Prognostic value of PET parameters in patients with pleomorphic lung cancer: Results from a single institution.

OBJECTIVES: Pleomorphic lung carcinoma (PLC) is a rare histotype of non-small cell lung cancer (NSCLC) characterized by aggressive clinical course, poor response to therapy and poor prognosis. Therefore, aim of our study is to analyze with 18F-FDG PET/CT a subset of patients affected by PLC to evaluate their metabolic characteristics in terms of SUVmax, MTV and TLG, in order to correlate them with overall survival (OS) and disease-free survival (DFS). MATERIAL AND METHODS: We retrospectively analyzed 49 consecutive patients with histologically defined PLC occurred to our Institution between 2003 and 2014. All patients underwent F18-FDG PET-CT before surgery and primary tumor was automatically segmented using an isocontour threshold method. SUV threshold for tumor segmentation was defined as the 41 % of lesion SUVmax. Total volume of the segmented VOI (MTV, centimeters cubed) and average SUV (SUVavg, grams per milliliter) in the segmented VOI were measured. RESULTS: In our population men were significantly more affected than women (42:7). According to Youden criteria, SUVmax, MTV41 and TLG41 best cut-off values to predict 2-year mortality were, 18.95, 27.89 and 290.45, respectively, with TLG41 showing best specificity (85 %) and positive predictive value (82.4 %). As concerning 2-year recurrence, SUVmax, MTV41 and TLG41 best cut-off values were 10.08, 27.89 and 134.85, with SUVmax showing best sensitivity (96.7 %) and negative predictive value (85.7 %). ROC curves confirmed that SUVmax, MTV41 and TLG41 were equally accurate to predict 2-year mortality and 2-year recurrence in our population. CONCLUSION: Metabolic biomarkers such as SUVmax, MTV and TLG can be used as a prognostic index for disease progression, recurrence and death in patients with PLC, independently from other clinical/pathological prognostic elements.

Bora phosphorylation substitutes in trans for T-loop phosphorylation in Aurora A to promote mitotic entry.

Polo-like kinase 1 (Plk1) is instrumental for mitotic entry and progression. Plk1 is activated by phosphorylation on a conserved residue Thr210 in its activation segment by the Aurora A kinase (AURKA), a reaction that critically requires the co-factor Bora phosphorylated by a CyclinA/B-Cdk1 kinase. Here we show that phospho-Bora is a direct activator of AURKA kinase activity. We localize the key determinants of phospho-Bora function to a 100 amino acid region encompassing two short Tpx2-like motifs and a phosphoSerine-Proline motif at Serine 112, through which Bora binds AURKA. The latter substitutes in trans for the Thr288 phospho-regulatory site of AURKA, which is essential for an active conformation of the kinase domain. We demonstrate the importance of these determinants for Bora function in mitotic entry both in Xenopus egg extracts and in human cells. Our findings unveil the activation mechanism of AURKA that is critical for mitotic entry.

Tumor-infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer.

PURPOSE: The prognostic role of tumor-infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer (BC) is debated. We evaluated the association of TILs and clinico-pathological features with distant disease-free survival (DDFS) in patients with ER+/HER2- BC treated at a single institution. PATIENTS AND METHODS: A mono-institutional case-cohort series of 987 patients with early ER+/HER2- BC was retrospectively analyzed. TILs were considered both as continuous variable, and dichotomized in low (< 5%) vs high (≥ 5%). The main outcome was DDFS. Median follow-up was 7.5 years (0.1-10). Univariate and multivariable Cox proportional hazards regression with inverse sub-cohort sampling probability weighting were used to evaluate the risk across groups. RESULTS: Median TIL count was 2% (Q1-Q3 1-4%). Higher TILs were positively associated with number of lymph nodes involved (p = 0.003), tumor grade (p < 0.0001), peritumoral vascular invasion (p = 0.003), higher Ki-67 (p = 0.0001), luminal B subtype (p < 0.0001), and chemotherapy use (p < 0.00019). In multivariable regression analysis, only higher Ki-67 expression retained significant association with TILs. At univariate Cox regression analysis, TIL expression (≥ 5% vs. < 5%) was not associated with DDFS (HR 1.08, 95% CI 0.80-1.46, p = 0.62). In patients treated with adjuvant chemotherapy, high TILs were associated with better DDFS (HR 0.52, 95%CI 0.33-0.83, p = 0.006), particularly in the group with Ki-67 ≥ 20% (HR 0.50, 95%CI 0.29-0.86, p = 0.01). CONCLUSION: High TILs in ER+/HER2- BC are significantly associated with clinico-pathological features of dismal outcome. TIL prognostic value seems different in patients treated with or without chemotherapy. Our findings suggest that the high-risk subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches.

