The evolving role of microsatellite instability in colorectal cancer: A review

Microsatellite instability (MSI) is a molecular marker of a deficient mismatch repair (MMR) system and occurs in approximately 15% of colorectal cancers (CRCs), more frequently in early than late-stage of disease. While in sporadic cases (about two-thirds of MSI-H CRCs) MMR deficiency is caused by an epigenetic inactivation of MLH1 gene, the remainder are associated with Lynch syndrome, that is linked to a germ-line mutation of one of the MMR genes (MLH1, MSH2, MSH6, PMS2). MSI-H colorectal cancers have distinct clinical and pathological features such as proximal location, early-stage (predominantly stage II), poor differentiation, mucinous histology and association with BRAF mutations. In early-stage CRC, MSI can select a group of tumors with a better prognosis, while in metastatic disease it seems to confer a negative prognosis. Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible resistance to 5-FU in these tumors. The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, that resist tumor elimination. Based on these considerations, MSI-H CRCs seem to be particularly responsive to immunotherapy, such as anti-PD-1, opening a new era in the treatment landscape for patients with metastatic CRC

L'INTERVENTO DEL FARMACISTA NELL’EDUCAZIONE SANITARIA

Il fenomeno della diffusione delle sostanze di abuso tra i giovani ha assunto aspetti preoccupanti. Lo spaccio di droga avviene in tutte le strutture a cui accedono i giovani, nessuna esclusa e oggi anche nel web, una delle nuove frontiere del traffico illecito. All’interno di questo scenario la figura del farmacista ha dato contributi validi nella divulgazione, per tentare di salvaguardare la salute dei giovani anche attraverso la promozione diretta di campagne di educazione/sensibilizzazione che forniscano all’utente le informazioni necessarie a difendere la propria salute. Materiali e metodi: Abbiamo realizzato due conferenze inerenti l’informazione sulle sostanze di abuso e la nuova diffusione su Internet, presso le Scuole di Cefalù: Liceo Classico Mandralisca, e I.P.S.S.E.O.A Alberghiero. Nel questionario pre-conferenza sono state rivolte domande per indagare su quali fossero le reali conoscenze sulle sostanze di abuso da parte dei ragazzi e delle figure con cui normalmente si relazionano. Per il post-conferenza si puntava a capire,attraverso un altro questionario, se la visione nei confronti delle sostanze di abuso fosse cambiata dopo avere ascoltato i pericoli che si corrono. Risultati: Alla ricerca hanno partecipato 26 maschi di età compresa tra 16-24 anni con una prevalenza di età di 17 e 51 femmine di età compresa tra 16-20 anni con prevalenza di 17-18 anni. In pre-conferenza il 95% ha risposto negativamente alla domanda se ritenessero di avere una buona conoscenza sulle sostanze di abuso. Al quesito se avessero assunto sostanze di abuso, hanno risposto tutti no, tranne un ragazzo che però non ha specificato quale sostanza. Per quanto riguarda il post conferenza è stato chiesto se ritenessero positiva l’esperienza, hanno risposto tutti di si .Alla domanda se avessero adesso una maggiore conoscenza delle sostanze e dei loro pericoli, hanno risposto tutti di si, aggiungendo di essere più spaventati, dopo l’ascolto, all’idea di provarle. Conclusioni: Questo fa capire come i ragazzi agiscano da soli, cercando autonomamente informazioni su internet, proprio perché quasi sempre nessuno affronta con loro questi argomenti. Le differenze tra pre/post-conferenza, il 95% era all’oscuro sugli effetti delle droghe, sottolineano quanto sia importante la divulgazione della conoscenza in materia di sostanze d’abuso attraverso l’intervento del farmacista anello di congiunzione diretta con il cittadino verso una corretta educazione sanitaria. Questo sottolinea l’importanza della prevenzione sotto forma di informazione, specie se portata agli adolescenti, oggi sempre più vittime di falsi miti e della nuova frontiera dell’illegalità che si chiama Internet

Molecular Targeted Approaches for Advanced BRAF V600, N-RAS, c-KIT, and GNAQ Melanomas

The introduction of a newly developed target therapy for metastatic melanomas poses the challenge to have a good molecular stratification of those patients who may benefit from this therapeutic option. Practically, BRAF mutation status (V600E) is commonly screened although other non-V600E mutations (i.e., K-R-M-D) could be found in some patients who respond to therapy equally to the patients harboring V600E mutations. Furthermore, other mutations, namely, N-RAS, KIT, and GNAQ, should be sequenced according to distinct melanoma specific subtypes and clinical aspects. In our report, a practical flow chart is described along with our experience in this field

Comparison between three different equations for the estimation of glomerular filtration rate in predicting mortality after coronary artery bypass

