Sorafenib as first- or second-line therapy in patients with metastatic renal cell carcinoma in a community setting.

AIM: The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. PATIENTS & METHODS: Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). RESULTS: Median OS was 17.2 months (95% CI: 15.5-19.6): 19.9 months (95% CI: 15.9-25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1-18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9-6.7): 6.6 (95% CI: 4.9-9.3) and 5.3 months (95% CI: 4.3-6.0) in first- and second-line patients, respectively. CONCLUSION: The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.

Chemotherapy-induced nausea and vomiting in Italian cancer centers: results of CINVDAY, a prospective, multicenter study.

PURPOSE: Guideline consistency in the prevention of chemotherapy-induced nausea and vomiting (CINV) remains low (29% in the Pan European Emesis Registry study) and very low (11%) in regimens with a high emetogenic risk. The aim of this study was to evaluate the guideline consistency of CINV prophylaxis for acute emesis in daily clinical practice in Italy. METHODS: This was a prospective, observational, multicenter study. Patients scheduled to receive antitumor treatment on a single prespecified day were included. Data on patient characteristics (demographic and clinical), type of anticancer therapy, and type of antiemetic therapy prescribed for acute emesis were collected on electronic data capture forms. Chemotherapy regimens and antiemetic prophylaxis were categorized according to the MASCC 2011 guidelines. The study was approved by the local ethics committees. RESULTS: From July 2013 to February 2014, a total of 502 patients were enrolled at 26 study sites. Median age was 62 years (range 27-87 years). Colorectal cancer and breast cancer were the most common malignancies. The emetogenic potential of the chemotherapy regimens used was high (HEC) (23.7%), moderate (MEC) (40.6%), low (31.3%) or minimal (4.4%). Overall, guideline consistency was 19.3%. Consistency reached 45% when the various 5HT3 receptor antagonists were considered equivalent and interchangeable in MEC regimens. Adherence to guidelines was lowest for MEC and Minimal risk groups. Ten percent of patients in HEC and MEC regimens did not receive any 5HT3 receptor antagonists. NK1 receptor antagonists were used in 8% of all regimens. CONCLUSIONS: Our study indicates that antiemetic guideline inconsistency remains an issue in daily clinical oncology practice in Italy.

The evolution of technological strategies in the prevention of dialysis water pollution: sixteen years' experience.

AIM: This report attempts to illustrate the positive impact on the quality of dialysis water produced over a 16-year period through the progressive optimization of technological procedures. METHODS: Fundamental steps included the following: elimination of polyvinyl chloride (PVC), periodical controls, introduction of stainless steel and/or polyethylene polymer and substitution of single-pass reverse osmosis (SRO) with double-pass reverse osmosis (DRO). Daily overnight automatic thermal disinfection of distribution piping rings represented the final step. RESULTS: A dramatic improvement was observed in 645 water samples obtained from distribution piping. The measures applied resulted in a significant improvement of water quality, featuring levels of colony-forming units per milliliter ranging from 247.4 ± 393.7 in the presence of PVC and SRO to 14.1 ± 28.0 with stainless steel and DRO and 2.8 ± 3.2 with cross-linked polyethylene thermoplastic polymer and DRO (p < 0.01). CONCLUSIONS: Dialysis water should be viewed by nephrologists as a medicinal product, and every effort should be made to ensure a high-quality liquid.

Microbiological surveillance and state of the art technological strategies for the prevention of dialysis water pollution.

METHODS: The present report attempts to illustrate the positive impact on the microbiological quality of dialysis patients over a 15-year period through the progressive implementation of state-of-the-art technological strategies and the optimization of microbiological surveillance procedures in five dialysis units in Sardinia. RESULTS: Following on better microbiological, quality controls of dialysis water and improvement of procedures and equipment, a drastic improvement of microbiological water quality was observed in a total of 945 samples. The main aim was to introduce the use of microbiological culture methods as recommended by the most important guidelines. The microbiological results obtained have led to a progressive refining of controls and introduction of new materials and equipment, including two-stage osmosis and piping distribution rings featuring a greater capacity to prevent biofilm adhesion. The actions undertaken have resulted in unexpected quality improvements. CONCLUSIONS: Dialysis water should be viewed by the nephrologist as a medicinal product exerting a demonstrable positive impact on microinflammation in dialysis patients. A synergic effort between nephrologists and microbiologists undoubtedly constitutes the most effective means of preventing dialysis infections.

Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia.

BACKGROUND: Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC) has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia. METHODS: From April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478) were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing. RESULTS: Overall, KRAS tumour mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was surprisingly different within the island: 87/204 (43%) in North Sardinia vs. 58/274 (21%) in Middle-South Sardinia (p<0.001). Among 384 CRC cases whose DNA was available, only one (0.3%) patient carried a mutation in BRAF gene; PIK3CA was found mutated in 67 (17%) patients. A significant inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 19/183 (10%) cases from northern vs. 48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies of KRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy. CONCLUSIONS: Our findings support the hypothesis that differences in patients' origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.

Macroalgae and DGT as indicators of available trace metals in marine coastal waters near a lead-zinc smelter.

The levels of Cd, Cu, Pb, and Zn were determined in the commonest species of green, red, and brown algae collected from five coastal sites in south-western Sardinia (Italy), an area with a long history of mining and smelting. The usefulness of employing Enteromorpha sp. and Padina pavonica (L.) Thivy to monitor metal pollution was evaluated, while diffusive gradients in thin films (DGT) devices were used to measure dissolved metals in seawater. Levels of Cd and Pb were high enough to be of environmental concern in the whole study area. A significant relationship was found between the content of Pb in P. pavonica and DGT-labile Pb in seawater, suggesting that gross elemental concentrations of nonessential metals such as Pb in algal tissues are apparently controlled by the abundance of dissolved metal species in the ambient seawater. The results pointed out the usefulness of using both DGT and algal methods for a better understanding of trace metal availability in coastal waters.

A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population.

BACKGROUND: In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. METHODS: Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. RESULTS AND CONCLUSION: Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764_8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations.

Prospective, multicenter, randomized trial of a new organizational modality for providing information and support to cancer patients.

PURPOSE: No structured modality for providing information and support to patients in oncology wards has been validated in clinical trials. METHODS: This is a pragmatic, two-arm, cluster randomized trial, with the oncology ward as random assignment unit. Centers were allocated to implement a Point of Information and Support (PIS) or to a control group. The PIS included a library for cancer patients and a specifically trained oncology nurse. End points, measured at patient level, were psychological distress and satisfaction with received information. Both intent-to-treat and per-protocol analyses considering clustering were performed. RESULTS: Thirty-eight Italian cancer centers were randomly assigned, and 6 months after PIS creation, 3,286 unselected, consecutive cancer patients were surveyed (1,654 in the experimental group and 1,632 in the control group). Three thousand one hundred ninety-seven (97%) questionnaires were collected and deemed valid. Fifty-two percent of centers (11 of 21 centers) in the experimental arm did not implement the PIS in accordance with the protocol. Overall, 34% of patients showed moderate to severe psychological distress, and only 9% declared dissatisfaction. Intent-to-treat analysis did not yield significant differences. Although the per-protocol analysis did show a reduction in psychological distress (28.9% for functioning PIS v 33.3% for no PIS) and dissatisfaction (6.4% for functioning PIS v 9.3% for no PIS), differences did not reach significance. CONCLUSION: This is the first cluster randomized trial aiming to demonstrate that a structured modality of providing information reduces psychological distress. We did not find this, but we believe results should be interpreted cautiously, particularly because of the low compliance with PIS implementation. Context analysis preceding such interventions is essential.

Dose-dense primary chemotherapy, as part of multidisciplinary treatment, for inoperable stage III B breast cancer--long-term results of a phase II trial.

BACKGROUND: Primary chemotherapy as part of multidisciplinary approach is the established treatment for inoperable stage III B breast cancer. The primary endpoints were conversion to operable disease and feasibility of conservative surgery (breast-conserving therapy: BCT); secondary were clinical and pathological complete response rate, local and distant control and safety of the primary regimen. METHODS: Between 1998 and 2001, 40 inoperable breast cancer patients < or =60 years, 72% T4abc and 28% T4d, received 6 cycles of primary PEV dose-dense regimen: cisplatin 50 mg/m2, epirubicin 100 mg/m2 and vinorelbine 25 mg/m2, i.v. (q 14). Modified radical mastectomy (MRM) or BCT was performed, followed by adjuvant chemotherapy, radiotherapy and hormone therapy. RESULTS: All patients were converted to operable disease, and BCT was feasible in 24% of T4abc patients. After a median follow-up of 84 months (range 58-96), local and distant relapses were 7.5% (0% in BCT ) and 25% (25% in BCT), respectively. Clinical response was 80% (clinical complete response [cCR]: 20%); pathological complete response (pCR) was 40% in breast, 50% in axilla (pLN0); 32% both in breast and axilla. Neutropenia (G4, 30%), leukopenia (G4, 25%), alopecia (G2, 100%), nausea and vomiting (G4, 20%) were the most common toxicities. CONCLUSIONS: The PEV dose-dense regimen seems to be highly effective in terms of resectability and pCR. Toxicity, mainly hematological, was acceptable. Successful BCT is feasible, in selected patients, without compromising local and distant control.

Origin and distribution of the BRCA2-8765delAG mutation in breast cancer.

BACKGROUND: The BRCA2-8765delAG mutation was firstly described in breast cancer families from French-Canadian and Jewish-Yemenite populations; it was then reported as a founder mutation in Sardinian families. We evaluated both the prevalence of the BRCA2-8765delAG variant in Sardinia and the putative existence of a common ancestral origin through a haplotype analysis of breast cancer family members carrying such a mutation. METHODS: Eight polymorphic microsatellite markers (D13S1250, centromeric, to D13S267, telomeric) spanning the BRCA2 gene locus were used for the haplotype analysis. Screening for the 8765delAG mutation was performed by PCR-based amplification of BRCA2-exon 20, followed by automated sequencing. RESULTS: Among families with high recurrence of breast cancer (> or = 3 cases in first-degree relatives), those from North Sardinia shared the same haplotype whereas the families from French Canadian and Jewish-Yemenite populations presented distinct genetic assets at the BRCA2 locus. Screening for the BRCA2-8765delAG variant among unselected and consecutively-collected breast cancer patients originating from the entire Sardinia revealed that such a mutation is present in the northern part of the island only [9/648 (1.4%) among cases from North Sardinia versus 0/493 among cases from South Sardinia]. CONCLUSION: The BRCA2-8765delAG has an independent origin in geographically and ethnically distinct populations, acting as a founder mutation in North but not in South Sardinia. Since BRCA2-8765delAG occurs within a triplet repeat sequence of AGAGAG, our study further confirmed the existence of a mutational hot-spot at this genomic position (additional genetic factors within each single population might be involved in generating such a mutation).

Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial.

BACKGROUND: To determine whether a dose-dense regimen improves outcome in early breast cancer patients, we compared outcomes with the same fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapeutic regimen administered every 3 weeks (FEC21) or administered every 2 weeks (FEC14 including support with filgrastim, a granulocyte colony-stimulating factor) in a multicenter phase III randomized trial. METHODS: A total of 1214 patients with early-stage breast cancer were randomly assigned to receive six cycles of FEC14 (604 patients) or of FEC21 (610 patients). Study endpoints were overall survival and event-free survival. Associations were assessed by multivariable analysis with adjustment for age; tumor size; grade; proliferative rate; and menopausal, lymph node, estrogen receptor, and progesterone receptor status. All statistical tests were two-sided. RESULTS: Patients in the FEC14 arm had fewer dose reductions or treatment delays or discontinuation (26%) than those in the FEC21 arm (33%) (difference = 7%, 95% confidence interval [CI] = 2% to 12%; P = .008). FEC14 therapy, compared with FEC21 therapy, was associated with more asthenia (36% versus 29%, difference = 7%, 95% CI = 2% to 12%; P = .01), bone pain (33% versus 4%, difference = 29%, 95% CI = 25% to 33%; P < .001), anemia (38% versus 19%, difference = 19%, 95% CI = 14% to 24%; P < .001), and thrombocytopenia (8% versus 2%, difference = 6%, 95% CI = 4% to 9%; P < .001), but with less leukopenia (12% versus 45%, difference = 33%, 95% CI = 28% to 37%; P < .001). No acute myelogenous leukemia or myelodysplastic syndrome was observed. At a median follow-up of 10.4 years, no statistically significant difference in the hazard of death (hazard ratio [HR] = 0.87, 95% CI = 0.67 to 1.13) or recurrence (HR = 0.88, 95% CI = 0.71 to 1.08) was found between FEC14 and FEC21 groups after adjustment by multivariable analysis. Although the study was underpowered for subset analysis, we found no evidence that the effect of the treatment type was associated with any of the potential prognostic factors. CONCLUSION: Our results support the long-term safety of FEC14 chemotherapy as an adjuvant treatment of breast cancer. However, this therapy was not associated with improved outcome, but because of the limited statistical power of our study, we cannot rule out a modest improvement in outcome associated with FEC14 therapy.

Spectrum and prevalence of BRCA1 and BRCA2 germline mutations in Sardinian patients with breast carcinoma through hospital-based screening.

BACKGROUND: Factors that are predictive of carrying BRCA1 and BRCA2 germline mutations in patients with breast carcinoma are awaited widely. The genetically homogeneous Sardinian population may be useful for defining the role of such genetic alterations further through a clinical evaluation program. METHODS: One hundred two of 659 patients with breast carcinoma (15.5%) who were collected consecutively had a family history of breast carcinoma and were screened for BRCA1/2 mutations by denaturing high-performance liquid chromatography and DNA sequencing. RESULTS: Three deleterious germline BRCA1/2 mutations were detected in 15 of 102 families (14.7%), including 13 families (86.7%) with BRCA2 mutations and 2 families (13.3%) with BRCA1 mutations. A single variant, BRCA2-8765delAG, was the most recurrent mutation in the series and was found in 12 of 102 families (11.8%) and in 18 of 657 patients (2.7%). The average age at diagnosis was significantly younger in families with BRCA1/2 mutations (48.6 yrs) compared with the age of patients who had no detectable mutation (52.9 yrs; P = 0.039). Moreover, BRCA1/2 mutations were found at a significantly higher rate in families who had at least 1 member with ovarian carcinoma or male breast carcinoma (5 of 12 families; 41.7%) than in families without such an association (10 of 90 families; 11.1%; P = 0.003). CONCLUSIONS: BRCA2 mutations were approximately 6 times more prevalent than BRCA1 mutations. A diagnosis of breast carcinoma before age 50 years, ovarian carcinoma, male breast carcinoma, and 3 affected generations all were associated significantly with BRCA1/2 mutations. Although the current findings provided further support for the hypothesis that additional breast carcinoma susceptibility genes remain to be identified, such indicators of the presence of BRCA1/2 mutations may be useful in counseling patients about undergoing genetic testing.

Effects of media information on cancer patients' opinions, feelings, decision-making process and physician-patient communication.

BACKGROUND: The objective of the current study was to determine the influence of media information on the opinions and feelings of patients with cancer and to measure the factors that affected the decision-making process and physician-patient communication. METHODS: The study consisted of a sequence of 2 nationwide surveys across the same dynamic target population of 2600 unselected patients with cancer who attended 1 of 13 centers throughout Italy. The authors measured the changes in patients' opinions and attitudes at the peak of a media campaign promoting the Di Bella therapy, an unproven cancer treatment method, and after the publicized demonstration of its ineffectiveness. An identical 10-item questionnaire was used. RESULTS: Opinions and feelings changed in the two surveys according to the way the media described the efficacy of the treatment, but physician-patient communication and the decision-making process remained unchanged. Multivariate analysis confirmed the enormous influence of the media on patient opinions (odds ratio [OR], 4.67; P < 0.0001), feelings of hope (OR, 3.63; P < 0.0001), and confusion (OR, 0.51; P < 0.0001), but not on physician-patient communication or the decision-making process. Educational level influenced almost all of the studied factors, and communication and decision-making also were influenced by the patients' gender and place of residence. There was no significant correlation with patient age. CONCLUSIONS: The media play a powerful role in affecting patients' opinions and feelings; the physician-patient communication and the decision-making process are not subject to media influence but are related primarily to level of education. The power of the media should be directed toward improving the spread of scientific knowledge to encourage behavioral changes, particularly among individuals with lower levels of education.

Capecitabine in combination with docetaxel and epirubicin in patients with previously untreated, advanced breast carcinoma.

BACKGROUND: The objective of this study was to evaluate the activity and safety of oral capecitabine in combination with docetaxel and epirubicin (TEX) as first-line treatment for patients with locally advanced/metastatic breast carcinoma. METHODS: This open-label, Phase II study was conducted at six Italian centers. Treatment consisted of epirubicin, 75 mg/m(2) (intravenous bolus), and docetaxel, 75 mg/m(2) (1-hour infusion), both administered on Day 1, plus oral capecitabine, 1000 mg/m(2) twice daily, on Days 1-14 of each 3-week treatment cycle. RESULTS: A total of 67 patients received 392 cycles of treatment, with a median of 6 cycles in patients with Stage III disease (n = 34 patients) and a median of 8 cycles in patients with Stage IV disease (n = 33 patients). The objective response rate was 82%, including complete responses in 21% of patients. A greater proportion of patients with Stage III disease achieved tumor responses compared with patients who had Stage IV disease (97% vs. 67%, respectively). Among 34 patients with Stage III disease, pathologic complete responses were confirmed in 10 patients (29%). TEX chemotherapy demonstrated an acceptable safety profile. There was a low incidence of Grade 3 adverse events, and Grade 4 adverse events were particularly rare (4%). The most common Grade 3-4 adverse event was febrile neutropenia, which occurred in 16% of patients. CONCLUSIONS: TEX combination therapy has important antitumor activity and an acceptable safety profile in this setting. A large, randomized, Phase III trial is ongoing to compare TEX chemotherapy with an epirubicin plus docetaxel regimen in patients with untreated, advanced breast carcinoma.