Impact of image guidance on toxicity and tumour outcome in moderately hypofractionated external-beam radiotherapy for prostate cancer.

To report toxicity and efficacy outcome of moderately hypofractionated image-guided external-beam radiotherapy in a large series of patients treated for prostate cancer (PCa). Between 10/2006 and 12/2015, 572 T1-T3N0M0 PCa patients received 70.2 Gy in 26 fractions at 2.7 Gy/fraction: 344 patients (60%) with three-dimensional conformal radiotherapy (3D-CRT) and 228 (40%) with intensity-modulated radiotherapy (IMRT). Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median age was 74 years (interquartile range 69-77). Compared with 3D-CRT, in IMRT group more high-risk patients (29% vs 18%; P = 0.002) and more high-volume target (75% vs 60%; P < 0.001) were included. Acute gastro-intestinal (GI) toxicity G > 1 were registered in 8% and in 11% IMRT and 3D-CRT patients, respectively, whereas late GI G > 1 were observed in 2% and 16% IMRT and 3D-CRT patients, respectively. Acute genito-urinary (GU) toxicity G > 1 were registered in 26% and 40% IMRT and 3D-CRT patients, respectively, whereas late GU G > 1 occurred in 5% IMRT and 15% 3D-CRT patients. Multivariate proportional hazard Cox models confirmed significantly greater risk of late toxicity with 3D-CRT compared to IMRT for GU > 1 (P = 0.004) and for GI > 1 (P < 0.001). With a median 4-year follow-up, overall survival (OS), clinical progression-free survival (cPFS) and biochemical PFS (bPFS) for the whole series were 91%, 92% and 91%, respectively. cPFS and bPFS were significantly different by risk groups. Multivariate Cox models for bPFS and cPFS showed no difference between irradiation techniques and a significant impact of risk group and initial PSA. Moderately hypofractionated radiotherapy is a viable treatment option for localized PCa with excellent tumour control and satisfactory toxicity profile. IMRT seems associated with a reduction in toxicity, whereas tumour control was equal between IMRT and 3D-CRT patients and depended mainly on the risk category.

Nipple-sparing mastectomy with different approaches: surgical incisions, complications, and cosmetic results. Preliminary results of 100 consecutive patients at a single center.

Nipple- and areola-sparing mastectomy is a novel surgical approach that preserves the nipple-areolar complex. Patients with moderate and/or severe breast ptosis are usually not eligible for this surgical approach. In this study, we aimed to demonstrate the feasibility of nonconventional surgical approaches for nipple-sparing mastectomy. One hundred consecutive patients diagnosed with primary breast cancer (BC) were enrolled in this study. Clinical and pathological data such as body mass index, smoking status, breast ptosis, complications, and aesthetic satisfaction (Breast-Q test) were collected. According to different types of breast ptosis, surgical procedures were classified as (a) hemi-periareolar, (b) round block, (c) vertical pattern, and (d) wise pattern skin incisions. We performed statistical analysis to assess the correlation with complications, degree of ptosis, and breast-Q scores. Among the 117 surgical procedures performed in 100 patients with BC, no significant associations are verified considering clinical and pathological data, complications, pre- and postsurgery satisfactions, and other parameters. Different surgical approaches represent the evolution of "classic" nipple-sparing mastectomy, thus meeting the cosmetic and oncological results. These procedures are safe and also indicated in cases conventionally considered as not eligible for nipple-areola preservation.

