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Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC.

We assessed the predictive accuracy of the Warfarin Pharmacogenetics Consortium (IWPC) algorithm in a prospective cohort of 376 high-risk elderly patients (≥65 years) who required new treatment with warfarin for either medical (non valvular atrial fibrillation) or surgical conditions (heart valve replacement), had ≥1 comorbid conditions, and regularly used ≥2 other drugs. Follow-up visits were performed according to clinical practice and lasted for a maximum of 1 year. Two hundred and eighty-three (75%) patients achieved a stable maintenance dose. Warfarin maintenance doses were low on average (median 20.3 mg/week, interquartile range, 14.1–27.7 mg/week) and were substantially overestimated by the IWPC algorithm. Overall the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable dose was equal to 37.5%, (95% CI 32.0–43.3%). IWPC algorithm explained only 31% of the actual warfarin dose variability. Modifications of the IWPC algorithm are needed in high-risk elderly people.

The Systolic Blood Pressure Intervention Trial-CKD substudy (SPRINT-CKD) has suggested a lower blood pressure (BP) target in CKD patients. However, it is questionable whether the SPRINT-CKD results may be generalized to CKD patients under nephrology care. To compare SPRINT-CKD cohort versus referred CKD patients in terms of patients’ risk profile and outcomes, we pooled four prospective cohorts of consecutive CKD patients referred to 40 Italian renal clinics. We implemented the same inclusion/exclusion criteria adopted in SPRINT and same endpoints: (1) a composite of fatal and non-fatal cardiovascular (CV) events (2) all-cause mortality and (3) ESRD (composite of chronic dialysis, transplantation or 50% eGFR decline). Findings were compared with those attained in the control arm of SPRINT-CKD trial that mirrored standard BP management in clinical practice. Out of 2847 patients referred to renal clinics, only 20.1% (n = 571) were identified as eligible for SPRINT-CKD. Age (72 ± 9 years), gender (42.2% female) and systolic BP (142 ± 10 mmHg) did not differ from the SPRINT-CKD while referred patients had a worse risk profile at baseline: larger prevalence of prior CV disease (25.7% versus 19.5%), higher Framingham risk score (31.9 ± 14.6% versus 27.2 ± 24.7%) and lower GFR (38 ± 11 versus 48 ± 10 mL/min/1.73 m2). During 4.0 years of follow-up, 86 CV events (50 fatal), 78 all-cause death and 59 ESRD occurred with annual incidence rates higher than those observed in the SPRINT-CKD control group (CV events 4.18 vs 3.19; all-cause death 3.64 vs 2.21; ESRD 2.80 vs 0.41%/year). The SPRINT-CKD cohort is poorly representative of the CKD population under nephrology care, thus suggesting that conclusions may not apply to patients referred to nephrologist.

To assess the role of clinical, biochemical, and morphological parameters, as added to cytology, for improving pre-surgical diagnosis of palpable thyroid nodules. Patients with a palpable thyroid nodule were eligible if surgical intervention was indicated after a positive or suspicious for malignancy FNAC (TIR 4–5 according to the 2007 Italian SIAPEC-IAP classification), or two inconclusive FNAC at a ≥3 months interval, or a negative FNAC associated with one or more risk factor. Reference standard was histological malignancy diagnosis. Likelihood ratios of malignancy, sensitivity, specificity, negative (NPV), and positive predictive value (PPV) were described. Multiple correspondence analysis (MCA) and logistic regression were applied. Cancer was found in 433/902 (48%) patients. Considering TIR4–5 only as positive cytology, specificity, and PPV were high (94 and 91%) but sensitivity and NPV were low (61 and 72%); conversely, including TIR3 among positive, sensitivity and NPV were higher (88 and 82%) while specificity and PPV decreased (52 and 63%). Ultrasonographic size ≥3 cm was independently associated with benignity among TIR2 cases (OR of malignancy 0.37, 95% CI 0.18–0.78). In TIR3 cases the hard consistency of small nodules was associated with malignity (OR: 3.51, 95% CI 1.84–6.70, p< 0.001), while size alone, irrespective of consistency, was not diagnostically informative. No other significant association was found in TIR2 and TIR3. The combination of cytology with clinical and ultrasonographic parameters may improve diagnostic definition of palpable thyroid nodules. However, the need for innovative diagnostic tools is still high.