Background This study was undertaken to compare the accuracy of chronic kidney disease-epidemiology collaboration (eGFRCKD-EPI) to modification of diet in renal disease (eGFRMDRD) and the Cockcroft-Gault formulas of Creatinine clearance (CCG) equations in predicting post coronary artery bypass grafting (CABG) mortality. Methods Data from 4408 patients who underwent isolated CABG over a 11-year period were retrieved from one institutional database. Discriminatory power was assessed using the c-index and comparison between the scores’ performance was performed with DeLong, bootstrap, and Venkatraman methods. Calibration was evaluated with calibration curves and associated statistics. Results The discriminatory power was higher in eGFRCKD-EPI than eGFRMDRD and CCG (Area under Curve [AUC]:0.77, 0.55 and 0.52, respectively). Furthermore, eGFRCKD-EPI performed worse in patients with an eGFR ≤29 ml/min/1.73m2 (AUC: 0.53) while it was not influenced by higher eGFRs, age, and body size. In contrast, the MDRD equation was accurate only in women (calibration statistics p = 0.72), elderly patients (p = 0.53) and subjects with severe impairment of renal function (p = 0.06) whereas CCG was not significantly biased only in patients between 40 and 59 years (p = 0.6) and with eGFR 45–59 ml/min/1.73m2 (p = 0.32) or ≥ 60 ml/min/1.73m2 (p = 0.48). Conclusions In general, CKD-EPI gives the best prediction of death after CABG with unsatisfactory accuracy and calibration only in patients with severe kidney disease. In contrast, the CG and MDRD equations were inaccurate in a clinically significant proportion of patients

mTOR Pathway Expression as Potential Predictive Biomarker in Patients with Advanced Neuroendocrine Tumors Treated with Everolimus

Background: Everolimus (Eve), which is a mammalian target of Rapamicin (mTOR) inhibitor, is part of the therapeutic armamentarium of neuroendocrine tumors (NETs). Currently, there are no validated biomarkers predicting Eve efficacy in NETs. In this study, we explore whether the expression of phosphorilated (p)-mTOR and p70S6-kinase (S6K), a downstream effector of mTOR, correlates with the outcome of patients with NET that were treated with Eve. Methods: Tissue specimens that were derived from NETs treated with Eve at our Institution were examined for the expression levels of p-mTOR and p-S6K by immunohistochemistry. Response rate (RR), progression-free survival (PFS), and overall survival (OS) were analyzed in two groups: p-mTOR/p-S6K positive (group 1) and p-mTOR/p-S6K negative (group 2). Univariate and multivariate Cox regression analysis were performed. Results: Twenty-four patients with advanced NETs that were treated with Eve were included in the analysis. Eight out 24 (33.3%) patients were both p-mTOR and p-S6K positive. A better median PFS and OS in group 1 (18.2 and 39.9 months) as compared to group 2 (13 and 32.4 months) was depicted, with a toxicity profile that was comparable with data literature. Conclusions: Our study suggests that the activation of mTOR pathway can predict better outcomes in patients with NET treated with Eve. However, these results warrant further confirmation in a prospective setting

Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study

Purpose: Temozolomide (TEM) based therapy has been reported being effective in the treatment of metastatic neuroendocrine neoplasms (NEN), with response rates ranging from 30 to 70%. Among patients affected by advanced glioblastoma or melanoma and treated with TEM, loss of tumoral O6-methylguanine DNA methyltransferase (MGMT) is correlated with improved survival. In NEN patients, the role of MGMT deficiency in predicting clinical outcomes of TEM treatment is still under debate. Methods: In this study we evaluated 95 patients with advanced NENs undergoing treatment with TEM-based therapy. MGMT promoter methylation status was evaluated with two techniques: methylation specific-polymerase chain reaction or pyrosequencing. Results: Treatment with TEM-based therapy was associated with an overall response rate of 27.4% according to RECIST criteria (51.8% of patients with and 17.7% without MGMT promoter methylation). Response to therapy, progression free survival and overall survival was correlated to MGMT status at univariate and multivariate analysis. Methylation of MGMT promoter could be a strong predictive factor of objective response and an important prognostic factor of a longer PFS and OS. Conclusion: According to our results, MGMT methylation status, evaluated with methylation specific-polymerase chain reaction or pyrosequencing, should have an important role in patients with metastatic NENs, in order to guide therapeutic options. These results need further confirmation with prospective studies