Validation of a short questionnaire to record adherence to the Mediterranean diet: An Italian experience.

BACKGROUND AND AIMS: A greater adherence to the Mediterranean diet has been associated with a reduced risk of major chronic diseases and cancer. The aim of the study was to assess the validity of a new short self-administered 15-item questionnaire (QueMD) to measure adherence to the Mediterranean diet in Italy. METHODS AND RESULTS: Four-hundred and eighty three participants to cancer-screening programmes at the European Institute of Oncology, Milan (Italy) were invited to join this study. Those interested compiled the QueMD and a validated Food Frequency Questionnaire (FFQ) reporting their usual food consumption during the previous six months. We derived the alternate Mediterranean score (aMED) from both questionnaires with values ranging from 0 (minimal adherence) to 9 (maximal adherence). Complete dietary data were available for 343 individuals (participation rates 71.0%). Spearman correlation coefficient between the responses to the 15 questions of the QueMD and corresponding food intake derived from the FFQ ranged from 0.15 to 0.84. A moderate correlation was found between the aMED scores calculated from the QueMD and the FFQ (intraclass correlation coefficient 0.50; 95% CI, 0.42-0.58), while agreement between the two instruments was only poor to fair for 7 of the 9 single items composing the aMED score, with values ranging from 53.0% for wholegrain products to 79.5% for fruits. CONCLUSION: This new self-administered 15-item questionnaire could be a useful tool to assess adherence to the Mediterranean diet in the Italian population.

High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma.

BACKGROUND: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.

Risk of malignancy in resected pancreatic mucinous cystic neoplasms.

BACKGROUND: Pancreatic mucinous cystic neoplasms (MCNs) are rare mucin-producing cystic tumours defined by the presence of ovarian-type stroma. MCNs have a malignant potential and thus surgery is frequently performed. The aim of this cohort study was to define better the criteria for surgical resection in patients with MCN. METHODS: This multicentre retrospective study included all resected MCNs between 2003 and 2015 in participating centres. Lesions without ovarian-type stroma were excluded. Patient characteristics, preoperative findings, histopathology findings and follow-up data were recorded. RESULTS: The study included 211 patients; their median age was 53 (range 18-82) years, and 202 (95·7 per cent) were women. Median preoperative tumour size was 55 (range 12-230) mm. Thirty-four of the 211 (16·1 per cent) were malignant, and high-grade dysplasia (HGD) was found in a further 13 (6·2 per cent). One-third of MCNs in men were associated with invasive cancer, compared with 15·3 per cent in women. Five cases of malignant transformation occurred in MCNs smaller than 4 cm. All cases of malignancy or HGD were associated with symptoms or features of concern on preoperative cross-sectional imaging. In multivariable analysis, raised carbohydrate antigen 19-9 (odds ratio (OR) 10·54, 95 per cent c.i. 2·85 to 218·23; P < 0·001), tumour size (OR 4·23, 3·02 to 11·03; P = 0·001), mural nodules (OR 3·55, 1·31 to 20·55; P = 0·002) and weight loss (OR 3·40, 2·34 to 12·34; P = 0·034) were independent factors predictive of malignant transformation. CONCLUSIONS: Small indeterminate MCNs with no symptoms or features of concern may safely be observed as they have a low risk of malignant transformation.

Radiation-induced acute dysphagia : Prospective observational study on 42 head and neck cancer patients.

