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Summary Background Gemcitabine has been widely studied in elderly patients affected by advanced non-small cell lung cancer (NSCLC). A prolonged constant infusion (10 mg/m2/min) has been proposed as a way to improve its efficacy. Aim of this study is to describe activity and toxicity of single-agent gemcitabine given as prolonged infusion in the treatment of elderly patients with advanced NSCLC. Patients and methods Patients aged 70 years or older, with stage IV or IIIB (effusion/supraclavicular nodes) NSCLC, good performance status (0 or 1 according to ECOG classification) who had never received chemotherapy were eligible. Gemcitabine was administered at the dose of 1200 mg/m2 by prolonged infusion (10 mg/m2/min) on days 1 and 8 of each cycle. Courses were repeated every 21 days, for a maximum of 6 cycles, unless disease progression or severe toxicity. A single stage phase 2 design was applied, with 51 patients required to estimate a 25% ± 10% response rate. Ten responses were required to define the treatment as active. Results Fifty-one patients were enrolled, with a median age of 76 years (range 70–83). Two complete responses and seven partial responses were observed, for an overall response rate of 17.6% (95% exact C.I.: 8.4–30.9%). The median time to disease progression was 16.1 weeks (95% C.I.: 11.1–20.6) and the median overall survival was 41.3 weeks (95% C.I.: 27.6–50.6). There were 2 toxic deaths, due to bleeding and liver toxicity, and one patient had an ischemic stroke. Other non-haematological toxicities were: fatigue (44% of patients), grade 2–3 pulmonary toxicity (8%), grade 2–3 hepatic toxicity (16%). Nausea and stomatitis were mild and no cases of cardiac toxicity were observed. Haematological toxicity was mild, with no case of febrile neutropenia. Conclusion Gemcitabine at prolonged constant infusion produced a response rate lower than that required by study design and should no longer be of interest for the treatment of elderly patients with advanced NSCLC.

BACKGROUND: Metformin is known to be rarely associated with lactic acidosis, a serious condition with a poor prognosis. AIM: To review the National Pharmacovigilance Network of the Italian Medicines Agency reporting cases of metformin-associated lactic acidosis. MATERIALS AND METHODS: The National Pharmacovigilance Network of the Italian Medicines Agency, was searched for cases of lactic acidosis that occurred in a 10 years period (from November 2001 to October 2011). Data were analyzed, to identify associated clinical features. A systematic literature research was performed to identify other large case series on metformin associated lactic acidosis. RESULTS: Metformin was the antidiabetic drug most frequently associated with lactic acidosis in the assessed period. Metformin-associated lactic acidosis was the most frequent serious adverse reaction related to metformin reported to the national authority (18.2% of all 650 adverse drug reactions reported). There were 59 cases of metformin-associated lactic acidosis (mortality rate of 25.4%). In most patients (89.8%) there was at least one risk factor for the occurrence of lactic acidosis. The predictors of death were low arterial blood pH and absence of acute renal failure. The systematic research of the literature identified only six case-series with more than 30 patients. CONCLUSIONS: This is the second largest case series ever reported on metformin-associated lactic acidosis. We confirmed that this rare complication of metformin is frequently fatal. Death can be predicted when the patient arrive in the hospital with low pH and, not intuitively, if the patient has no acute kidney injury. Risk minimisation measures taken at national level to prevent this serious complication are described.

Purpose: Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity. Patients and Methods: From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients). Results: Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non–G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non–G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively). Conclusion: EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.

Purpose To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non—small-cell lung cancer treated with chemotherapy. Patients and Methods Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm. Results Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival. Conclusions Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non—small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

The authors analyze the most current methods for the treatment of ulcerated breast cancer in the elderly. They describe a peculiar case recently observed, characterized by an ulcerative lesion spreading from the hemiclavicle to the foreaxilla including the axillary cavity, causing a large phlebo-lymphaedema, anaesthesia and paresis of the homoteral upper limb. After an initial treatment with tamoxifen a scapulo-humeral disarticulation and a suture of the cutaneous wide defect were performed using a myo-skin graft which included the deltoid muscle. A radiotherapeutic treatment followed by tamoxifen therapy was carried out. No distant metastases and no local relapses were registered in the one year follow up. The Authors on the basis of their experience and according to the review of the Literature suggest that age itself is not a limiting factor to the therapeutic approach of ulcerated breast cancer.

Studies performed to date on the prevalence of biliary lithiasis (BL) in chronic renal failure patients on hemodialysis (HD) have given contradictory results. The aims of the present study were to evaluate the prevalence of BL and its main associated risk factors in a population of hemodialysis patients, and to compare the results with those we had obtained previously in an overt population of the same zone. The study included 171 patients (83 M, 88 F), mean age 62.5 years and mean duration of dialysis 66.7 months. The screening protocol also included body mass index (BMI), a number of biochemical parameters and an ultrasound scan of the gallbladder and biliary tract. The general prevalence of BL was 33.3% (30.1% in men and 36.4% in women), and this figure was significantly higher than that found in our previous study. Prevalence increased with age in both sexes (Mantel-Haenszel Chisquared = 5.4, p < 0.03), but not with duration of dialysis. The main risk factors, evaluated with multiple logisstic regression, were the presence of diabetes mellitus and high serum phosphorus levels. Specific symptoms were also significantly associated in BL patients. No association was found with parity, BMI or serum lipid alterations. In conclusion, the prevalence of BL in a Sicilian population of HD patients was higher than that found in an overt population of the same area and the associated main risk factors were not coincident. Further studies are needed to establish the role played by the phase of end-stage renal disease before HD and to correct the metabolic disturbances to limit a high percentage of morbidity in a disease already in itself sufficiently disabling.

