Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Live concerts reduce cancer inpatients' anxiety.

In Italy a new experience of music medicine called "The Music Givers" is spreading among Oncology Units; it aims to organise weekly live concerts (length 45-60 min) followed by a buffet. Purpose of the present study is to evaluate the effect of the format of The Music Givers on cancer in-patients' anxiety. State-Trait Anxiety Inventory (STAI-Y) was administered to 111 in-patients before and after the concerts. After the concerts we observed a 3.87 point decrease in state anxiety (p < .001) and statistically significant differences in most of the domains assessed by STAI-Y. These results invite a reflection on the importance of offering to inpatients events such as live music concerts, in order to improve their psychological condition during hospitalisation.

Complementary needs behind complementary therapies in cancer patients.

OBJECTIVE: Although many studies indicate that the use of complementary and alternative medicine by cancer patients is common and widespread, few studies have focused on unmet needs of patients using complementary therapies (CTs). The aim of the present study was to evaluate, through a quantitative approach, possible associations between the use of CTs and the presence of specific unmet needs in cancer patients. METHODS: In six Italian oncology departments, 783 patients were interviewed about CTs use and completed the Needs Evaluation Questionnaire. Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. RESULTS: At the time of the survey, 38.3% of patients were using one or more types of CTs. According to Needs Evaluation Questionnaire, the use of CTs was associated (p < .05) with the need to be more involved in therapeutic choices (40% vs. 31.7%), the need to have a better dialogue with clinicians (44.4% vs. 37.2%), and the need to have more economic-insurance information in relation to their illness (46.1% vs. 36.4%). Statistical significance was confirmed with multivariable analysis for the last two items, whereas three more needs were associated with the use of CTs after adjustment: to receive more explanation on treatments (46.8% vs. 41.0%), to receive more comprehensible information (38% vs. 31.9%), and to receive more attention from nurses (16% vs. 12.1%). CONCLUSIONS: Our study shows interesting differences regarding perceived needs between cancer patients who use and who do not use CTs. Unmet needs that are more expressed in CTs users should be known and, when possible, could be taken into account to improve both psychosocial interventions in the context of conventional care process and the quality of the relationship between patient and medical and nursing staff.

Activity and safety of RAD001 (everolimus) in patients affected by biliary tract cancer progressing after prior chemotherapy: a phase II ITMO study.

BACKGROUND: Biliary tract cancer (BTC) is a highly lethal disease for which the best available therapy remains undetermined. The mammalian target of rapamycin (mTOR) pathway is up-regulated in several cancers, including BTC, and preclinical evidence indicates that mTOR inhibition may be effective in the treatment of BTC. We sought to evaluate the activity and tolerability of the mTOR inhibitor RAD001-everolimus-in patients with BTC progressing after prior chemotherapy. PATIENTS AND METHODS: This was an open-label, single-arm, phase II study (EUDRACT 2008-007152-94) conducted in eight sites in Italy. Patients with locally advanced, metastatic or recurrent BTC progressing despite previous chemotherapy received a daily oral dose of everolimus 10 mg administered continuously in 28-day cycles. The two primary end points were disease control rate (DCR) and objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS) and time-to-progression (TTP). RESULTS: Thirty-nine patients were enrolled. The DCR was 44.7%, and the ORR was 5.1%. One patient showed a partial response at 2 months and one patient showed a complete response sustained up to 8 months. The median (95% confidence interval) PFS was 3.2 (1.8-4.0) months, and the median OS was 7.7 (5.5-13.2) months. The median TTP was 2.0 (1.7-3.7) months. Most common toxicities were asthenia (43.6%), thrombocytopenia (35.9%), pyrexia (30.8%) and erythema, mainly of mild-to-moderate severity. Two patients required dose reduction due to adverse events. CONCLUSION: Everolimus demonstrated a favourable toxicity profile and encouraging anti-tumour activity. Further trials are needed to establish the role of everolimus in the treatment of BTC. EUDRACT 2008-007152-94.

Breast metastases from oligodendroglioma: an unusual extraneural spread in two young women and a review of the literature.

BACKGROUND: Extraneural dissemination of oligodendroglioma is rare. Cases of breast metastases have never been described in the literature. CASE REPORTS: We report the first two cases of young women with initial diagnosis of anaplastic oligodendroglioma who experienced mammary gland metastases and a review of the literature. RESULTS: Immunohistochemical analysis performed on material from both primary and metastatic sites did not allow to draw any conclusion on possible etiopathogenetic hypothesis. A review of literature yielded 35 cases of extracranial metastatic oligodendroglioma from 1989 to 2012. CONCLUSION: Though rare, extracranial dissemination from oligodendroglioma may occur not only in long surviving heavily pre-treated patients. The review of literature and these two cases suggest that spread is primarily to bone and then from bone to other organs through hematogenous route mostly due to leptomeningeal or dura mater invasion. Chemotherapy regimens similar to those commonly used for non metastatic oligodendroglioma are recommended for patients with good performance status.