PURPOSE: Acute toxicity in head and neck (H&N) cancer patients treated with definitive radiotherapy (RT) has a crucial role in compliance to treatments. The aim of this study was to correlate doses to swallowing-associated structures and acute dysphagia. METHODS: We prospectively analyzed 42 H&N cancer patients treated with RT. Dysphagia (grade ≥ 3) and indication for percutaneous endoscopic gastrostomy (PEG) insertion were classified as acute toxicity. Ten swallowing-related structures were considered for the dosimetric analysis. The correlation between clinical information and the dose absorbed by the contoured structures was analyzed. Multivariate logistic regression method using resampling methods (bootstrapping) was applied to select model order and parameters for normal tissue complication probability (NTCP) modelling. RESULTS: A strong multiple correlation between dosimetric parameters was found. A two-variable model was suggested as the optimal order by bootstrap method. The optimal model (Rs = 0.452, p < 0.001) includes V45 of the cervical esophagus (odds ratio [OR] = 1.016) and Dmean of the cricopharyngeal muscle (OR = 1.057). The model area under the curve was 0.82 (95% confidence interval 0.69-0.95). CONCLUSION: Our results suggested that the absorbed dose to the cricopharyngeal muscle and cervical esophagus might play a relevant role in the development of acute RT-related dysphagia.

Periodontal disease, edentulism, and pancreatic cancer: a meta-analysis.

Background: Periodontal disease (PD), now our commonest infectious disorder leads to tooth loss, and has been linked to various systemic diseases, including various types of cancer. The aim of this study is to provide a systematic review and a meta-analysis of the relationship between PD, edentulism, and pancreatic cancer (PC). Patients and methods: From an initial review of 327 references we selected eight studies concerning periodontitis or edentulism with sufficient quantitative information to allow us to examine the risk of PC. We used relative risks (RRs), hazard ratios, or odds ratios to measure the association between periodontitis, edentulism, and PC. We employed random effects models to obtain summary risks, and we also provide measures of study differences and possible biases. Results: The summary RR for periodontitis and PC was 1.74 [95% confidence interval (CI) 1.41-2.15] and 1.54 for edentulism (95% CI 1.16-2.05). There was no evidence of heterogeneity for either variable, and no evidence of publication bias. The studies included reports from three continents, suggesting that the association is generalizable. Most of the studies were adjusted for variables thought to be associated with PC, such as gender, smoking, BMI, diabetes, and alcohol. Conclusions: Using meta-analysis, both periodontitis and edentulism appear to be associated with PC, even after adjusting for common risk factors. As yet, the mechanisms linking oral disease and PC are uncertain, but could be related to changes in the oral microbiome-an area of current research.

Sentinel node biopsy after neoadjuvant treatment in breast cancer: Five-year follow-up of patients with clinically node-negative or node-positive disease before treatment.

PURPOSE: It is controversial whether sentinel node biopsy (SNB) without axillary dissection (AD) should be performed in cN1/2 breast cancer patients who become cN0 after neoadjuvant treatment, since the false negative rate (FNR) may be unacceptably high. We assessed outcomes to address this issue. METHODS: We retrospectively assessed 396 cT1-4, cN0/1/2 patients, who became or remained cN0 after neoadjuvant treatment and underwent SNB with at least one sentinel node (SN) found, and AD not performed if the SN was negative. RESULTS: After a median follow-up of 61 months (interquartile range 38-82), five-year overall survival was 90.7% (95% CI, 87.7-93.7) in the whole cohort, 93.3% (95% CI, 90.0-96.6) in those initially cN0, and 86.3% (95% CI, 80.6-92.1) in those initially cN1/2 (P = 0.12). Axillary failure occurred in only 1 (0.7%) initially cN1/2 patient who became cN0. In initially cN0 patients, and also initially cN1/2 patients who responded well to neoadjuvant treatment (ypT0/ypTx), SN-negativity was a significant predictor of good outcome, consistent with the known prognostic significance of axillary status, and suggesting that SN status accurately reflected axillary status. By contrast, in initially cN1/2 patients found to be ypT1/2/3, SN status (and whether or not AD was performed) had no influence on survival. CONCLUSIONS: These findings suggest that SNB is acceptable in cN1/2 patients who become cN0 after neoadjuvant therapy.

Oncological results of oncoplastic breast-conserving surgery: Long term follow-up of a large series at a single institution: A matched-cohort analysis.

