Trattamento chemioterapico neoadiuvante secondo schema FOLFOXIRI in pazienti con carcinoma del pancreas localmente avanzato. Studio di fase II.

Il carcinoma del pancreas rappresenta la quarta causa di morte per neoplasia nei paesi occidentali con una mortalità che approssima la sua incidenza. La chirurgia rappresenta l’unico trattamento potenzialmente curativo e la radicalità della resezione costituisce un importante fattore prognostico con un vantaggio in termini di sopravvivenza globale a favore dei pazienti con margini di resezione negativi. Purtroppo, solo il 20% dei pazienti presenta una malattia resecabile alla diagnosi mentre un ulteriore 20% è caratterizzato da un quadro localmente avanzato o a resecabilità borderline in base all’infiltrazione di segmenti di vasi venosi (in particolare vena porta o vena mesenterica superiore) o arteriosi (arteria mesenterica superiore o rami del tripode celiaco). Questi pazienti hanno un’importante probabilità di presentare margini infiltrati alla chirurgia o di avere una malattia micrometastatica e sono, dunque, potenzialmente candidabili a trattamenti medici. Negli ultimi anni il trattamento medico del carcinoma del pancreas ha subito notevoli miglioramenti grazie all’utilizzo di regimi polichemioterapici che hanno dimostrato una maggiore attività ed efficacia rispetto al tradizionale trattamento con gemcitabina. In particolare un recente studio francese di fase III che ha utilizzato un regime di combinazione di 5-fluorouracile/acido folinico, irinotecano e oxaliplatino (FOLFIRINOX), ha dimostrato una sopravvivenza mediana di circa 11 mesi e un tasso di risposte obiettive superiore al 30%, in pazienti con malattia metastatica. Pertanto, la disponibilità di regimi chemioterapici attivi ha portato a testare il loro utilizzo anche nella malattia localmente avanzata o a resecabilità borderline con l’obiettivo di selezionare meglio i pazienti potenzialmente resecabili e di aumentare il tasso di resezioni radicali. Sulla base di queste premesse abbiamo deciso di effettuare uno studio di fase II in pazienti con carcinoma del pancreas localmente avanzato o borderline per resecabilità al fine di valutare l’attività della schedula FOLFOXIRI, un regime chemioterapico che prevede sempre la combinazione di 5-fluorouracile/acido folinico, irinotecano e oxaliplatino ma in cui, rispetto al FOLFIRINOX, il 5-Fluorouracile viene somministrato solo in infusione continua, omettendo il bolo, e l’irinotecano ad un dosaggio lievemente ridotto. Questo regime è stato selezionato in quanto già ampiamente utilizzato dal nostro gruppo nel trattamento dei tumori del colon-retto e perché promettente in termini di tossicità rispetto al regime francese. L’obiettivo principale dello studio è stata la valutazione delle resezioni chirurgiche radicali dopo chemioterapia neoadiuvante con FOLFOXIRI, ipotizzando un aumento del tasso di resezioni radicali dal 30% previsto al 50%. Da settembre 2011 a luglio 2014, sono stati arruolati nello studio e trattati con FOLFOXIRI, 50 pazienti affetti da carcinoma del pancreas localmente avanzato o borderline resectable, in buone condizioni generali (ECOG PS 0-1) e di età inferiore o uguale a 75 anni, che rispettavano tutti i criteri di inclusione e di esclusione dello studio. Il trattamento chemioterapico neoadiuvante con FOLFOXIRI ha dimostrato risultati interessanti nella popolazione analizzata, sia in termini di attività che di efficacia, aumentando il disease control rate, il downstaging e la percentuale di pazienti sottoposti a chirurgia radicale

Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favorable prognostic profile in prostate cancer patients

VEGFR-2 and P2X7 receptor (P2X7R) have been described to stimulate the angiogenesis and inflammatory processes of prostate cancer. The present study has been performed to investigate the genetic interactions among VEGFR-2 and P2X7R SNPs and their correlation with overall survival (OS) in a population of metastatic prostate cancer patients. Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time PCR technique. The survival dimensionality reduction (SDR) methodology was applied to investigate the genetic interaction between SNPs. One hundred patients were enrolled. The SDR software provided two genetic interaction profiles consisting of the combination between specific VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes. The median OS was 126 months (95% CI, 115.94-152.96) and 65.65 months (95% CI, 52.95-76.53) for the favorable and the unfavorable genetic profile, respectively (p < 0.0001). The genetic statistical interaction between VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes may identify a population of prostate cancer patients with a better prognosis

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores

Natural History of Non-Small-Cell Lung Cancer with Bone Metastases

We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age &gt;65 years, non-adenocarcinoma histology, ECOG Performance Status &gt;2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection

Trattamento chemioterapico metronomico con Uracile/Tegafur (UFT) e Ciclofosfamide (CTX) in associazione a Celecoxib in pazienti con diagnosi di carcinoma metastatico del tratto gastroenterico. Valutazione clinica, farmacodinamica e farmacocinetica.

Lo studio di fase II argomento della tesi valuta il ruolo di un trattamento chemioterapico metronomico (basse dosi di farmaco somministrati per lunghi periodi di tempo) con Uracile/Tegafur e ciclofosfamide in associazione a celecoxib, in un setting di pazienti con diagnosi di carcinoma metastatico del tratto gastroenterico pretrattati con chemioterapia standard. Dopo il fallimento degli adeguati standard terapeutici, il trattamento chemioterapico metronomico, sembra rappresentare una valida opzione terapeutica in grado di produrre una promettente attività antitumorale, attraverso l’inibizione del processo angiogenetico con un basso profilo di tossicità. L’obiettivo primario dello studio è determinare un incremento della sopravvivenza libera da progressione (PFS) dal 50% al 70% a due mesi; obiettivi secondari dello studio sono la valutazione dell’ attività antitumorale del trattamento, l’impatto sulla qualità di vita, la determinazione della variazione dei livelli plasmatici di TSP-1, VEGF, sVEGFR-2, e l’analisi dei polimorfismi del gene della TSP-1 e del VEGF. I risultati preliminari dimostrano che il trattamento chemioterapico metronomico con UFT, CTX e celecoxib nel setting di pazienti valutato è fattibile: i risultati clinici mostrano una promettente attività in termini di PFS con un profilo di tossicità accettabile. Sono ancora in corso le valutazioni farmacodinamiche e farmacocinetiche

EGFR and AKT1 overexpression are mutually exclusive and associated with a poor survival in resected adenocarcinomas of the stomach and gastro-esophageal junction

Background: Trastuzumab is effective for the treatment of advanced gastric cancers with HER2 amplification. Beside HER2 amplification, several molecular targets are under evaluation in metastatic gastric tumors. We evaluated the role of HER2, EGFR, MET, AKT1 and phospho-mTOR expression in resected stage II-III adenocarcinomas. Methods: 92 patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated using immunohistochemistry. Antibodies anti- HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded tumors’ slides. Using FISH, HER2 amplification was evaluated in cases with a 2+ staining. Results: EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p=0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p=0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was mutually exclusive with that of EGFR and together defined a subgroup of tumors with a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p=0.005). Conclusion: EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers

Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients

Purpose To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) combined to Cyclophosphamide (CTX) and followed by weekly Paclitaxel, in older patients (≥65 years) with diagnosis of high risk breast cancer. The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). Methods The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. Results Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. Conclusions This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these finding