Potential health hazards for the environment and people living nearby landfills and incinerators are claimed to be related to several methods of waste management. Independent systematic review of the scientific literature is a key procedure to support the lay public and policy makers to achieve informed decisions.The study design and potential biases of papers retrieved in this comprehensive literature search were analyzed.The most consistent result is that the risks of congenital anomalies and hospitalization due to respiratory disease are likely to be real nearby special waste landfills. From the very little information on exclusively urban waste depots it is reasonable to say that correct management of landfill does not increase the risk of these health effects. It is confirmed that historically incinerators are an important source of pollution and harm for the health of populations living nearby; however, changes in technology are producing more reassuring results.A moderate level of confidence is possible in limited areas of knowledge, implying the need to overcome the limitations of current studies about exposure assessment and to control confounders at the individual level.

The TORCH (Tarceva or Chemotherapy) trial randomized patients with advanced non–small-cell lung cancer to first-line erlotinib followed by second-line cisplatin/gemcitabine versus. standard inverse sequence. The trial, designed to test noninferiority in overall survival, was stopped at interim analysis because of inferior survival in the experimental arm. Quality of life (QoL), a secondary outcome, is reported here.

Aims and Background An appropriate use of drugs should follow the registered indications. Different reasons can induce oncologists to prescribe drugs off-label. The aim of this study was to describe incidence and characteristics of these prescriptions in Italy.Methods Patients submitted to chemotherapy in 15 Italian oncology centers were evaluated for two randomized non-consecutive days of two weeks in May 2006.Results The study enrolled 644 patients receiving 1,053 drugs. Overall, 199 of 1053 (18.9%) prescriptions were off-label. In 92 of 199 cases (46.2%), the drugs were used for a neoplasm for which they were not approved, but there was scientific evidence (one or more randomized clinical trials or more phase II studies published in a major oncology journal) justifying the prescription. In 27 cases (13.6%), the drugs were prescribed for a rare neoplasm (cisplatin and gemcitabine in mesothelioma). In 20/21 cases (10.1%/10.5%), drugs were used in association/alone in contrast with the approved use (capecitabine in association in colorectal cancer). In 28/11 cases (14.0%/5.6%), the drugs were used in lines of chemotherapy subsequent/previous to that approved.Conclusions Off-label use of antineoplastic drugs, in this observational survey, represents less than 20% of the prescriptions, and most of them are based on scientific evidence of efficacy.

Herein, we present a randomized phase III Italian-Canadian trial named TORCH (Tarceva or Chemotherapy). In TORCH, we are investigating whether erlotinib as first-line therapy until progression followed by chemotherapy with cisplatin/gemcitabine will not be inferior in terms of survival to the standard arm, consisting of first-line cisplatin/gemcitabine for 6 cycles, followed at progression by erlotinib until second progression. The primary objective is overall survival, and an adjunctive primary endpoint is activity of first-line treatment with erlotinib in terms of progression-free rate after 9 weeks of treatment. Secondary objectives include response rate, progression-free survival, toxicity, quality of life, and exploratory evaluations of tumor tissue and blood samples for biologic or genomic determinants of outcome. The study design is based on a noninferiority survival comparison with about 900 patients expected to be recruited. An early analysis of activity will be performed in the experimental arm (first-line erlotinib followed by chemotherapy).

The objective of the current study was to compare, in a large multicenter study, the discriminating accuracy of four prognostic models developed to predict the survival of patients undergoing nephrectomy for nonmetastatic renal cell carcinoma (RCC).A total of 2404 records of patients from 6 European centers were retrospectively reviewed. For each patient, prognostic scores were calculated according to four models: the Kattan model, the University of California at Los Angeles integrated staging system (UISS) model, the Yaycioglu model, and the Cindolo model. Survival curves were estimated by the Kaplan–Meier method and compared by the log‐rank test. Discriminating ability was assessed by the Harrell c‐index for censored data. The primary end point was overall survival (OS), and the secondary end points were cancer‐specific survival (CSS) and disease recurrence‐free survival (RFS).At last follow‐up, 541 subjects had died of any causes, with a 5‐year OS rate of 80%. The 5‐year CSS and RFS rates were 85% and 78%, respectively. All models discriminated well (P < 0.0001). The c‐indexes for OS were 0.706 for the Kattan nomogram, 0.683 for the UISS model, and 0.589 and 0.615 for the Yaycioglu and Cindolo models, respectively. The Kattan nomogram was found to improve discrimination substantially in the UISS intermediate‐risk patients.The current study appears to better define the general applicability of prognostic models for predicting survival in patients with nonmetastatic RCC treated with nephrectomy. The results suggest that postoperative models discriminate substantially better than preoperative ones. The Kattan model was consistently found to be the most accurate, although the UISS model was only slightly less well performing. The Kattan model can be useful in the UISS intermediate‐risk patients. Cancer 2005. © 2005 American Cancer Society.

Background Clinical trials with non-profit promoters are frequently performed in oncology and represent a highly valuable source of information.Methods To describe the costs of insurance policies and their determinants, data were collected from 12 Italian non-profit promoters of cancer trials. The cost of policies was expressed as per-patient premium.Results Sixty-two quotations issued by only two companies were collected, relative to 44 trials proposed for quotation between December 1998 and February 2003. Only the date of quotation was significantly associated with the cost (P = 0.0003) of quotations by Company A for policies with a deductible, with cost increasing over time. Date of quotation (P = 0.0002), sample size (P = 0.008) and number of study arms (P = 0.02) were independently associated with the cost of no-deductible policies quoted by Company A. Only the number of study arms was significantly associated with cost (P = 0.0001) in no-deductible policies quoted by Company B.Conclusion There is insufficient competition among companies for insurance of cancer trials with non-profit promoters. Many variables that affect the trial risk profile from a clinical perspective are not associated with insurance cost. Date of quotation is among the strongest determinants of the cost, which has sharply increased over time. This trend may become a serious problem for non-profit promoters of cancer clinical trials.

Colorectal cancer is one of the most common cancers in the elderly. Information on tolerability and efficacy of 5-Fluorouracil-based chemotherapy in such patients is limited. Primary aim of the study was to describe tolerability and activity of chemotherapy with the “de Gramont” schedule (FU bolus 400 mg/m2FU continuous infusion 600 mg/m2folinic acid 100 mg/m2on days 1 and 2, every 2 weeks), in patients with advanced colorectal cancer aged 70 or older.

Patients with small hepatocellular carcinoma (HCC) are usually treated with hepatic resection or percutaneous ethanol injection (PEI).

Background:Following the demonstration that vinorelbine improves survival and quality of life compared with best supportive care in elderly patients with advanced non-small-cell lung cancer (NSCLC), we started the three-arm prospective Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial of vinorelbine, gemcitabine and gemcitabine+vinorelbine. Design:Within the randomized phase 3 trial, pilot single-stage phase 2 studies were planned for gemcitabine and for gemcitabine+vinorelbine. Eligible patients are aged 70 or more, with stage IV or IIIb (with metastatic supraclavear nodes or malignant pleural effusion) NSCLC. Single-agent gemcitabine is given at 1200 mg/m2on days 1 and 8; in the combination, gemcitabine is given at 1000 mg/m2and vinorelbine at 25 mg/m2, both on days 1 and 8, every 3 weeks. Results:As planned 49 patients were enrolled in each group. Median age was 74 in both groups. Two-thirds of patients had stage IV disease. The response rate was 18.4% (95% exact CI 8.8–32.0) with both treatments. With single-agent gemcitabine main toxicities were grade 4 thrombocytopenia and grade 2 hepatic toxicity, in one patient each, and grade 2 pulmonary toxicity in two patients. With gemcitabine+vinorelbine combination there were grade 4 neutropenia and thrombocytopenia (one patient each), grade 3 anemia requiring red blood cell transfusion (two patients), and grade 4 fever in two patients. Four patients, with severe cardiac comorbidities, suffered grade 3 heart toxicity with atrial flutter or fibrillation, followed by congestive heart failure responsive to treatment. Conclusion:Both single-agent gemcitabine and the gemcitabine+vinorelbine combination are sufficiently active and tolerable to allow continuation of the MILES study.

IMPORTANCE: Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited. OBJECTIVE: To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis. DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized clinical phase 3 trial was conducted from May 8, 2012, to December 9, 2015, at 3 Italian centers. Patients aged 18 to 75 years with unresectable, previously untreated, or single line–treated mCRC were recruited. Follow-up was completed December 31, 2019, and data were analyzed from February 26 to July 24, 2020. INTERVENTIONS: Patients received 12 biweekly cycles of standard oxaliplatin-based regimens (modified FOLFOX-6 [levo–folinic acid, fluorouracil, and oxaliplatin]/modified CAPOX [capecitabine and oxaliplatin]) plus bevacizumab administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm). MAIN OUTCOMES AND MEASURES: The primary end point was the objective response rate (ORR) measured with Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival, overall survival, safety, and quality of life (QOL). RESULTS: Overall, 230 patients (136 men [59.1%]; median age, 62.3 [interquartile range, 53.3-67.6] years) were randomly assigned to the standard arm (n?=?115) or the experimental arm (n?=?115). The median duration of follow-up was 68.3 (95% CI, 61.0-70.0) months. No difference in ORR (57.4% [95% CI, 47.8%-66.6%] in the standard arm and 56.5% [95% CI, 47.0-65.7] in the experimental arm; P?=?.89) or progression-free survival (10.5 [95% CI, 9.1-12.3] months in the standard arm and 11.7 [95% CI, 9.9-12.9] months in the experimental arm; P?=?.15) was observed. However, the median overall survival was 29.8 (95% CI, 22.5-41.1) months in the experimental arm compared with 24.1 (95% CI, 18.6-29.8) months in the standard arm (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.99; P?=?.04). Moreover, the experimental arm was associated with a significant reduction in the rate of severe diarrhea (6 [5.3%] vs 19 [16.5%]; P?=?.006) and nausea (2 [1.8%] vs 8 [7.0%]; P?=?.05) and improved physical functioning (mean [SD] change from baseline, 0.65 [1.96] vs -7.41 [2.95] at 24 weeks; P = .02), and constipation scores (mean [SD] change from baseline, -17.2 [3.73] vs -0.62 [4.44]; P = .003). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, sequential administration of bevacizumab plus chemotherapy did not improve ORR, the primary end point. However, the overall survival advantage, fewer adverse effects, and better health-related QOL associated with sequential bevacizumab administration might provide the basis for exploring antiangiogenic combination treatments with innovative perspectives. TRIAL REGISTRATION: EudraCT Identifier: 2011-004997-27; ClinicalTrials.gov Identifier: NCT01718873

Aims and Background It has been demonstrated that breast cancer screening induces a 30% reduction of specific mortality. In May 1990, we started a pilot screening program to assess the feasibility of carrying out such a program in Campania (southern Italy). Herein we report the results of the first round of the program from three municipalities (Giugliano, Mugnano and Qualiano) that lie within the local health district no. 23, close to the city of Naples.Methods Women between the ages of 50 and 69 years were sent a personalized letter inviting them to attend the screening test; those not responding were sent a second invitation. The screening test consisted of clinical examination followed by two-view mammography. Second–level diagnostic tools were sonography, fine needle aspiration (manual, echo-guided and stereotaxic) and surgical biopsy.Results Out of 5,732 women invited for the first round, 1,813 (31.6%) attended the screening. Attendance rate was higher among younger women. Ninety-one women were positive at the screening test and underwent further examination (recall rate, 5.0%). Among them, 19 had surgical biopsy (biopsy rate, 1.0%) that led to breast cancer diagnosis in 11 cases. The benign/malignant biopsy rate was 0.73. Detection rate was 6.07 × 1,000 screened women and varied among age categories, increasing within the 60–69 subgroup; detection rate/expected incidence ratio in the overall group was 4.5 and also increased within the older age category. Seven out of 11 cancers were at UICC stage 0-I. Among 327 self-referring women, 38 were positive (recall rate, 11.6%), and 14 underwent biopsy (biopsy rate, 4.3%), which showed cancer in 7 cases (benign/malignant biopsy rate, 1.0). In addition, 2 inflammatory cancers were diagnosed without surgical biopsy. Thus 9 cancer cases were detected in this group. Self-referring women differed from responding women in that they had a higher frequency of symptoms or familiar history of cancer, and a higher educational level and awareness of preventive medicine. Clinical examination added no diagnostic advantage in the responding group but did not significantly worsen the recall rate. In the self-referring group, one case of inflammatory cancer was missed by mammography and diagnosed by clinical examination.Conclusion The early results (recall rate = 5%, detection rate/expected incidence ratio = 4.5, benign/malignant biopsy rate = 0.73, advanced cancers = 36.4%) are encouraging and indicate the validity of the program. Strategies to improve attendance rate are planned.

Summary Ten year disease-free survival (DFS) results of the Naples randomized trial of adjuvant tamoxifen (TM), 30 mg per day for 2 years versus no therapy according to receptor levels, are reported. From Feb. 1, 1978, through Dec. 31, 1983, 308 pre- and postmenopausal patients with early breast cancer entered the trial. Estrogen receptor (ER) data were available on 239 (77.6%) patients, progesterone receptor (PgR) data on 194 (63.0%), and both receptor data on 181 (58.8%).

Tocilizumab, an IL-6 receptor antagonist, was suggested as a possible treatment of severe or critical COVID-19 pneumonia in a small Chinese study. The TOCIVID-19 trial evaluates efficacy and tolerability of tocilizumab in the treatment of patients with severe or critical COVID-19 pneumonia.

When is chemotherapy too well tolerated? This Viewpoint discusses the possibilities that some patients receive inadequate doses of chemotherapy using the conventional dose calculation method based on body surface area and that a correlation between hematological toxicity and treatment efficacy could be used to titrate therapy.