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International audience; Biosecurity is crucial for infectious disease prevention, more importantly in the absence of vaccination. The need for improving the implementation of biosecurity practices was highlighted in French duck farms following the 2016-2017 H5N8 Highly Pathogenic Avian Influenza (HPAI) epidemic. Farmers have multiple reasons for not implementing biosecurity practices: external (time, money) and internal (socio-psychological). The purpose of this study was to determine how sets of socio-psychological factors (i.e. knowledge on biosecurity and avian influenza transmission, attitudes, personality traits, social background) affect the adoption of on-farm biosecurity practices. Biosecurity practices and socio-psychological determinants were assessed during 127 duck farm visits, in South West France, using both questionnaires and on-farm observations. Factorial analysis of mixed data (FAMD) and hierarchical clustering analysis (HCA) identified three groups of farmers with different socio-psychological profiles: the first group was characterized by minimal knowledge, negative attitudes towards biosecurity, little social pressure and a low level of conscientiousness. The second group was characterized by more extensive experience in poultry production, higher stress and social pressure. The third group was characterized by less experience in poultry production, better knowledge and positive attitudes towards biosecurity, increased self-confidence and orientation towards action. The first group had a significantly lower adoption of biosecurity measures than the two other groups. A better understanding of the factors involved in farmers' decision-making could improve the efficiency of interventions aiming at improving and maintaining the level of on-farm biosecurity in the duck industry.

Objectives This article reports findings on the usability and staff use of 5 condition- specific pamphlets of high prevalence in long-term care (LTC): dementia, heart failure, chronic obstructive pulmonary disease, renal failure, and frailty. The pamphlets were created in response to residents', families', and staff's recommendations for activating early reflections and communication about end-of-life care. Design A mixed-method (qualitative and quantitative) survey design was used. Step 1 collected survey data on the usability of the pamphlets. Step 2 collected survey data on pamphlet use. Settings and Participants Two nurses with specialized palliative care training, 2 resident/family representatives, 10 condition-specific specialists, and 33 LTC palliative leads reviewed the pamphlets for usability prior to distribution. A total of 178 LTC home staff in 4 participating LTC homes reported on pamphlet use. Measures Specialists and resident/family representatives were asked to provide open comments and LTC home palliative leads were asked to complete a survey on the accuracy, readability, and relevance of the pamphlets. After 6 months of distribution, all staff in participating LTC homes were asked to complete a survey on pamphlet use, usefulness, and comfort with distribution. Results The pamphlets were reportedly accurate, relevant, and easy to understand. Following 6 months of availability, most staff in LTC had read the pamphlets, found the information useful, and planned to share them. However, half of the staff questioned their role in pamphlet distribution and most had not distributed them. Regulated staff (ie, staff affiliated with a regulated profession) expressed more comfort sharing the pamphlets than care aides and support staff. Conclusions/Implications Condition-specific pamphlets appear to hold promise in providing residents and families with relevant information that may activate early reflections and conversations about end-of-life care. However, structured implementation strategies, training, and discussions are required to improve staff comfort with distribution and explore roles in distribution and follow-up.

Objective Difficulty to recognize or canulate the right adrenal vein is the most frequent cause of adrenal venous sampling (AVS) failure. We aimed to assess multinomial regression modeling (MRM) of peripheral and left adrenal vein samplings to detect lateralization of aldosterone secretion when the right AVS is missing. Methods Simultaneous bilateral AVS samplings were performed before (basal) and after intravenous cosyntropin injection in 188 consecutive patients between December 1989 and September 2015. Different reference standards for lateralization of aldosterone secretion were defined for basal and for postcosyntropin AVS and according to lateralization index cutoffs at least 2 and at least 4. MRMs were built to detect lateralization of aldosterone secretion according to these reference standards using only peripheral and left adrenal veins samplings (without the right AVS). Detection accuracy was assessed by the area under the receiver operating characteristic (AUROC) curves and detection sensitivities were reported for specificity at least 95%. Results For basal AVS with lateralization index at least 2, AUROC were respectively 0.931 [95% confidence interval (CI) 0.894-0.968] and 0.922 (95% CI 0.882-0.962) for right and left lateralization of aldosterone secretion detection and MRM could detect respectively 65.5 and 62.7% of the right and left lateralization of aldosterone secretion. For AVS after cosyntropin with lateralization index at least 4, AUROC were respectively 0.964 (95% CI: 0.940-0.987) and 0.955 (95% CI: 0.927-0.983) for right and left lateralization of aldosterone secretion, and MRM could detect respectively 77.2 and 72.9% of the right and left lateralization of aldosterone secretion. Conclusion MRM can detect lateralization of aldosterone secretion without the right AVS in most patients and could eliminate the need for repeat AVS when right adrenal vein canulation is nonselective or impossible.