PURPOSE: Oncoplastic surgery is a well-established discipline that combines conserving treatment for breast cancer with immediate plastic reconstruction. Although widely practiced, the oncologic outcomes of this combined approach are reported only in small series. The aim of the present paper is to assess the safety of oncoplastic surgery for invasive primary breast cancer. METHODS: We compared 454 consecutive patients who underwent an oncoplastic approach between 2000 and 2008 for primary invasive breast tumors (study group) with twice the number of patients who received conservation alone in the same interval time (control group). Disease free survival and overall survival were estimated using the Kaplan-Meier method. The log-rank test was used to assess differences between groups. RESULTS: The median follow-up was 7.2 years. The overall survival is similar within the two groups, being 91.4% and 91.3% at 10-yr in the study group and in the control group respectively. The disease free survival is slightly lower in the oncoplastic group (69 vs.73.1% at 10-yr). The difference is not statistically significant. DISCUSSION: We have compared a large series of primary breast cancer patients that have undergone oncoplastic surgery (454) with a control group (908) and they were followed for a prolonged period of time. It provides the best available evidence to suggest that oncoplastic surgery is a safe and reliable treatment option for the managing of invasive breast cancer.

Fluorodeoxyglucose positron emission tomography in pulmonary carcinoid tumors.

AIM: The role of fluorodeoxyglucose positron emission tomography (FDG-PET) as an additional investigation to computer tomography for pulmonary carcinoid tumors remains controversial. The aim of this study was to assess the role of FDG-PET for the diagnosis and staging of pulmonary carcinoid tumors. METHODS: We performed a retrospective mono-institutional analysis of data from 97 patients with pathologically confirmed pulmonary carcinoid tumor who had been operated on between July 1998 and April 2009 and had had a preoperative FDG-PET scan performed. RESULTS: Sixty-five (67%) of the 97 tumors were typical (TC) and 32 (33%) atypical (AC) carcinoid tumors. Overall FDG-PET sensitivity was 67% being lower for TC (60%) than for AC (81%) (P=0.04). FDG-PET negative tumors were smaller than FDG-PET positive tumors, with a respective median size of 15 and 17 mm (P=0.02). Median SUVmax for FDG-PET-positive tumors was 4.0 (2.8-5.1) with no difference between TC and AC tumors. Median Ki-67 expression was respectively 4.7% and 3.1% for FDG-PET positive and FDG-PET negative tumors (P=0.05). During a median follow-up of 49 months (interquartile range 30-63 months), 9 patients (4TC, 5AC) developed recurrent disease. Neither SUVmax nor Ki-67 expression resulted associated with disease-free survival. CONCLUSION: With an overall sensitivity of 67%, FDG-PET has shown to be useful in the preoperative work-up of patients with suspect lung carcinoid tumors. In particular it could have a role in larger tumors. These results warrant a prospective evaluation of FDG-PET in the staging of lung carcinoid tumor.

MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project.

BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics. METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses. RESULTS: Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair. CONCLUSIONS: Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype.

Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium.

BACKGROUND: The potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations. PATIENTS AND METHODS: We used data from nine case-control studies from the International Pancreatic Cancer Case-Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random-effects model. From a subset of four studies, we also calculated pooled estimates of association for supplementary and total vitamin D intake. RESULTS: Risk of pancreatic cancer increased with dietary intake of vitamin D [per 100 international units (IU)/day: OR = 1.13, 95% confidence interval (CI) 1.07-1.19, P = 7.4 × 10(-6), P-heterogeneity = 0.52; ≥230 versus <110 IU/day: OR = 1.31, 95% CI 1.10-1.55, P = 2.4 × 10(-3), P-heterogeneity = 0.81], with the association possibly stronger in people with low retinol/vitamin A intake. CONCLUSION: Increased risk of pancreatic cancer was observed with higher levels of dietary vitamin D intake. Additional studies are required to determine whether or not our finding has a causal basis.

Colorectal liver metastases are more often super wild type. Toward treatment based on metastatic site genotyping?

