Improving Quality in Nanoparticle-Induced Cytotoxicity Testing by a Tiered Inter-Laboratory Comparison Study.

The quality and relevance of nanosafety studies constitute major challenges to ensure their key role as a supporting tool in sustainable innovation, and subsequent competitive economic advantage. However, the number of apparently contradictory and inconclusive research results has increased in the past few years, indicating the need to introduce harmonized protocols and good practices in the nanosafety research community. Therefore, we aimed to evaluate if best-practice training and inter-laboratory comparison (ILC) of performance of the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay for the cytotoxicity assessment of nanomaterials among 15 European laboratories can improve quality in nanosafety testing. We used two well-described model nanoparticles, 40-nm carboxylated polystyrene (PS-COOH) and 50-nm amino-modified polystyrene (PS-NH2). We followed a tiered approach using well-developed standard operating procedures (SOPs) and sharing the same cells, serum and nanoparticles. We started with determination of the cell growth rate (tier 1), followed by a method transfer phase, in which all laboratories performed the first ILC on the MTS assay (tier 2). Based on the outcome of tier 2 and a survey of laboratory practices, specific training was organized, and the MTS assay SOP was refined. This led to largely improved intra- and inter-laboratory reproducibility in tier 3. In addition, we confirmed that PS-COOH and PS-NH2 are suitable negative and positive control nanoparticles, respectively, to evaluate impact of nanomaterials on cell viability using the MTS assay. Overall, we have demonstrated that the tiered process followed here, with the use of SOPs and representative control nanomaterials, is necessary and makes it possible to achieve good inter-laboratory reproducibility, and therefore high-quality nanotoxicological data.

Evalutation of the perceived quality in the Orthopedics/Traumatology Unit at Carlo Poma Hospital in Mantova.

The background and the aim of the work: The Department of Orthopedics and Traumatology of the "Carlo Poma" Hospital (Social Territorial Health Authority of Mantova), has pointed out in 2017, through the questionnaires survey over the citizens satisfaction, an appreciation decrease compared to the previous years. The obtained data were not sufficiently explanatory of the reasons for that kind of deterioration and also not enough specific to define possible corrective measures. The aim of this work was to identify the patients' perception regarding the hospitalization phases (from booking to follow up), taking into account five kind of operations and pathologies: 1st knee, shoulder and tibio-talar arthroscopy; 2nd hip and knee prosthesis; 3rd upper limb traumatology; 4th lower limb traumatology and 5th orthogeriatrics. METHODS: The research is based on 29 narrations resulted from orthopedic patients between 30 and 80 days after the time of discharge. RESULTS: The phases of care path which get the highest level of satisfaction are those concerning the operation and the outpatient visit followed by rehabilitation and assistive continuation. The most negative phase was the discharge but, also the needs assistance respond, the reception, the microclimate and the pre-operative medical assessment resulted contradictory. At the same time the three most significant areas of improvement were: the organization (critical for upper limb traumatology, arthroscopy and prosthetics); the health features (critical for the lower limb, orthogeriatrics and traumatology) and medical information (the most critical issues were those concerning the upper limb traumatology while the less were the orthogeriatrics ones). CONCLUSION: Use the narration to go into the orthopedic patient needs and perceptions allows to activate appropriate and customized organizational and professional changes in order to answer adequatly to the patient's needs to limit litigation and defence medicine expences.

In vitro toxicity assessment of oral nanocarriers.

The fascinating properties of nanomaterials opened new frontiers in medicine. Nanocarriers are useful systems in transporting drugs to site-specific targets. The unique physico-chemical characteristics making nanocarriers promising devices to treat diseases may also be responsible for potential adverse effects. In order to develop functional nano-based drug delivery systems, efficacy and safety should be carefully evaluated. To date, no common testing strategy to address nanomaterial toxicological challenges has been generated. Different cell culture models are currently used to evaluate nanocarrier safety using conventional in vitro assays, but overall they have generated a huge amount of conflicting data. In this review we describe state-of-the-art approaches for in vitro testing of orally administered nanocarriers, highlighting the importance of developing harmonized and validated standard operating procedures. These procedures should be applied in a safe-by-design context with the aim to reduce and/or eliminate the uncertainties and risks associated with nanomedicine development.