OBJECTIVE: To determine whether provision of vaccine-health-literacy-promoting information in text message vaccine reminders improves receipt and timeliness of the second dose of influenza vaccine within a season for children in need of 2 doses. METHODS: During the 2012–2013 season, families of eligible 6-month through 8-year-old children were recruited at the time of their first influenza vaccination from 3 community clinics in New York City. Children (n = 660) were randomly assigned to “educational” text message, “conventional” text message, and “written reminder-only” arms. At enrollment, all arms received a written reminder with next dose due date. Conventional messages included second dose due date and clinic walk-in hours. Educational messages added information regarding the need for a timely second dose. Receipt of second dose by April 30 was assessed by using χ2 tests. Timeliness was assessed by receipt of second dose by 2 weeks after due date (day 42) using χ2 and over time using a Kaplan-Meier analysis. RESULTS: Most families were Latino and publicly insured with no significant between-arm differences between groups. Children in the educational arm were more likely to receive a second dose by April 30 (72.7%) versus conventional (66.7%) versus written reminder-only arm (57.1%; P = .003). They also had more timely receipt by day 42 (P < .001) and over time (P < .001). CONCLUSIONS: In this low-income, urban, minority population, embedding health literacy information improved the effectiveness of text message reminders in promoting timely delivery of a second dose of influenza vaccine, compared with conventional text messages and written reminder only.

Many young children identified with developmental concerns in pediatric settings do not receive early intervention (EI). We assessed the impact of a video decision aid and text message reminder on knowledge and attitudes regarding developmental delay and EI as well as referral completion. We conducted a pilot randomized controlled trial in an urban setting and enrolled 64 parent-child dyads referred to EI. Compared with controls, participants who received the intervention demonstrated increased knowledge regarding developmental delay and EI as well as more favorable attitudes in certain topics. Although we did not find a significant difference between arms in EI intake and evaluation, we found a pattern suggestive of increased intake and evaluation among participants with low health literacy in the intervention arm. Additional study is needed to identify strategies that improve the EI referral process for families and to understand the potential targeted role for decision aids and text messages.

We compared results of a modified version of the Asthma Control Test using parent proxy report (PP-ACT) with results reported by children and parents using the validated Childhood-Asthma Control Test (C-ACT). 104 parent-child dyads with a child aged 6 to 12 years with asthma were randomized to complete PP-ACT followed by C-ACT or C-ACT followed by PP-ACT. Scores ≤19 indicated uncontrolled asthma. We calculated sensitivity, specificity, positive predictive value, and negative predictive value for the PP-ACT in comparison with the C-ACT, and calculated concordance between the 2 scales. The PP-ACT had sensitivity of 86% and negative predictive value of 88% for detecting uncontrolled asthma. More than 75% of surveys were concordant (κ = 0.54, moderate agreement). Our results suggest that while the PP-ACT missed few children with uncontrolled asthma and may simplify reporting of asthma control in circumstances when child report is not feasible or creates barriers to survey receipt, limitations of proxy reporting should be considered.

Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design. Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks. Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277–84. ©2016 AACR.