Recent data showed that metastatic colorectal (mCRC) tumors exhibiting extended RAS-BRAF mutations were resistant to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, making these drugs suitable for the so-called "super" wild-type (WT) patients only. This study aimed to compare the extended RAS-BRAF mutation frequency and characteristics according to location of tumor sampling. All consecutive mCRC specimens (N = 1659) referred to our institution from January 2008 till June 2014 were included in the analysis. Tumor genotyping (first for KRAS exon 2, then for BRAF exon 15, and later for KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4) was performed with high-resolution melting analysis or allelic discrimination. The factors predicting for the presence of mutation were explored using multivariate binary logistic regression. Overall, the prevalence of KRAS exon 2 was 36.8%, and it was lower in liver metastases (N = 138/490; 28.2%) in comparison with primary tumors (N = 442/1086; 40.7%), lung metastases (16/32; 50%), or other metastatic sites (15/51; 29.4%; P < 0.0001). Similarly, in the 1428 samples analyzed, BRAF mutations were less often found in liver metastases (N = 9/396; 2.3%) as compared to primary tumors (N = 79/959; 8.2%), lung metastases (N = 2/29; 6.9%), or other metastatic locations (N = 2/44; 4.5%; P < 0.0002). Overall occurrence of extended RAS mutation was 51.7%. Of the 503 samples tested, the prevalence of extended RAS-BRAF mutations was twice as low in liver metastases (N = 53/151; 34.2 %) as compared to primary tumors (N = 191/322; 59.3%, P < 0.0001). Univariate analysis identified age ≤65 years, male gender, and liver localization as predictors of super WT status. At multivariate analysis, only liver metastases were retained (RR 2.85 [95% CI 1.91-4.30]). Colorectal liver metastases are twice as likely to exhibit a super WT genotype as compared to other tumor locations independently from other factors. This molecular feature has the potential to influence therapeutic strategy in mCRC patients.

Undetectable HCV-RNA at treatment-week 8 results in high-sustained virological response in HCV G1 treatment-experienced patients with advanced liver disease: the International Italian/Spanish Boceprevir/Peginterferon/Ribavirin Name Patients Program.

In many countries, first-generation protease inhibitors (PIs)/peginterferon/ribavirin (P/R) still represent the only treatment option for HCV-infected patients. Subjects with advanced disease and previous failure to P/R urgently need therapy, but they are under-represented in clinical trials. All treatment-experienced F3/4 Metavir patients who received boceprevir (BOC)+P/R in the Italian-Spanish Name Patient Program have been included in this study. Multivariate logistic regression analysis (MLR) was used to identify baseline and on-treatment predictors of SVR and adverse events (AEs). Four hundred and sixteen patients, mean age 57.7 (range 25-78 years), 70% males, 69.5% (289/416) F4, 14% (41/289) Child-Pugh class A6, 24% (70/289) with varices and 42% (173/416) prior null responders to P/R, were analysed. Overall, SVR rate (all 381 patients who received one dose of BOC) was 49%, (58% in F3, 45% in F4, 61% in relapsers, 51% in partial, 38% in null responders, and 72% in subjects with undetectable HCV-RNA at treatment-week (TW)8. Among patients with TW8 HCV-RNA ≥ 1000 IU/L, SVR was 8% (negative predictive value = 92%). Death occurred in 3 (0.8%) patients, while decompensation and infections were observed in 2.9% and 11%, respectively. At MLR, SVR predictors were TW4 HCV-RNA ≥ 1log10 -decline from baseline, undetectable TW8 HCV-RNA, prior relapse, albumin levels ≥3.5 g/dL and platelet counts ≥100 000/µL. Metavir F4, Child-Pugh A6, albumin, platelets, age and female gender were associated with serious and haematological AEs. Among treatment-experienced patients with advanced liver disease eligible for IFN-based therapy, TW8 HCV-RNA characterised the subset with either high or poor likelihood of achieving SVR. Using TW8 HCV-RNA as a futility rule, BOC/P/R appears to have a favourable benefit-risk profile.