A case of urinary incontinence by hydroxychloroquine in a geriatric patient.

WHAT IS KNOWN AND OBJECTIVE: Rheumatoid arthritis is an autoimmune disorder characterized by persistent synovitis and systemic inflammation. Genetic factors account for approximately 50% of cases of rheumatoid arthritis and environmental factors include smoking. Urinary incontinence may occur as a medication adverse effect. We present the first report of a case of hydroxychloroquine-induced urinary incontinence in rheumatoid arthritis. DETAILS OF THE CASE: A 71-year-old female with a history of rheumatoid arthritis developed urinary incontinence as an adverse drug reaction to hydroxychloroquine administered at therapeutic doses. Urinary incontinence remitted with drug withdrawal and reappeared on rechallenge. The Naranjo's algorithm indicated that hydroxychloroquine was a probable cause of this adverse drug reaction. The likely mechanism of this adverse drug is a direct action of the quinolone on the urinary system. WHAT IS NEW AND CONCLUSION: This is the first report of hydroxychloroquine-induced urinary incontinence. The absence of previous reports suggest that the drug rarely causes this adverse effect. Methotrexate is most often used as first-line treatment, and several other drugs are now available to act as Disease-Modifying Antirheumatic Drugs (DMARDs). These drugs may be used alone or combined with methotrexate, most often to increase efficacy and reduce toxicity. The introduction of new biological agents, such as abatacept, rituximab, tocilizumab and inhibitors of tumour necrosis factor, has opened new therapeutic perspectives but are restricted by high costs and risk of infections. Thus, antimalarial drugs, especially the quinolones chloroquine (CQ) and hydroxychloroquine (HCQ), are still in use, and the latter is very efficacious. An advantage of HCQ is its low toxicity compared with other antimalarial drugs. Common side-effects of HCQ and the other antimalarial drugs include gastrointestinal effects such as nausea and vomiting, as well as skin rashes and headache, whereas their most common and severe side-effect is retinopathy. No case of urinopathy has been reported previously with HCQ.

Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is an emerging treatment for patients with locally advanced pancreatic carcinoma, and can be combined with radiochemotherapy and intra-arterial plus systemic chemotherapy. METHODS: This observational study compared two groups of patients with locally advanced pancreatic carcinoma treated with either primary RFA (group 1) or RFA following any other primary treatment (group 2). RESULTS: Between February 2007 and May 2010, 107 consecutive patients were treated with RFA. There were 47 patients in group 1 and 60 in group 2. Median overall survival was 25·6 months. Median overall survival was significantly shorter in group 1 than in group 2 (14·7 versus 25·6 months; P = 0·004) Patients treated with RFA, radiochemotherapy and intra-arterial plus systemic chemotherapy (triple-approach strategy) had a median overall survival of 34·0 months. CONCLUSION: RFA after alternative primary treatment was associated with prolonged survival. This was further extended by use of a triple-approach strategy in selected patients. Further evaluation of this approach seems warranted.

Low dose fractionated cisplatin plus gemcitabine for elderly patients with advanced non small cell lung cancer: a retrospective analysis.

The aim of the study was to evaluate safety and efficacy of gemcitabine-cisplatin in elderly patients with advanced non small cell lung cancer (NSCLC). This study included 59 patients aged >70 years consecutively admitted to our Department. treatment consisted of gemcitabine 1000 mg/m(2) on days 1 and 8, and low-dose fractionated cisplatin 20 mg/m(2) on days 1, 2, 3 of a 21-day cycle. Toxicity was graded according to the world Health Organization (WHO) criteria.A total of 281 cycles was administered. Hematological toxicities of grade 3 and 4 were seen in 17% and 5% of patients, respectively. Grade 3 gastrointestinal toxicity was 3%, grade 2 neuropathy was 2%. Twenty-nine partial responses with an objective response rate of 49% were obtained. No complete responses were observed. The median progression-free survival (PFS) and overall survival (OS) were 7.8 and 15.5 months respectively. Cisplatin-based combination chemotherapy at low doses appears to be safe and active in older patients with advanced NSCLC.

A multi-centre retrospective review of second-line therapy in advanced pancreatic adenocarcinoma.

INTRODUCTION: Limited information on second-line treatment in patients with pancreatic adenocarcinoma is available. At time of first-line treatment failure, approximately half of the patients are candidates for further treatment. MATERIAL AND METHODS: A retrospective review of 183 patients submitted to second-line therapy has been performed to identify prognostic factors, provides useful information for patients counseling and generates hypotheses for future studies. Inclusion criteria were: cytological or histologic diagnosis of pancreatic adenocarcinoma and prior gemcitabine-including chemotherapy. Any age, performance status (PS) and chemotherapy regimen were considered. RESULTS: One hundred and eighty-three patients (106 males; 168 metastatic; median age 62 years; median PS 1; 63 submitted to prior curative surgery, 32 to prior radiotherapy) with a median previous progression-free survival (PFS) of 6.7 months were included. Median and 6-month PFS after initiation of salvage therapy were 3.0 months and 20%. Median, 1 and 2 years, overall survival after initiation of salvage therapy were 6.2 months, 17 and 4%, respectively. Previous PFS, CA19.9 levels and age independently predicted OS. CONCLUSION: Re-challenge with gemcitabine and 5-fluorouracil administration may have a role in selected patients.

Comparison of incidence of sepsis in cancer patients that underwent systemic or loco-regional chemotherapy.

In this retrospective non controlled trial we evaluated the incidence of sepsis in cancer patients in two different periods (January-June 2003 versus January-June 2004). The main difference in these two periods was that in our oncology department we changed from systemic chemotherapy to loco-regional chemotherapy using less myelosuppressive drugs and developed the domiciliary assistance. The aim of the study was to assess the incidence of sepsis in order to demonstrate a reduction of the infection related to the change of chemotherapy. In addition, this study may be able to describe the epidemiology of sepsis in cancer patients afferent to our oncology department. The incidence of sepsis was reduced in the second period from 24.3% to 6.2%. The pathogens more frequently isolated in this study were coagulase-negative staphylococci (CNS) followed by Escherichia coli and Staphylococcus aureus. Less invasive therapy may reduce infective complication of chemotherapy. The epidemiology of sepsis may be very helpful to design empiric therapeutic protocol for febrile patients that have received chemotherapy.

Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer.

OBJECTIVES: This study evaluated the clinical activity and toxicity of combination chemotherapy with irinotecan and oxaliplatin in patients with advanced pancreatic cancer that had progressed despite > or =1 course of a gemcitabine-containing regimen. METHODS: Thirty patients with metastatic pancreatic cancer and Karnofsky performance status > or =70 received oxaliplatin 60 mg/m2 on days 1 + 15 and irinotecan 60 mg/m2 on days 1 + 8 + 15 every 4 weeks. Patients were assessed on the basis of clinical benefit response, changes in serum tumour marker CA 19-9, objective tumour response, time to progressive disease (TTP), and survival. RESULTS: Six patients (20%) had clinical benefit response (median duration of 7.2 months). CA 19-9 levels were reduced > or =50% from baseline in 8 patients (26%) and remained stable in 8 patients. CT scans revealed that 3 patients (10%) had a partial response and 7 (23%) had stable disease. Two patients (7%) were down-staged and underwent surgery. Median TTP was 4.1 months, median survival was 5.9 months and the 1-year survival rate was 23.3%. The most serious adverse events were grade 3-4 leukopenia in 2 patients (6%), grade 3 neuropathy in 2 (6%) and grade 3 diarrhoea in 1 (3%). CONCLUSION: Chemotherapy with irinotecan and oxaliplatin is an active and well-tolerated combination in patients with advanced pre-treated pancreatic cancer.

Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology.

Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.

Intra-arterial chemiotherapy for invasive bladder cancer.

Standard treatment for transitional cell carcinoma confined to the bladder is radical cystectomy that allow to obtain an overall 5-year disease-free survival rate only of 50-70%. It has been demonstrated that intra-arterial chemotherapy produces the same survival outcomes as radical cystectomy. This study aimed to evaluate the activity and toxicity of a bladder-sparing loco-regional treatment. Five patients with transitional cell carcinoma of the bladder (4 locally advanced and 1 pelvic relapse) were treated with doxorubycin 25 mg/m2, cisplatin 40 mg/m2 and methotrexate 50 mg/m2, all infused bolus via internal iliac arteries on day 1, every three weeks. We obtained 3 complete responses, 1 stable disease and 1 progression of disease. The treatment was well tolerated with a minimal hematological toxicity and no others major toxicity. Median disease free survival was 8 months (1-17), median overall survival was 22 months (2-55). This loco-regional regimen of chemotherapy is active and safe in locally advanced bladder cancer patients and permits a prolonged good quality of life regarding the maintenance of the physiological functions of the lower urinary tract.

Molecular therapy: clinical applications. intra-arterial adenoviruses administration.

Gene therapy involves the introduction of foreign DNA into somatic cells to produce a therapeutic effect. The therapeutic gene is transferred into the tumor cells using a vector. Transfer may either be in vivo in which the DNA and vector are directly introduced into the body, or ex vivo, in which cells are removed from the body, transfected with DNA and then reintroduced into the patients. The mode of gene transfer can be classified into chemical, physical and viral (1). Viruses are the most popular vectors in clinical trials because they invade cells and manipulate the cell's machinery to make viral protein; but the immune response they provoke can rapidly destroy the viral vector or the infected cells, blocking production of the useful protein. Most nonviral vector fly under the radar of immune system, but most of them have not been as efficient as viruses in shuttling genes into cells and the genes that were delivered didn't remain active for long. Intra-arterial administration can have advantages over intravenous, and intralesion routes.

Regional combined with systemic chemotherapy in unresectable biliary tract cancers: a phase II study.

Unresectable biliary tract cancers have a very poor prognosis. No good systemic chemotherapeutic regimen is available. This study aimed to evaluated the activity and toxicity of a novel approach of combined loco-regional and systemic chemotherapy. Twenty four patients with advanced or metastatic biliary tumors were treated with epiadriamycin 50 mg/m2 and cisplatin 60 mg/m2 administered bolus in proper hepatic artery on day 1, combined with systemic continuous infusion of 5-fluorouracil 200 mg/m2/day, from day 1 to day 14, every 3 weeks. The overall response rate was 8/24 (33%), including one complete response and 7 partial responses (stable disease 46%, progression 21%). The treatment was well tolerated with a minimal hematological toxicity; the major clinical problem was the deep venous thrombosis related to central venous catheter, that occurred in 5 patients (21%). Median overall survival was 14,6 months and 1-year and 2-year survival were 54% and 38% respectively. Performance status improved in 33% of patients and weight gain more than 7% was observed in 17%. This novel combined loco-regional and systemic chemotherapeutic regimen is active and safe for advanced biliary tract cancer patients.

Randomised trial of gemcitabine versus flec regimen given intra-arterially for patients with unresectable pancreatic cancer.

Gemcitabine is considered the golden standard treatment for unresectable pancreatic adenocarcinoma. Intra-arte-rial drug administration had shown a deep rationale with some interesting results. In a multicenter phase III trial, we compared gemcitabine given weekly with a combination of 5-fluoruracil, leucovorin, epirubicin, carboplatin (FLEC) administered intra-arteriously as first-line therapy in unresectable pancreatic adenocarcinoma. Patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arteriously at three-weekly interval for 3 times. The primary end point was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=.036). Survival at 1 year was increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both group (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, FLEC regimen given intra-arteriously, improved survival in patient with unresectable pancreatic adenocarcinoma.

General practitioners' management of low back pain: impact of clinical guidelines in a non-English-speaking country.

STUDY DESIGN: Cross-sectional. OBJECTIVES: To evaluate the assessment of patients with low back pain by general practitioners (GPs) in a non-English-speaking country and to compare their behavior with AHCPR and CSAG clinical guidelines. SUMMARY OF BACKGROUND DATA: The diffusion of clinical guidelines (and their everyday application by health care professionals) is a significant problem. Because most guidelines are developed in English, concerns over their diffusion are obviously greater in non-English-speaking countries. METHODS: A questionnaire was sent to all the GPs in the province of Mantua, Italy (n = 318). The authors evaluated what examinations are routinely performed and what danger symptoms and signs prompt referral of patients. GPs indicated the frequency of their prescription of radiographs, computed tomography scans, magnetic resonance imaging, laboratory tests, and consultations. The findings were compared with a "gold standard": the AHCPR and CSAG clinical guidelines. RESULTS: The response rate was 68.2%. Only 28.0% of GPs perform all the tests considered important by the clinical guidelines, and 33.0% were aware of all the red flags. Correspondence with the clinical guideline recommendations ranged from 14.6% to 89.4%. There is a clear tendency to overprescribe examinations in acute cases, whereas in chronic cases underprescription is sometimes seen. CONCLUSIONS: In a non-English-speaking country the evaluation of low back pain by GPs does not reflect current recommendations, and the situation is seen to be worse than in English-speaking countries. Concerns over the diffusion of guidelines must therefore be considered greater in non-English-speaking countries, where thorough presentation to GPs of the existing "evidence-based" guidelines is to be recommended.