Cytotoxicity and antibacterial activity of a new generation of nanoparticle-based consolidants for restoration and contribution to the safe-by-design implementation.

Works of art are constantly under physical, chemical and biological degradation, so constant restoration is required. Consolidation is an important step in restoration, and traditional approaches and materials have already shown their limitations. To solve these problems, new nanoparticle-based consolidants were developed. No information on their toxicity is yet available. In this work, we focused our attention on potential risks posed by three commercially available nanoparticle-based consolidants: silica (SiO2 NPs), silanized silica (silanized SiO2 NPs) and calcium hydroxide (nanolime) nanoparticle dispersions. Occupational exposure impact was tested on three in vitro models mimicking inhalation, dermal contact and systemic routes. While no toxic effects were observed for nanolime and silanized SiO2 NPs, bare SiO2 NPs showed a dose- and time-dependent damage in all considered models. Corrosion test on EpiSkin® revealed no viability reduction. Works of art degradation is partially due to microorganism activity. Consolidant antibacterial activity was evaluated on three representative bacterial strains. Silica NPs-based consolidants showed effect on specific bacterial groups, while no specificity was observed with nanolime. In conclusion, silanized SiO2 NPs-based consolidant emerged as the safest and bacteriologically active product. The different biological impact of bare and silanized SiO2 NPs highlights the importance of safe-by-design approach in developing nanoparticle-containing products.

Management of oral anticancer drugs: feasibility and patient approval of a specific monitoring program.

BACKGROUND: Oral anticancer drugs are an attractive treatment option, even if patient-focused education and specific nursing staff are needed to support home care intervention. Our aim was to assess the feasibility of a nurse monitoring program for patients taking oral chemotherapy, and to evaluate the patients' approval of the program. METHODS: At the beginning of oral chemotherapy treatment, outpatients completed a specific form so that we could assess their comprehension of the information related to therapy. Nurses gave patients a diary to record drug intake and toxicity at home, and phone calls were planned to evaluate toxicity or modification of the treatment plan during the first and second cycles of therapy. Finally, patients were requested to complete a specific form to express their level of agreement with the program. RESULTS: Eighty-one patients were included in the analysis. Nurse intervention at the beginning of therapy resulted in an increased proportion of patients having received correct information related to treatment, with a level of confidence rising to more than 90% for all items considered. One hundred ninety-one of 243 planned phone calls were made, corresponding to 78.6% of the planned activity. The diary proved a valid tool for patients and 144 of 153 diaries were completed at home (94%). Only 5 patients (6%) had unplanned hospital admission for toxicity, probably because of early intervention by nursing staff. Only 2 out of 63 patients expressed a negative opinion, while the remaining patients expressed their approval of the program. CONCLUSION: Our model proved practicable and accepted by patients, thus supporting the role of nurse intervention in training and monitoring patients receiving oral chemotherapy.

Suppression of microbunching instability using bending magnets in free-electron-laser linacs.

The microbunching instability driven by collective effects of the beam inside an accelerator can significantly degrade the final electron beam quality for free electron laser (FEL) radiation. In this Letter, we propose an inexpensive scheme to suppress such an instability in accelerators for next generation FEL light sources. Instead of using an expensive device such as a laser heater or RF deflecting cavities, this scheme uses longitudinal mixing associated with the transverse spread of the beam through bending magnets inside the accelerator transport system to suppress the instability. The final uncorrelated energy spread increases roughly by the current compression factor, which is important in seeded FEL schemes in order to achieve high harmonic short-wavelength x-ray radiation.

Impact of use of oral anticancer drugs on activity of Italian oncology practices: results of a survey conducted by the Italian Society of Medical Oncology (AIOM).