Il trattamento di prima e seconda linea nel carcinoma gastrico

Despite the progressive decline of its incidence and mortality over the past decades, gastric cancer remains the forth most common cause of cancer-related death in Europe. While historically gastric adenocarcinoma has been classifed according to the Lauren classifcation in intestinal and diffuse subtype, the knowledge of the complex molecular mechanisms underlying its carcinogenesis has led to new molecular classifcations which can represent the starting point for the development of a personalized approach also in this disease. From a clinical point of view, while the addition of trastuzumab in the therapeutic armamentarium paved the way for the introduction of targeted therapy in the frst-line treatment, only recently the confrmation of the role of second-line therapy along with the approval of ramucirumab as a standard of care in this setting led to a new concept of continuum of care in gastric cancer. Furthermore, also the pivotal role of nutritional counseling and support both in early- and advanced-stage disease has been recently confrmed in many retrospective and prospective series

Prognostic role of aspartate aminotransferase-lymphocyte ratio index in patients with metastatic colorectal cancer: results from the randomized ITACa trial

BACKGROUND: The aim of this study was to investigate the role of pre-treatment aspartate aminotransferase-lynphocyte ratio (ALRI) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT) + bevacizumab (B) or CT alone. PATIENTS AND METHODS: Patients randomly received CT+B or CT alone as first-line therapy. CT consisted of either FOLFOX4 or FOLFIRI at the clinician's discretion. RESULTS: Out of the 284 patients enrolled, increased ALRI levels were associated with shorter PFS and OS (p<0.0001). At baseline, median PFS was 10.3 months (95% CI 9.4-12.0) and 8.0 months (95 % CI 6.8-8.9), and median OS was 25.2 months (95 % CI 21.3-30.2) and 18.8 months (95 % CI 16.6-21.7) for patients with low (<14) and high (≥14) ALRI levels, respectively (HR 1.43, 95% CI 1.12-1.82, p=0.004; HR=1.51, 95% CI 1.17-1.96, p<0.001). Interaction tests on ALRI levels and treatment efficacy in the CT+B and the CT groups were statistically significant for PFS (p=0.0003), but not for OS (p=0.228). CONCLUSION: Our results indicate that ALRI is a good prognostic and predictive marker for mCRC patients candidate for CT+B

Mutazioni somatiche di BRAF in pazienti affetti da melanoma maligno metastatico ed efficacia clinica degli approcci terapeutici a bersaglio molecolare con inibitori di BRAF

L’introduzione di terapie a bersaglio molecolare ha rivoluzionato la prognosi dei pazienti affetti da melanoma in stadio avanzato. Attualmente è possibile determinare lo status molecolare del melanoma analizzando geni quali C-KIT, BRAF ed N-RAS per la scelta di strategie terapeutiche mirate. Mutazioni di BRAF si riscontrano in circa il 50% dei melanomi: tra queste la V600E e la V600K sono maggiormente frequenti e ben studiate nei pregressi protocolli di sperimentazione fase II/III con inibitori di BRAF. Questi ultimi (Dabrafenib e Vemurafenib) hanno dimostrato chiara efficacia nell’indurre risposte obiettive nel melanoma avanzato. Con il presente lavoro presentiamo le preliminari valutazioni delle correlazioni tra tipologie di mutazioni somatiche del gene BRAF riscontrate in una coorte di melanomi in stadio IV e le risposte cliniche a tale inibitori selettivi. A partire dal giugno 2011, 19 pazienti (10 M; 9F; età media 55 anni) affetti da melanoma stage IV BRAF+ sono stati arruolati in protocolli terapeutici con Dabrafenib (150 mg 2 volte/die) o Vemurafenib (960 mg 2volte/die) presso l’Università di Modena. Il restaging strumentale della malattia veniva eseguito a 8 settimane dall’inizio della terapia. Sono state riscontrate mutazione hot spot V600E (c.1799T>A) in 18 pazienti, in due differenti pazienti sono state individuate le rare mutazioni V600M (c.1798G>A) e V600R (c.1790T>G). In un melanoma è stata evidenziata una doppia mutazione (V600E; V600M) ed il relativo paziente, trattato con Dabrafenib, ha presentato una rapida regressione delle importati lesioni metastatiche. In due casi la ricerca mutazionale in BRAF, risultata inizialmente negativa, è stata poi riscontrata in una successiva analisi. I dati clinici preliminari evidenziano una risposta obiettiva già nelle primissime settimane di terapia, buona tolleranza con scarsi effetti collaterali sia nei pazienti con mutazioni V600E che in quelli con le rare mutazioni V600 M e V600R. Il periodo di sopravvivenza medio libero da progressione dei 15 pazienti con follow-up di almeno 8 settimane è stato di 7 mesi. In 9 pazienti persiste la risposta terapeutica ad oggi. La doppia mutazione di BRAF potrebbe costituire un fattore prognostico positivo per la risposta agli inibitori di BRAF. Nei casi negativi alla ricerca mutazionale, dovrebbe essere routinariamente impiegate indagini più approfondite atte ad evidenziare non solo la presenza della comune V600E ma anche delle varianti meno comuni degli esoni 11 e 15