Background Kounis syndrome (KS) is characterized by concurrent presence of anaphylactic and cardiac components. Available evidence suggests that antibiotics are frequently associated to KS. We therefore analyzed KS cases associated with antibiotics use from the two largest pharmacovigilance databases. Methods Two pharmacovigilance databases, EudraVigilance and VigiLyze, were searched for cases reporting the adverse reaction "Kounis Syndrome" with antibiotics as suspected active substance. We analyzed the period from December 1st, 2001 to February 16th, 2016. For the most reported active substance, proportional reporting ratio (PRR) was calculated. Results A total of 10 cases of KS associated with antibiotic use were retrieved from EudraVigilance database. Mean patients' age was 58.2years and 70% were male. The most frequently reported suspected antibiotic was the combination amoxicillin/clavulanic acid (four cases). VigiLyze database reported 13 KS cases associated to antibiotics. Mean age was 56years and 61% of patients were male. The most frequently reported antibiotic was again the combination amoxicillin/clavulanic acid (five cases). Seven duplicate cases were identified, leaving a total of 16 cases of KS, with six of them associated to amoxicillin/clavulanic acid use. The PRR value for amoxicillin/clavulanic acid against other kinds of antibiotics was 2.62 considering EudraVigilance data and 1.61 considering VigiLyze data. Conclusions This analysis provided a complete picture of the cases of KS associated with antibiotic use and identified a possible association between amoxicillin/clavulanic acid and KS. Since the number of cases is low, especially considering its wide use, further analyses are needed to confirm the association.

Introduction The coincidental occurrence of a cardiac symptomatology (e.g. an acute coronary syndrome or a myocardial infarction), during an anaphylactic or anaphylactoid episode is known as Kounis Syndrome. A variety of drugs, substances, food and environmental exposures are associated with this reaction. There is an exponential increase in the number of published scientific articles reports on this syndrome, but since it is rare, the largest case series published so far included only 10 and 6 patients. Methods We searched the global World Health Organization database called VigiBase™ to detect all cases of Kounis Syndrome ever reported (last update December 31st 2014). Results We identified 51 cases of Kounis Syndrome reported to International Pharmacovigilance Agency (VigiBase™). All these cases were reported in the period 2010–2014 and almost half cases (22 reports) belonged to the year 2014. Most cases occurred in the USA and non-steroidal anti-inflammatory drugs were the most frequent trigger drugs. Discussion We collected pharmacovigilance international data representing the largest case series ever published on the recently identified Kounis Syndrome.

INTRODUCTION: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, severe and potentially fatal cutaneous adverse drug reaction (the mortality rate is up to 10 %) associated with numerous and apparently heterogeneous drugs. The aetiology is unknown. OBJECTIVE: To report Italian cases of DRESS over a 10-year period. METHODS: We searched the National Pharmacovigilance Network (NPN) for the term 'drug reaction with eosinophilia and systemic symptoms' from 1 January 2004 to 1 January 2014, to identify all reports of DRESS. Each case was checked to avoid duplication. RESULTS: In the NPN, we identified 91 serious cases of DRESS: 68 were spontaneous, still-unpublished reports, while 23 additional cases were derived from screening of the scientific literature, performed by marketing authorization holders. Notably, the single common element linking all cases of DRESS was intake of a drug containing an aromatic ring. CONCLUSION: Thanks to the largest national DRESS case series ever reported, we were able to hypothesize, for the first time, that there is an association between use of drugs containing an aromatic ring in their chemical structure and DRESS. This might aid understanding of the aetiology of DRESS and facilitate diagnosis.

Background. Endothelial cell damage occurs during vasculitic processes in vivo. With the alteration of the endothelium, exposure to basement membrane components may occur with induction of humoral immunity. Methods. In the present study, we evaluated the prevalence of antibodies against the basement membrane antigen laminin (LMN) in patients with ANCA-associated systemic vasculitis (AASV), pathologic controls (systemic lupus erythematosus, mixed cryoglobulinaemia, Henoch Schonlein purpura, primary glomerulonephritis) and normal individuals. Results. By ELISA, 21.6% of AASV (16/74) and 10% of pathologic controls (3/30), but only one of the normal controls (2.8%) had these antibodies (P = 0.02). When AASV patients were divided into two groups according to diagnosis and ANCA antigen specificity, antibodies to LMN were found in 27.5% of MPO-ANCA positive microscopic polyangiitis patients (11/40) vs only 14.7% of PR3-ANCA positive Wegener granulomatosis patients (5/34). There was no correlation between the presence or titre of anti-LMN antibodies and the main clinical and laboratory parameters. Conclusion. These results indicate that basement membrane antigens may become immunogenic in patients with AASV, especially in those with MPO-ANCA positivity. These antibodies are most likely the result of endothelial damage secondary to the initial inflammatory process but may well perpetuate further vascular damage in some patients.