AIMS AND BACKGROUND: In recent years, the number of oral anticancer drugs used in clinical practice has rapidly increased. The Italian Society of Medical Oncology (AIOM) conducted a survey to describe the impact of the use of oral anticancer drugs on the daily activity of Italian oncology practices. METHODS AND STUDY DESIGN: A survey questionnaire was distributed to the coordinators of the regional sections of AIOM. A 6-month period was considered, from January 1, 2010 to June 30, 2010. The survey addressed (1) quantitative aspects of the use of oral anticancer drugs; (2) practical aspects in the management of patients treated with these drugs; (3) issues related to treatment costs and reimbursement procedures. RESULTS: Thirty-six questionnaires were received from institutions distributed throughout the Italian territory. Oral anticancer drugs (both chemotherapy and molecularly targeted agents) accounted for a significant proportion (17%) of prescribed treatments. Among the responding institutions, there were different dispensation procedures of oral drugs to patients: drugs were dispensed by the pharmacist (57%) or directly by the medical oncologist (23%) or nurse (20%). The medical oncologist played a major role in the communication with patients (73% alone and a further 24% in cooperation with other professional figures) and was the point of reference in the event of side effects in 97% of cases. In most cases, the reimbursement of drug costs was separated ("File F" procedure) from the flat fare received by the hospital for outpatient visits or day-hospital access. CONCLUSIONS: Optimal organization of oral anticancer treatment warrants the cooperation and integration of multiple professional figures. At least three figures are involved in patient management in the hospital: the medical oncologist, the nurse, and the hospital pharmacist. Oral anticancer treatments are associated with specific reimbursement issues: in the majority of cases, the cost of the drug is reimbursed separately from the cost of patient access.

Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments.

BACKGROUND: This open-label study compared docetaxel/gemcitabine vs. paclitaxel/gemcitabine and a weekly (W) vs. 3-weekly (3 W) schedule in metastatic breast cancer (MBC). METHODS: Patients relapsed after adjuvant/neoadjuvant anthracycline-containing chemotherapy were randomized to: A) gemcitabine 1000 mg/m2 Day 1,8 + docetaxel 75 mg/m2 Day 1 q3W; B) gemcitabine 1250 mg/m2 Day 1,8 + paclitaxel 175 mg/m2 Day 1 q3W; C) gemcitabine 800 mg/m2 Day 1,8,15 + docetaxel 30 mg/m2 Day 1,8,15 q4W; D) gemcitabine 800 mg/m2 Day 1,15 + paclitaxel 80 mg/m2 Day 1,8,15 q4W. Primary endpoint was time-to-progression (TTP). Secondary endpoints were overall survival (OS) and overall response rate (ORR). RESULTS: Interim analysis led to accrual interruption (241 patients enrolled of 360 planned). Median TTP (months) was 8.33 (95% CI: 6.19-10.16) with W and 7.51 (95% CI: 5.93-8.33) with 3 W (p=0.319). No differences were observed in median TTP between docetaxel and paclitaxel, with 85.6% and 87.0% of patients progressing, respectively. OS did not differ between regimens/schedules. ORR was comparable between regimens (HR: 0.882; 95% CI: 0.523-1.488; p=0.639), while it was significantly higher in W than in the 3 W (HR: 0.504; 95% CI: 0.299-0.850; p=0.010) schedule. Grade 3/4 toxicities occurred in 69.2% and 71.9% of patients on docetaxel and paclitaxel, and in 65.8% and 75.2% in W and 3 W. CONCLUSIONS: Both treatment regimens showed similar TTP. W might be associated with a better tumour response compared with 3 W. TRIAL REGISTRATION: Clinicaltrial.gov ID NCT00236899.

Assessment of in vitro temporal corrosion and cytotoxicity of AZ91D alloy.

Magnesium alloys represent a valuable option for the production of bioresorbable implantable medical devices aimed to improve the therapeutic approach and minimize the potential risks related to biostable materials. In this regard, the degradation process needs to be carefully evaluated in order to assess the effectiveness of the regenerative support and the eventual toxic effects induced by the released corrosion products. Aluminium is one of the most common alloying element that raised several safety concerns, contributing to shift the investigation toward Al-free alloys. To delve into this issue, a long-term investigation (up to 28 days) was performed using AZ91D alloy, due to its relevant Al content. Immersion tests in phosphate buffered saline (PBS) solution was performed following the ASTM standards and the corrosion behaviour was evaluated at fixed time points by means of electrochemical techniques. Cytotoxic effects were assessed by culturing human neuroblastoma cells with conditioned medium derived from immersion tests at different dilution degree. An increase in the resistance corrosion with the time was observed. In all the investigated cases the presence of Al in the conditioned media did not induce significant toxic effects directly correlated to its content. A decrease of cell viability was only observed in the case of 50 % dilution of PBS conditioned for the longest immersion period (i.e., 28 days).

Biological characterization and selection criteria of adjuvant chemotherapy for early breast cancer: experience from the Italian observational NEMESI study.

BACKGROUND: International treatment guidelines recommend administration of adjuvant chemotherapy in early breast cancer based on clinical, prognostic and predictive parameters. METHODS: An observational study (NEMESI) was conducted in 63 Italian oncology centres in patients with early breast cancer. Age, performance status, concomitant disease, menopausal status, histology, tumor dimension (pT), axillary lymph node status (pN), grading (G), estrogen and progesterone receptor (ER and PgR), proliferative index (ki67 or MIB-1), human epidermal growth factor receptor 2 (HER2) and type of adjuvant treatment were recorded. The primary objective of the study was to define parameters influencing the decision to prescribe adjuvant chemotherapy and the type of chemotherapy. RESULTS: Data for 1894 patients were available. 69.0% postmenopausal, 67.0% pT1, 22.3% pTmic/pT1a/pT1b, 61.0% pN0, 48.7% luminal A, 18.1% luminal B, 16.1% HER2 positive, 8.7% triple negative, 8.4% unknown. 57.8% received adjuvant chemotherapy: 38.1% of luminal A, 67.3% luminal B, 88.2% HER2-positive, 97.6% triple negative. Regimens administered: 9.1% CMF-like, 48.8% anthracyclines, 38.4% anthracyclines plus taxanes, 3.7% taxanes alone. Increasing pT/pN and, marginally, HER2-positive were associated with the prescription of anthracyclines plus taxanes. Suboptimal schedules (CMF-like or AC/EC or FEC-75) were prescribed in 37.3% receiving chemotherapy, even in HER2-positive and triple negative disease (36.5% and 34.0%, respectively). CONCLUSIONS: This study showed an overprescription of adjuvant chemotherapy for early breast cancer, particularly referred to luminal A. pT, pN and, marginally, HER2 were the principal determinants for the choice of chemotherapy type. Suboptimal chemotherapy regimens were adopted in at least one third of HER2-positive and triple negative.

Adjuvant chemotherapy of pT1a and pT1b breast carcinoma: results from the NEMESI study.

BACKGROUND: The prognosis of pT1a-pT1b breast cancer (BC) used to be considered very good, with a 10-y RFS of 90%. However, some retrospective studies reported a 10-y RFS of 81%-86% and suggested benefit from adjuvant systemic therapy. METHODS: To evaluate the variables that determined the choice of adjuvant chemotherapy and the type of chemotherapy delivered in pT1a-pT1b BC, we analysed the small tumours enrolled in the NEMESI study. RESULTS: Out of 1,894 patients with pathological stage I-II BC enrolled in NEMESI, 402 (21.2%) were pT1a-pT1b. Adjuvant chemotherapy was delivered in 127/402 (31.59%). Younger age, grading G3, high proliferative index, ER-negative and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy. An anthracycline without taxane regimen was administered in 59.1% of patients, anthracycline with taxane in 24.4%, a CMF-like regimen in 14.2% and taxane in 2.4%. Adjuvant chemotherapy was administered in 88.4% triple-negative and 73.46% HER2-positive pT1a-pT1b BC. Adjuvant trastuzumab was delivered in 30/49 HER2-positive BC (61.2%). CONCLUSIONS: Adjuvant chemotherapy was delivered in 31.59% T1a-pT1b BC treated at 63 Italian oncological centres from January 2008 to June 2008. The choice to deliver chemotherapy was based on biological prognostic factors. Anthracycline-based chemotherapy was administered in 83.5% patients.

Irinotecan during pregnancy in metastatic colon cancer.

BACKGROUND: Colon cancer during pregnancy is a relatively rare occurrence. To date there has been sparse clinical evidence about the safety of chemotherapy in this setting because the available data derive only from single-institution case reports. METHODS: Irinotecan and fluorouracil, as part of the FOLFIRI regimen, were administered to a 33-year-old pregnant woman at an estimated gestational age of 23+ weeks. She had been diagnosed with adenocarcinoma of the transverse colon with liver and lymph node metastases. RESULTS: Chemotherapy was administered from the 23+th to the 28+th week of gestational age. Chemotherapy was stopped because of disease progression. At 30 weeks' gestational age, the patient underwent an emergency cesarean section and colon resection. She gave birth to a healthy male infant with no particular problems in neurological, respiratory, cardiovascular, digestive and nutritional function. At follow-up, the 13-month-old child had achieved all appropriate growth and developmental milestones. CONCLUSIONS: Our report demonstrates the safety of exposure to FOLFIRI for both mother and fetus. The absence of any abnormalities in the infant makes irinotecan and fluorouracil a valid therapeutic option for colon cancer during pregnancy.

Importance of adherence to guidelines in breast cancer clinical practice. The Italian experience (AIOM).

AIMS AND BACKGROUND: Project RIGHT (Research for the Identification of the most effective and hIGHly accepted clinical guidelines for cancer Treatment) is promoted by the Italian Association of Medical Oncology (AIOM) to evaluate the concordance between AIOM breast cancer guidelines and clinical practice in Italy. In RIGHT-1, feasibility and the appropriateness of indicators were assessed in patients with early breast cancer. RIGHT-2 evaluated the compliance with guidelines in a nationwide program. METHODS: Thirty-five Italian centers participated in the RIGHT-2 survey. Ten indicators were evaluated to verify an agreement between 2005 AIOM breast cancer guidelines and practice. Patients with clinical stage I-II invasive breast cancer, age ≤70 years, who had their first visit at the oncology center between October 2005 and November 2006 were included. RESULTS: In RIGHT-2, ≥90% adherence for the diagnosis indicator and three therapy indicators were observed. The lowest degree of compliance (0%) was observed for the follow-up indicator in asymptomatic patients. CONCLUSIONS: In RIGHT-2, compliance to the 2005 AIOM breast cancer guidelines was 64%. When the follow-up indicator was eliminated, overall adherence to AIOM guidelines was 71%. The results highlight the need to continue improving the already good standards of breast cancer care.

Reduced use of chemotherapy at the end of life in an integrated-care model of oncology and palliative care.

AIMS AND BACKGROUND: When there is little hope of a clinical benefit, too delayed a withdrawal from chemotherapy might be detrimental for a patient's quality of life. We evaluated appropriately timed cessation of chemotherapy in our Oncology Department after integration of a Supportive and Palliative Care Unit. METHODS: We carried out a review of deceased patients in our department from January 2006 to December 2009. Activities of the Supportive and Palliative Care Unit started in late 2007. We analyzed the characteristics of patients near the end of life and chemotherapy use within 30 days of death as an aggressiveness of cure index. RESULTS: During the considered period, 361 hospitalized patients died: 69 in 2006, 77 in 2007, 97 in 2008 and 118 in 2009; 102 never received chemotherapy. Sixty-one of the remaining 259 patients died within 30 days of the last drug administration. The percentage of patients receiving chemotherapy in their last 30 days fell from 19% in 2006 and 20% in 2007, to 16% in 2008 and 14% in 2009. CONCLUSIONS: Supportive and Palliative Care Unit integration decreased chemotherapy use in the last 30 days of life. A careful evaluation of prognostic factors of advanced cancer patients and provision of appropriate supportive and palliative cares can reduce the use of futile anticancer chemotherapy and preserve a patient's qualify of life.

Disparity in the "time to patient access" to new anti-cancer drugs in Italian regions. Results of a survey conducted by the Italian Society of Medical Oncology (AIOM).

AIMS AND BACKGROUND: In 2009, the Italian Society of Medical Oncology (AIOM) conducted a survey to describe the impact of regional pharmaceutical formularies on the disparity of access to eight new drugs among cancer patients treated in Italian regions. The survey documented some regional restrictions for some anti-cancer drugs. In the study, we analyzed the "time to patient access" to new anti-cancer drugs in Italian regions. METHODS: In March 2010, we analyzed the availability of 17 new anti-cancer drugs at a regional level, specifically the coherence of regional authorizations compared with national authorizations approved by the Italian Medicines Agency (AIFA). In the regions with pharmaceutical formularies, we analyzed the characteristics of technical-scientific committees for the evaluation of inclusion of hospital drugs in these formularies. We also analyzed the time from EMA (CMPH) authorization to AIFA marketing authorization, the time from AIFA marketing authorization to patient availability, and the total time from EMA (CMPH) authorization to patient availability of the drugs in all Italian regions, for 11 of these drugs. RESULTS: Some drugs were included in all the regional pharmaceutical formularies, without restrictions, whereas other drugs were not included in one and others were not included in more than one formulary. Median time from EMA to AIFA was 11.2 months (range, 2.9-17.1). Median time from AIFA to patient availability was 1.4 months (range, 0.0-50.5) in regions with drug formularies versus 0.0 months in regions without drugs formularies. Median total time from EMA to patient availability was longer in regions with formularies (13.3 months; range, 2.9-65.3) than in regions without formularies (11.2 months; range, 2.9-24.0), where drugs are immediately available after AIFA marketing authorization. Moreover, the interval was very long (range, 2.9-65.3) for some drugs in regions with formularies. CONCLUSIONS: The analysis confirmed that the presence of multiple hierarchical levels of drug evaluation can create disparity in drug availability for Italian citizens.

Concurrent vs sequential adjuvant chemotherapy and hormone therapy in breast cancer: a multicenter randomized phase III trial.

BACKGROUND: The most appropriate timing of chemotherapy and hormone therapy administration is a critical issue in early breast cancer patients. The purpose of our study was to compare the efficacy of concurrent vs sequential administration of adjuvant chemotherapy and tamoxifen. METHODS: Women with node-positive primary breast cancer were randomly assigned to receive tamoxifen (20 mg/d for 5 years) during (concurrent arm) or after (sequential arm) adjuvant chemotherapy. Chemotherapy consisted of alternating regimens of cyclophosphamide, epidoxorubicin, and 5-fluorouracil and cyclophosphamide, methotrexate, and 5-fluorouracil every 21 days for a total of 12 cycles. The primary endpoint was overall survival (OS), and secondary endpoints were toxic effects and disease-free survival (DFS). No provision for interim analyses was made in the original study protocol. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models, adjusted for age, menopausal status, tumor stage, and lymph node and hormone receptor status, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: From 1985 to 1992, 431 patients were randomly assigned and studied according to the intention-to-treat principle. After a maximum of 15.4 years of follow-up (median 12.3 years), the estimated actuarial 10-year OS was equivalent for the two study arms (concurrent arm: 111 patients, 66%, 95% CI = 59% to 72%; sequential arm: 114 patients, 65%, 95% CI = 59% to 72%, P = .86). No differences in DFS and toxic effects were evident. Four interim analyses were performed, but no alpha error adjustment was necessary because of the largely negative results of this final analysis (sequential vs concurrent arm: HR of death = 1.06, 95% CI = 0.78 to 1.44, P = .76; HR of relapse = 1.16, 95% CI = 0.88 to 1.52, P = .36). CONCLUSIONS: No statistically significant differences in OS, DFS, and toxic effects between concurrent and sequential adjuvant chemo- and hormone therapies were observed. Our study does not support the superiority of one schedule of chemo- and hormone-therapy administration over the other. However, because of the limited statistical power of the study, these results must be considered with caution.

Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.

CONTEXT: Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available. OBJECTIVE: To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. DESIGN, SETTING, AND PATIENTS: The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data. INTERVENTIONS: Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy. MAIN OUTCOME MEASURE: Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy). RESULTS: The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of -17% (95% confidence interval, -26% to -7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001). CONCLUSION: The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00311636.

Comparison of hormonal receptor and HER-2 status between breast primary tumours and relapsing tumours: clinical implications of progesterone receptor loss.

Differences in hormone receptor and HER-2 status between primary tumour and corresponding relapse could have a substantial impact on clinical management of patients. The aim of this study was to evaluate change in expression of hormone receptors and HER-2 status between primary tumour and corresponding local recurrence or distant metastasis. We analysed 140 primary tumours and related recurrent or metastatic samples. Hormone receptors status was evaluated by immunohistochemistry, while HER-2 status by immunohistochemistry and silver in situ hybridisation. A change in HER-2 was rare; 3.7% of cases by immunohistochemistry and only 0.7% by silver in situ hybridisation analysis. A change in estrogen and progesterone receptors was seen in 6.4% and 21.4% of cases, respectively. Estrogen receptor change was not affected by adjuvant therapy, whereas progesterone receptor was influenced by adjuvant chemotherapy associated to hormone therapy (P = 0.0005). A change in progesterone receptor was more frequent in distant metastases than in local recurrences (P = 0.03). In the setting of estrogen receptor positive tumours, patients with progesterone receptor loss in local recurrence had a statistically significant lower median metastasis free survival compared to others patients; progesterone receptor positive, 112 months; progesterone receptor negative, 24 months (P = 0.005). A change between primary tumour and corresponding relapse is frequent for progesterone receptor, infrequent for estrogen receptor and rare for HER-2. In cases with changes in HER-2, it is worthwhile reassessing HER-2 status with both immunohistochemistry and in situ hybridisation analysis. Progesterone receptor loss seems to be influenced by therapy and to correlate with a worse prognosis.

Differences in the availability of new anti-cancer drugs for Italian patients treated in different regions. Results of analysis conducted by the Italian Society Of Medical Oncology (AIOM).

AIMS AND BACKGROUND: Italy is divided into 20 regions. As a consequence of local autonomy, following marketing authorization by the Italian Medicines Agency, each drug for hospital use is not immediately available, because its approval needs to undergo further steps that can be different among regions. The Italian Society of Medical Oncology conducted the present study to describe the impact of the existence of sub-national pharmaceutical formularies on the disparity of access to new anti-cancer drugs among patients treated in different Italian regions. METHODS: The availability of 8 new anti-cancer drugs at a regional level and the coherence of regional authorizations compared with national authorizations approved by the Italian Medicines Agency were analyzed as of April 2009. RESULTS: Fourteen regions and autonomous province of Trento have a regional pharmaceutical formulary. In most cases, the regional pharmaceutical formularies include the eight analyzed drugs, with therapeutic indications coherent with national marketing authorization indications. Five drugs (bevacizumab, trastuzumab, rituximab, erlotinib, sunitinib) were included in all the existing regional pharmaceutical formularies, without restrictions, whereas three drugs (cetuximab, sorafenib, pemetrexed) were found to have restrictions in some regions. CONCLUSIONS: The presence of multiple hierarchical levels of drug evaluation creates a potential element of disparity in the access to pharmacological therapies for Italian citizens.

Comparison of temsirolimus pharmacokinetics in patients with renal cell carcinoma not receiving dialysis and those receiving hemodialysis: a case series.

BACKGROUND: Intravenous temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved for the treatment of advanced renal cell carcinoma (RCC). Sirolimus, the principal metabolite of temsirolimus in humans, also exhibits mTOR inhibitory activity. OBJECTIVE: The purpose of this study was to compare the pharmacokinetics of temsirolimus and its metabolite, sirolimus, among patients with RCC not receiving dialysis and those receiving hemodialysis. METHODS: This was a single-center, unblinded, single-dose study. Patients with histologically confirmed metastatic RCC were eligible. A single 25-mg dose of temsirolimus was administered as a 30-minute intravenous infusion during the first round of chemotherapy. Blood samples were drawn at 0 (predose), 0.5 (end of infusion), 1.5, 2.5, 5.5, 24, 72, and 144 hours after infusion. In patients receiving hemodialysis, an additional blood sample was drawn 1 hour after each treatment to compare pre- and postconcentration. Temsirolimus concentrations were assayed in blood using HPLC coupled to mass spectrometry. Pharmacokinetic parameters (C(max), T(max), t((1/2)), AUC(0-infinity), total body clearance, volume of distribution at steady state, AUC ratio [the ratio of sirolimus to temsirolimus AUCs], and AUC sum [the algebraic sum of temsirolimus and sirolimus AUCs]) were calculated and analyzed statistically. RESULTS: In total, 13 consecutive patients (11 men and 2 women; 11 not receiving dialysis and 2 receiving hemodialysis) were included. No patient refused to participate in the study. Of those not receiving dialysis, the median age was 54 years (range, 36-77 years), and of those receiving hemodialysis, the median age was 60.5 years (60-61 years). There were no significant between-group differences in the pharmacokinetic parameters of temsirolimus and sirolimus. Moreover, in patients receiving hemodialysis, blood drug concentrations assessed immediately before hemodialysis were similar to those assayed 1 hour after the treatment. CONCLUSION: This study found that after single-dose administration of 25 mg of temsirolimus as a 30-minute intravenous infusion, neither temsirolimus nor sirolimus concentrations were significantly affected in these patients with RCC receiving hemodi-alysis compared with those not receiving dialysis.