuximab. Trastuzumab results are ongoing, while marimastat has not obtained clinical developments even if it has demonstrated to be an active drug in this setting of patients.

The vast majority of colorectal cancer patients who present with liver metastases are not initially candidates for hepatic resection. Although the combination of systemic chemotherapy and liver surgery can convert a significant proportion of patients from a palliative situation to a potentially curative situation, the majority of initially unresectable liver metastases do not respond sufficiently to initial chemotherapy to become resectable. More recently the addition of biologic agents (bevacizumab or cetuximab) to cytotoxic chemotherapy has increased the rate of tumor response, suggesting that the addition of these agents could improve resectability rate. Here we report the clinical case of a complete pathological response (pCR) in a 67-year-old male affected by metastatic colorectal cancer, with initially unresectable liver metastases, after treatment with chemotherapy and bevacizumab.

The epidermal growth factor receptor (EGFR) is frequently overexpressed in squamous cell carcinoma of head and neck (SCCHN). Different strategies to target the activated EGFR have reached the clinic. Cetuximab is a monoclonal antibody that selectively binds to the extracellular domain of the EGFR on the tumor cell, thereby inhibiting receptor-associated tyrosine kinase activation. Two randomized phase III clinical trials have recently demonstrated that cetuximab increases the activity of radiotherapy in the treatment of locally advanced SCCHN and of platinum-based chemotherapy in the treatment of metastatic SCCHN. Here we report the clinical case of a long-lasting complete response in a 57-year-old male, who was a current smoker and had a history of alcohol abuse, affected by recurrent locally advanced SCCHN after failure of radiotherapy and of platinum-based chemotherapy.

The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2x2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95\% confidence intervals (CI): 0.73-1.09) for patients receiving FA and 0.99 (95\% CI 0.80-1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95\% CI: 0.80-1.30) and 0.94 (95\% CI 0.73-1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients..