Systematic Review and Meta-Analysis on Neuropsychological Effects of Long-Term Use of Opioids in Patients With Chronic Noncancer Pain.

BACKGROUND AND OBJECTIVE: Opioid treatments are often prolonged because of the pathology causing pain. We focused on the cognitive functions in patients with chronic pain treated with opioids. This topic is currently controversial, but in practice, the consequences are important in patients' daily lives, social interactions, working ability, and driving. DATABASE AND DATA TREATMENT: Medline and Embase databases were searched for eligible articles. We included studies that enrolled patients with chronic noncancer pain, studies with patients receiving opioid treatment, studies with a control group not using opioids, and studies in which cognitive functions were evaluated with specific tests. The cognitive areas examined were as follows: attention, reaction time, executive functions, psychomotor speed, memory, and working memory. From 356 abstracts screened, 9 articles satisfied eligibility criteria and were included in our review: 7 observational and 7 experimental studies. We classified the pain treatments as follows: opioids, other drugs active on the central nervous system (CNS) (antidepressants/anticonvulsants), and treatments not specifically targeted to the CNS. RESULTS: Statistically significant differences were seen only with regard to attention between opioids alone and no centrally acting treatment (standardized mean difference [SMD]: -0.53, 95% confidence interval [CI] : -0.91, -0.15; P = 0.007; I2 = 23%) and between opioids combined with antidepressants and/or anticonvulsants and no centrally acting treatment (SMD: -0.62, 95% CI: -1.04, -0.20; P = 0.004; I2 = 0%). No other significant differences were observed. CONCLUSIONS: Opioids reduce attention when compared with treatments not targeted on the CNS. If opioids are used together with antidepressants and/or anticonvulsants, this effect increases. SIGNIFICANCE: These findings on the neuropsychological effects of opioids could be used to generate strategies to refine pain treatments.

Influence of chemotherapeutic drug-related gene polymorphisms on toxicity and survival of early breast cancer patients receiving adjuvant chemotherapy.

BACKGROUND: We investigated whether GSTT1 ("null" allele), GSTM1 ("null"allele), GSTP1 (A313G), RFC1 (G80A), MTHFR (C677T), TS (2R/3R) polymorphisms were associated with toxicity and survival in patients with early breast cancer (EBC) treated with adjuvant chemotherapy (CT). METHODS: This prospective trial included patients with stage I-III BC subjected to CT with CMF or FEC regimens. PCR-RFLP was performed for MTHFR, RFC1 and GSTP1, while PCR for TS, GSTT1 and GSTM1 genes. RESULTS: Among the 244 patients consecutively enrolled, 48.7% were treated with FEC and 51.3% with CMF. Patients with TS2R/3R genotype showed less frequently severe neutropenia (G3/G4) than those with TS2R/2R and 3R/3R genotype (p = 0.038). Patients with MTHFRCT genotype had a higher probability of developing severe neutropenia than those with MTHFR CC genotype (p = 0.043). Patients with RFC1GG or GSTT1-null genotype or their combination (GSTT1-null/RFC1GG) were significantly associated with a shorter disease free survival (DFS) (p = 0.009, p = 0.053, p = 0.003, respectively) and overall survival (OS) (p = 0.036, p = 0.015, p = 0.005, respectively). Multivariate analysis confirmed the association of RFC1GG genotype with a shorter DFS (p = 0.018) and of GSTT1-null genotype of a worse OS (p = 0.003), as well as for the combined genotypes GSTT1-null/RFC1GG, (DFS: p = 0.004 and OS: p = 0.003). CONCLUSIONS: Our data suggest that TS2R/2R and 3R/3R or MTHFR CT genotypes have a potential role in identifying patients with greater risk of toxicity to CMF/FEC and that RFC1 GG and GSTT1-null genotypes alone or in combination could be important markers in predicting clinical outcome in EBC patients.

Radiosurgery for intracranial meningiomas: A systematic review and meta-analysis.

BACKGROUND: Radiosurgery(RS), both in single and multiple sessions, have been performed for intracranial meningiomas. Different aspects are still controversial on this field. The aim of this systematic review is to summarize the current literature on long-term efficacy and safety of RS for meningiomas. METHODS: Online databases were searched for studies published until April 2015. The primary outcomes were disease control and progression-free-survival(PFS). The secondary outcomes were symptom control and radiation-induced toxicity. RESULTS: The estimate of disease control rate ranged from 87.0% to 100.0% at 5 years and from 67.0% to 100.0% at 10 years. The PFS rate ranged 78.0%-98.9% and 53.1%-97.2% at 5 and 10 years, respectively. The overall symptom control was 92.3%, the overall toxicity was 8.1%. CONCLUSIONS: RS can be considered a safe and effective treatment. Efforts are needed in standardizing the definition of local and symptom control and toxicity in order to properly compare different treatment schedules.

Feasibility and outcome of interval debulking surgery (IDS) after carboplatin-paclitaxel-bevacizumab (CPB): A subgroup analysis of the MITO-16A-MaNGO OV2A phase 4 trial.

BACKGROUND: Few data are available on the outcome of surgery after a bevacizumab-containing regimen. The MITO 16A- MaNGO OV2A phase 4 trial evaluates the outcomes of first-line CPB in a clinical-practice-like setting. Here we present the results of the subgroup of patients undergoing IDS after neoadjuvant treatment or suboptimal primary surgery. METHODS: 400 chemonaïve epithelial ovarian cancer patients, age≥18, ECOG PS 0-2 were eligible to receive C (AUC 5 d1, q21) plus P (175mg/m2 d1, q21) and B (15mg/kg d1 q21) for 6cycles followed by B maintenance until cycle 22nd. RESULTS: 79 patients (20%) underwent IDS. Overall, 74 patients received at least one administration of B before IDS. Median age was 61.2, 70% of the patients had FIGO IIIC disease. The median number of cycles before IDS was 3 both for chemotherapy and bevacizumab respectively. A residual disease ≤1cm was achieved in 64 patients (86.5%). Four percent of the patients experienced fever and 4% required blood transfusion after surgery. Surgical wound infection and/or dehiscence, pelvic abscess, intestinal sub-occlusion and fistula were experienced by one patient each. CONCLUSIONS: In the MITO16A-MaNGO OV2A phase 4 trial, combined chemotherapy and bevacizumab did not hamper IDS and the rate of perioperative complications was similar to what expected without bevacizumab. These data support the hypothesis that adding bevacizumab to first line chemotherapy for ovarian cancer might not be denied to patients for whom IDS is planned.

Exploring the Prognostic Role of Microsatellite Instability in Patients With Stage II Colorectal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Many studies have disclosed the prognostic effect of microsatellite instability (MSI) and/or loss of mismatch repair proteins in colorectal cancer. Nevertheless, little evidence supports their role in the decision-making of adjuvant therapy for patients with stage II disease. MATERIALS AND METHODS: The aim of this systematic review was to evaluate the prognostic and/or predictive role of MSI status in patients with stage II colorectal cancer on disease-free survival and overall survival. MEDLINE, EMBASE, and Cochrane libraries were searched to identify eligible studies. RESULTS: Only 2 of 389 articles identified fulfilled the eligibility criteria. In both treated and untreated patients, high-level MSI improved disease-free survival compared with low-level MSI, suggesting a prognostic role but not supporting the hypothesis of a predictive effect of MSI. CONCLUSIONS: Further studies are needed to explore the predictive role of MSI/mismatch repair proteins, because available data do not allow definitive conclusions.

Intraperitoneal Chemotherapy in Patients Pretreated for Ovarian Cancer Matched with Patients Treated with Parenteral Chemotherapy.

BACKGROUND: Our aim was to analyze the impact of intraperitoneal chemotherapy (IPC), administered with direct peritoneal puncture, on the survival of patients with pretreated ovarian cancer in a real-life setting. PATIENTS AND METHODS: This was a retrospective study comparing patients with advanced ovarian cancer treated with IPC (N=33) and patients treated with standard intravenous (i.v.) chemotherapy matching cases for known prognostic factors (age, platinum sensitivity, histological subgroup and grade). Data were then analyzed for survival with nested Cox multivariate regression. RESULTS: The case matching resulted in two homogeneous cohorts by age, platinum sensitivity, resistance to therapy and histology. When analyzed by hazard ratio (HR), the number of previous treatments and IPC vs. i.v. therapy were significant (HR=1.97 for i.v. and HR=1.90 for each incremental previous treatment line, multivariate p<0.001). When analyzing the patients with fewer than three previous treatment lines, IPC conferred a survival advantage of about 2.2 months (IPC=10.0 vs. i.v.=7.8 months, p=0.011). However, the survival advantage in heavily pre-treated patients (with three or more previous treatments) was not significant. One case, pre-treated with more lines of chemotherapy, with renal failure after intraperitoneal cisplatin was followed by death. None of the patients had bowel sub-occlusions and we recorded a lower incidence of local toxicity, such as cellulite, with IPC (two out of 33 cases). Two patients thereafter refused IPC due to abdominal pain. CONCLUSION: Our findings confirm that IPC is an effective approach compared to systemic chemotherapy for advanced ovarian cancer, even in pre-treated patients, including platinum-resistant cases. The survival benefit appears to be confined to non-heavily treated patients. Overall, direct intraperitoneal drug injection (without permanent devices) appears to be feasible, safe and possibly advantageous.

Long-term results of fertility-sparing treatment compared with standard radical surgery for early-stage epithelial ovarian cancer.

BACKGROUND: The objective of this study is to evaluate the safety of fertility-sparing surgery (FSS) for early-stage epithelial ovarian cancer (EOC). METHODS: A retrospective analysis was performed to identify patients treated for early-stage EOC and to compare the clinical outcomes of patients treated with FSS and radical surgery (RS). RESULTS: A total of 1031 patients were treated at two Institutions, 242 with FSS (group A) and 789 with RS (group B). Median duration of follow-up was 11.9 years. At univariate analyses, FSS was associated with decreased risk of relapse (P=0.002) and of tumour-related death (P=0.001). Multivariate analysis did not confirm the independent positive role of FSS neither on relapse-free interval (RFI) nor on cancer-specific survival (CSS). Tumour grade was associated with shorter RFI (P<0.001) and shorter CSS (P=0.001). The type of treatment did not influence CSS or RFI in any grade group. We also found a significant association between low-grade tumours and younger age. CONCLUSIONS: Fertility-sparing surgery is an adequate treatment for patients with stage I EOC. The clinical outcome of patients with G3 tumours, which is confirmed to be the most important prognostic factor, is not determined by the type of treatment received.

Quality of Life in Glaucoma: A Review of the Literature.

The ultimate goal of glaucoma management is the preservation of patients' visual function and quality of life (QoL). The disease itself as well as the medical or surgical treatment can have an enormous impact on a patient's QoL. Even the mere diagnosis of a chronic, irreversible, potentially blinding disorder can adversely affect the patient's sense of well-being and QoL by eliciting significant anxiety. Patients with primary open-angle glaucoma rarely present with visual symptoms, at least early in the course of the disease. A better understanding of patient-reported QoL can improve patient-physician interaction and enhance treatment adherence by customizing treatment options based on individual patient profile, thus optimizing long-term prognosis. These aspects are summarized and critically appraised in this article.

Impact on survival of timing and duration of adjuvant chemotherapy in radically resected gastric cancer.

PURPOSE: Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). METHODS: The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. RESULTS: Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. CONCLUSIONS: Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

Clinical presentation and in-hospital death in acute pulmonary embolism: does cancer matter?

Cancer is one of the most common risk factors for acute pulmonary embolism (PE), but only few studies report on the short-term outcome of patients with PE and a history of cancer. The aim of the study was to assess whether a cancer diagnosis affects the clinical presentation and short-term outcome in patients hospitalized for PE who were included in the Italian Pulmonary Embolism Registry. All-cause and PE-related in-hospital deaths were also analyzed. Out of 1702 patients, 451 (26.5 %) of patients had a diagnosis of cancer: cancer was known at presentation in 365, or diagnosed during the hospital stay for PE in 86 (19 % of cancer patients). Patients with and without cancer were similar concerning clinical status at presentation. Patients with cancer less commonly received thrombolytic therapy, and more often had an inferior vena cava filter inserted. Major or intracranial bleeding was not different between groups. In-hospital all-cause death occurred in 8.4 and 5.9 % of patients with and without cancer, respectively. At multivariate analysis, cancer (OR 2.24, 95 % CI 1.27-3.98; P = 0.006) was an independent predictor of in-hospital death. Clinical instability, PE recurrence, age ≥75 years, recent bed rest ≥3 days, but not cancer, were independent predictors of in-hospital death due to PE. Cancer seems a weaker predictor of all-cause in-hospital death compared to other factors; the mere presence of cancer, without other risk factors, leads to a probability of early death of 2 %. In patients with acute PE, cancer increases the probability of in-hospital all-cause death, but does not seem to affect the clinical presentation or the risk of in-hospital PE-related death.

Role of patient and tumor characteristics in sentinel lymph node metastasis in patients with luminal early breast cancer: an observational study.

Predicting the risk of sentinel lymph node (SLN) metastasis is important for clinical decision-making in the setting of early breast cancer (EBC). This study is aimed to identify tumor and patient characteristics that influenced the SLN metastatic involvement, with a focus on luminal subtypes. An observational study including women treated for EBC from 2005 to 2013 was conducted. Regression analyses were used to assess the association between SLN metastasis and age, menopausal status, tumor size, histological grading, presence of extensive "in situ" carcinoma components, lymphovascular invasion (LVI), and expression of Ki-67, hormone receptors, and HER2. Of 345 women, 84 (24.3 %) had at least one SLN metastasis; 63.1 % were macrometastases. Among all patients, 31.6 % exhibited LVI. In univariate analyses, tumor size, histological grade, and LVI were associated with SLN metastasis. The multivariate model confirmed only the association between LVI and SLN status (OR 3.27, 95 % CI 1.85-5.68; p < 0.0001). Luminal subtypes were detected in 86.1 % of women. In this subgroup, the multivariate model confirmed a significant relationship between LVI and SLN status (OR 3.47, 95 % CI 1.90-6.33; p < 0.0001). Since a proper histopathological assessment of LVI is not possible prior to surgery, this factor cannot be used to guide decisions on performing SLN biopsies. Nevertheless, when a SLN biopsy is refused or contraindicated, an LVI assessment on an excisional biopsy of the tumor could facilitate prognosis determination and treatment management.

Differential Protein Expression Profiles in Glaucomatous Trabecular Meshwork: An Evaluation Study on a Small Primary Open Angle Glaucoma Population.

INTRODUCTION: Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by impaired aqueous outflow and extensive remodeling in the trabecular meshwork (TM). The aim of this study was to characterize and compare the expression patterns of selected proteins belonging to the tissue remodeling, inflammation and growth factor pathways in ex vivo glaucomatous and post-mortem TMs using protein-array analysis. METHODS: TM specimens were collected from 63 white subjects, including 40 patients with glaucoma and 23 controls. Forty POAG TMs were collected at the time of surgery and 23 post-mortem specimens were from non-glaucomatous donor sclerocorneal tissues. Protein profiles were evaluated using a chip-based array consisting of 60 literature-selected antibodies. RESULTS: A different expression of some factors was observed in POAG TMs with respect to post-mortem specimens, either in abundance (interleukin [IL]10, IL6, IL5, IL7, IL12, IL3, macrophage inflammatory protein [MIP]1δ/α, vascular endothelial growth factor [VEGF], transforming growth factor beta 1 [TGFß1], soluble tumor necrosis factor receptor I [sTNFRI]) or in scarcity (IL16, IL18, intercellular adhesion molecule 3 [ICAM3], matrix metalloproteinase-7 [MMP7], tissue inhibitor of metalloproteinase 1 [TIMP1]). MMP2, MMP7, TGFß1, and VEGF expressions were confirmed by Western blot, zymography, and polymerase chain reaction. No difference in protein profile expression was detected between glaucomatous subtypes. CONCLUSION: The analysis of this small TM population highlighted some proteins linked to POAG, some previously reported and others of new detection (IL7, MIPs, sTNFαRI). A larger POAG population is required to select promising disease-associated biomarker candidates. FUNDING: This study was partially supported by the Fondazione Roma, the Italian Ministry of Health and the "National 5xMille 2010 tax donation to IRCCS-G.B. Bietti Foundation".

Needle Revision With 5-fluorouracil for the Treatment of Ahmed Glaucoma Valve Filtering Blebs: 5-Fluoruracil Needling Revision can be a Useful and Safe Tool in the Management of Failing Ahmed Glaucoma Valve Filtering Blebs.

PURPOSE: To determine the outcome of needling with adjunctive 5-fluorouracil (5-FU) in patients with a failing Ahmed glaucoma valve (AGV) implant, and to identify predictors of long-term intraocular pressure (IOP) control. METHODS: A prospective observational study was performed on consecutive patients with medically uncontrolled primary open-angle glaucoma (POAG) with AGV encapsulation or fibrosis and inadequate IOP control. Bleb needling with 5-FU injection (0.1 mL of 50 mg/mL) was performed at the slit-lamp. Patients were examined 1 week following the needling, and then at months 1, 3, and 6. Subsequent follow-up visits were scheduled at 6-month intervals for at least 2 years. Needling with 5-FU was repeated no more than twice during the first 3 months of the follow-up. Procedure outcome was determined on the basis of the recorded IOP levels. RESULTS: Thirty-six patients with an encapsulated or fibrotic AGV underwent 67procedures (mean 1.86 ± 0.83). Complete success, defined as IOP ≤ 18 mm Hg without medications, was obtained in 25% at 24 months of observation. The cumulative proportion of cases achieving either qualified (ie, IOP ≤ 18 mm Hg with medications) or complete success at 24 months of observation was 72.2%. In a univariate Cox proportional hazards model, age was the only variable that independently influenced the risk of failing 5-FU needling revision. Fourteen eyes (38.8%) had a documented complication. CONCLUSIONS: Needling over the plate of an AGV supplemented with 5-FU is an effective and safe choice in a significant proportion of POAG patients with elevated IOP due to encapsulation or fibrosis.

ACROSCORE: a new and simple tool for the diagnosis of acromegaly, a rare and underdiagnosed disease.

OBJECTIVE: Acromegaly, a disease caused by GH/IGF-I hypersecretion, is associated with a high mortality rate; early recognition is therefore necessary to ensure successful treatment and to avoid comorbidities. We have created a symptom/sign scoring tool (ACROSCORE) for physicians to use to identify acromegaly. DESIGN: To compare cases of acromegaly diagnosed between 1990 and 2014 against a control group affected by non-GH-secreting pituitary tumours to identify symptoms and signs that are most discriminative for acromegaly. PATIENTS: Confirmed acromegaly patients and patients affected by non-GH-secreting pituitary tumours. MEASUREMENTS: In all patients, signs, symptoms and comorbidities were recorded from medical records and collected using a specifically designed questionnaire. RESULTS: A total of 194 acromegaly patients [115 women; mean (SD) age 47·2 (14·2) years] and 243 patients affected by non-GH-secreting pituitary tumours [131 women; mean (SD) age 45·8 (15·8) years] were included. A strong association was observed for type 2/secondary diabetes [odds ratio (OR) 3·7], hyperhidrosis (OR 6·1), thyroid hyperplasia (OR 13·9), colorectal polyps (OR 10·4), spaced teeth (OR 25·4) and carpal tunnel syndrome (OR 4·3). Based on this information, a multivariable logistic model was built and a 14-point scoring system developed. A score of 0 excludes the risk of acromegaly [positive predictive value (PV(+)) = 0·6%]; scores 1-5 comprise a grey area; scores >5 indicate that a diagnosis of acromegaly cannot be excluded (PV(+) = 46·1%). CONCLUSIONS: Once validated in independent studies, ACROSCORE may represent a new tool for the clinical screening of acromegaly that can be used by general practitioners and nonendocrinology specialists.

Health-related quality of life in patients with primary open-angle glaucoma. An Italian multicentre observational study.

PURPOSE: As a progressive condition, glaucoma may impair health-related quality of life (HRQoL), due to vision loss and other factors. This study evaluated HRQoL in a cohort of patients treated for primary open-angle glaucoma (POAG) and assessed its association with clinical features. METHODS: This was an Italian, multicentre, cross-sectional, observational study with the subgroup of newly diagnosed patients with POAG prospectively followed up for one year. Patients with previous or new diagnosis (or strong clinical suspicion) of POAG aged >18 years were considered eligible. Information was collected on demographic characteristics, medical history, clinical presentation and POAG treatments. HRQoL was measured using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and Glaucoma Symptom Scale (GSS). Subscale and total scores were obtained and a Pearson correlation coefficient between instruments' scores calculated. RESULTS: A total of 3227 patients were enrolled from 2012 to 2013 and 3169 were analysed. Mean age was 66.9 years. A total of 93.8% had a previous diagnosis (median duration: 8.0 years). Median values for mean deviation and pattern standard deviation were 3.9 and 3.6 dB, respectively. Mean scores on most subscales of the NEI-VFQ-25 exceeded 75.0 and mean GSS subscale scores ranged between 70.8 and 79.7 (with a total mean score of 74.8). HRQoL scores on both scales were significantly inversely associated with POAG severity. CONCLUSION: In this large sample of Italians treated for POAG, disease severity was limited and HRQoL scores were high. QoL decreased with advancing disease severity. These findings confirm the role of vision loss in impairing QoL in POAG, underlying the importance of timely detection and appropriate treatment.

Osteopontin, E-cadherin, and ß-catenin expression as prognostic biomarkers in patients with radically resected gastric cancer.

A correlation between osteopontin, E-cadherin, ß-catenin, and cyclooxygenase 2 overexpression and poor clinicopathological features and prognosis has been previously suggested in gastric cancer. This translational study was aimed at assessing the correlation of these immunohistochemical biomarkers with outcome in patients with radically resected gastric cancer. We analyzed osteopontin, E-cadherin, ß-catenin, and cyclooxygenase 2 expression by immunohistochemistry in 346 primary gastric tumor tissue samples from patients enrolled in the ITACA-S trial. This phase III study randomized patients with radically resected gastric cancer to receive adjuvant chemotherapy with either 5-fluorouracil and leucovorin or a sequential regimen of infusional 5-fluorouracil and leucovorin plus irinotecan followed by cisplatin and docetaxel. High expression of osteopontin was correlated with high histological grade, diffuse histotype, and peritoneal relapse, but not with TNM stage. Moreover, osteopontin overexpression was associated with higher risk of tumor recurrence and metastases, and was an independent prognostic factor for both relapse-free and overall survival of gastric cancer patients following adjuvant chemotherapy. Abnormal E-cadherin expression and abnormal ß-catenin expression were correlated with more advanced disease stage, and as a consequence, with poor outcome. Our results suggest that osteopontin overexpression is a valuable independent predictor of tumor recurrence and survival in patients with radically resected gastric cancer.

KRAS mutations affect prognosis of non-small-cell lung cancer patients treated with first-line platinum containing chemotherapy.

UNLABELLED: KRAS mutations seem to indicate a poor outcome in Non-Small-Cell Lung Cancer (NSCLC) but such evidence is still debated. The aim of this planned ancillary study within the TAILOR trial was to assess the prognostic value of KRAS mutations in advanced NSCLC patients treated with platinum-based first-line chemotherapy. Patients (N = 540), enrolled in the study in 52 Italian hospitals, were centrally genotyped twice in two independent laboratories for EGFR and KRAS mutational status.Of these, 247 patients were eligible and included in the present study. The primary endpoint was overall survival (OS) according to KRAS mutational status in patients harboring EGFR wild-type.Sixty (24.3%) out of 247 patients harbored KRAS mutations. Median OS was 14.3 months and 10.6 months in wild-type and mutated KRAS patients, respectively (unadjusted Hazard Ratio [HR]=1.41, 95%Confidence Interval [CI]: 1.03-1.94 P = 0.032; adjusted HR=1.39, 95%CI: 1.00-1.94 P = 0.050). This study, with all consecutive patients genotyped, indicates that the presence of KRAS mutations has a mild negative impact on OS in advanced NSCLC patient treated with a first-line platinum-containing regimen. TRIAL REGISTRATION: clinicaltrials.gov identifierNCT00637910.

Long-Term Clinical Benefits of Neoadjuvant Chemotherapy in Women With Locally Advanced Cervical Cancer: Validity of Pathological Response as Surrogate Endpoint of Survival.

OBJECTIVE: Neoadjuvant chemotherapy (NACT) is a valid treatment option for women with locally advanced cervical cancer (LACC). This study aims to evaluate the impact of sociodemographic factors, clinical factors, and NACT regimens on survival endpoints. The role of pathological response to NACT as a surrogate endpoint of survival was also assessed. MATERIALS AND METHODS: Retrospective analysis of consecutive sample data from women with LACC (stages Ib2-IVa) who underwent NACT followed by radical surgery was performed. Response was classified as optimal response (including complete response and optimal partial response), suboptimal partial response, stable disease, and progressive disease. RESULTS: Four hundred forty-six women who had undergone surgery from 1992 to 2011 were analyzed. The overall optimal response was 35.4%. At a median follow-up of 12.7 years, 165 women (37.0%) experienced recurrence or died. Increase in patient age at surgery, International Federation of Gynecology and Obstetrics stage III/IV versus stage Ib2, and lymph-node positivity versus negativity seemed to impact negatively on survival, whereas neoadjuvant platinum-Taxol-containing regimens (compared with platinum-based regimens) improved survival. Response to NACT could be considered a surrogate endpoint of survival. CONCLUSIONS: Age, International Federation of Gynecology and Obstetrics stage III/IV, lymph-node involvement, and type of NACT administered have a significant impact on survival. Response to NACT is a good surrogate endpoint of survival in patients with LACC.

Estimating the risk of chemotherapy toxicity in older patients with cancer: The role of the Vulnerable Elders Survey-13 (VES-13).

OBJECTIVE: Some parameters of the Comprehensive Geriatric Assessment (CGA) are predictive of chemotherapy toxicity. The Vulnerable Elders Survey-13 (VES-13) is a short instrument that has been tested as a means of identifying patients who need a full CGA, but its ability to predict chemotherapy toxicity is still unclear. We performed a pooled analysis of four published clinical trials studying VES-13 as a means of diagnosing vulnerability, in order to evaluate its accuracy in predicting the risk of grade 3/4 toxicity in older patients undergoing chemotherapy. MATERIALS AND METHODS: The study involved patients aged ≥ 66 years with a diagnosis of solid or hematological cancer, all of whom were administered VES-13. The number of medications taken by each patient, their comorbidities, their Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score and index, the type of chemotherapy and treatment line, and their Mini Mental State Evaluation (MMSE), and Mini Nutritional Assessment (MNA) scores were recorded. Information was available concerning the grades 3-4 hematological and non-hematological toxicities experienced by each patient. RESULTS: The study involved 648 patients aged ≥ 66 years (mean age 76.2±4.5, range 66-90) of whom 336 (51.9%) were female. VES-13 identified 287 patients (44.3%) as vulnerable. Grades 3-4 hematological and non-hematological toxicities were more prevalent in the vulnerable subjects (35.2% vs 20.8%, p<0.0001, and 18.5% vs 10.8%, p=0.0055), who were also at higher risk of both (adjusted ORs 2.15, 95% CI 1.46-3.17, p<0.001); and 1.66 (95% CI 1.02-2.72, p=0.043). CONCLUSIONS: VES-13 could be considered to be a good candidate for future prospective studies to assess older patients with cancer at risk of toxicity.