Background: Patient portals may improve communication between families of children with asthma and their primary care providers and improve outcomes. However, the feasibility of using portals to collect patient-reported outcomes from families and the barriers and facilitators of portal implementation across diverse pediatric primary care settings have not been established. Objective: We evaluated the feasibility of using a patient portal for pediatric asthma in primary care, its impact on management, and barriers and facilitators of implementation success. Methods: We conducted a mixed-methods implementation study in 20 practices (11 states). Using the portal, parents of children with asthma aged 6-12 years completed monthly surveys to communicate treatment concerns, treatment goals, symptom control, medication use, and side effects. We used logistic regression to evaluate the association of portal use with child characteristics and changes to asthma management. Ten clinician focus groups and 22 semistructured parent interviews explored barriers and facilitators of use in the context of an evidence-based implementation framework. Results: We invited 9133 families to enroll and 237 (2.59%) used the portal (range by practice, 0.6%-13.6%). Children of parents or guardians who used the portal were significantly more likely than nonusers to be aged 6-9 years (vs 10-12, P=.02), have mild or moderate/severe persistent asthma (P=.009 and P=.04), have a prescription of a controller medication (P

Measles-mumps-rubella (MMR) vaccination is important for preventing disease outbreaks, yet pockets of under-vaccination persist. Text message reminders have been employed successfully for other pediatric vaccines, but studies examining their use for MMR vaccination are limited. This study assessed the impact of text message reminders on timely MMR vaccination.Parents (n=2054) of 9.5-10.5-month-old children from four urban academically-affiliated pediatric clinics were randomized to scheduling plus appointment text message reminders, appointment text message reminder-only, or usual care. The former included up to three text reminders to schedule the one-year preventive care visit. Both text messaging arms included a text reminder sent 2 days before that visit. Outcomes included appointment scheduling, appointment attendance, and MMR vaccination by age 13 months, the standard of care at study sites.Children of parents in the scheduling plus appointment text message reminders arm were more likely to have a scheduled one-year visit than those in the other arms (71.9% vs. 67.4%, relative risk ratio (RRR) 1.07 [95% CI 1.005-1.13]), particularly if no appointment was scheduled before randomization (i.e., no baseline appointment) (62.1% vs. 54.7%, RRR 1.14 [95% CI 1.04-1.24]). One-year visit attendance and timely MMR vaccination were similar between arms. However, among children without a baseline appointment, those with parents in the scheduling plus appointment text message reminders arm were more likely to undergo timely MMR vaccination (61.1% vs. 55.1%, RRR 1.11 [95% CI 1.01-1.21]).Text message reminders improved timely MMR vaccination of high-risk children without a baseline one-year visit.

The understanding of palliative care practices at home (PCH) is limited by the lack of available scientific knowledge. This is explained by the fact that its practices are relatively recent and they question our relationship with death and dying individuals. This study aims to contribute to the advancement of knowledge about PCH with the elderly. More specifically, with a perspective of social exclusion, it aims to understand how practices either do or do not produce social exclusion with seniors receiving palliative care. Nineteen participants from two local community services centers were interviewed and six multidisciplinary meetings were attended for observation. This study suggests that positive representations concerning the elderly in palliative care and recognition of their autonomy can avoid social exclusion, including its symbolic and identificatory dimensions. However, standardization of practices seems to contribute to institutional exclusion and foster nonrecognition.

Biosecurity compliance is an issue in all types of animal production. Poor compliance is frequently related to lack of knowledge or comprehension. Human dimensions, such as personality and attitudes were also suggested as being related to compliance. As part of a larger study, personality traits, experience, education and training of employees, visitors and growers were evaluated to assess their relationship with their compliance with biosecurity measures when entering and exiting poultry barns. Biosecurity compliance was evaluated using hidden cameras. One hundred fourteen individuals involved in a total of 2379 visits on 23 poultry farms responded to a personality test. Results demonstrated that several determinants of compliance exist, and some are related to personality, experience and education. Three personality traits were significantly associated with compliance: responsibility, complexity and action-oriented. Such information has important implications for the selection of job applicants or task attribution and to enhance effectiveness of training programs.

Biosecurity compliance is generally poor in all types of animal production systems around the world. Therefore, it is essential to define strategies to improve the implementation of biosecurity measures. This study evaluated the value of audits and visible cameras on compliance with biosecurity measures required when entering and exiting poultry barns on 24 poultry farms in Quebec, Canada. Short term (first two weeks) and medium term (six months later) compliance were determined. Application of biosecurity measures was evaluated using hidden cameras. Video viewing revealed a total of 2748 visits by 259 different individuals. Results showed that bimonthly audits did not have any impact on medium term compliance. Visible cameras had a significant impact on changing boots (OR=9.6; 1.9-48.4) and respecting areas (contaminated vs. clean) during the visit (OR=14.5; 1.2-175.1) for the short term period. However, six months later, compliance declined and was no longer significantly different from controls. Duration and moment of the visit, presence of the grower or an observer, barn entrance design, number of barns, number of biosecurity measures requested, type of boots worn, gender and being a member of a grower's family were significantly associated with biosecurity compliance.

Background and study aims The high-frequency endosonography miniprobe has been advocated prior to endoscopic treatment of superficial esophageal neoplasm. We conducted a retrospective study, which summarized our clinical experience with various miniprobe techniques in the assessment of early squamous cell carcinoma (SCC) and superficial adenocarcinoma on Barrett's mucosa (SAB). Patients and methods A total of 106 superficial and naive esophageal lesions were included in this series (52 SAB, 54 SCC). The results of the miniprobe staging were compared with pathology in order to determine the accuracy of this technique in differentiating mucosal from submucosal infiltration. Secondary aims were a comparison between the frequencies (20- vs. 30-MHz) and coupling methods (water-filled lumen vs. balloon-sheathed catheter) used. Results Overall accuracy, sensitivity, and specificity to differentiate T1sm from T1 m tumors were 73.5 %, 62 %, and 76.5 %, respectively. Overdiagnosis occurred in 18.6 % of the lesions. No statistically significant difference was found in the accuracy of the miniprobe staging between the two lesion types (SCC and SAB) ( P = 0.65), and results were significantly poorer in the distal part of the esophagus ( P = 0.00039). No significant difference was found between the two frequencies ( P = 0.51). Water-filled lumen proved to be superior to the balloon-sheathed catheter ( P = 0.015). Conclusion High-frequency miniprobe examination has a limited accuracy in the detection of submucosal invasion in early esophageal cancer. Further improvements in acoustic coupling and ultrasound technique are required to improve the miniprobe accuracy before its implementation into clinical routine.

International audience; Studies have linked the use of corporal punishment of children to the development of mental health disorders. Despite the recommendation of international governing bodies for a complete ban of the practice, there is little European data available on the effects of corporal punishment on mental health and the influence of laws banning corporal punishment. Using data from the School Children Mental Health Europe survey, the objective of this cross-sectional study was to examine the prevalence and legal status of corporal punishment across six European countries and to evaluate the association between parental use of corporal punishment and children's mental health. The study found that odds of having parents who reported using occasional to frequent corporal punishment were 1.7 times higher in countries where its use is legal, controlling for socio-demographic factors. Children with parents who reported using corporal punishment had higher rates of both externalized and internalized mental health disorders.

Thymidine (dThd) has been shown to increase the activity of BCNU in mice, possibly due to its ability to inhibit poly(ADP-ribose)polymerase (PADPRP), an enzyme thought to be active in DNA repair. The present phase I study characterized the pharmacokinetics and toxicity of dThd combined with BCNU. Sixty patients with refractory malignancies were infused with escalating doses of dThd from 7.5g/m2/day to 105.5 g/m2/day for 48 hr, along with 100 mg/m2/day of BCNU for 2 doses. Further dose escalation of dThd was limited by large fluid volumes required; therefore, the BCNU dose was escalated to a maximum of 160 mg/m2/day for 2 days. Plasma dThd concentrations were determined using high-performance liquid chromatography. At doses above 37.5 g/m2/day, steady-state concentrations of dThd approached or exceeded 1 mM, a concentration that nearly completely abolished BCNU-induced PADPRP activity in preclinical studies. Myelosuppression was consistent with BCNU dose but was not apparently increased by the coadministration of dThd. One patient had a partial response to therapy. Both the lack of effect of increasing dThd doses on BCNU-induced myelosuppression and the low response rate suggest that the schedule of drug administration was not optimal to inhibit PADPRP, or that PADPRP may not be essential in repairing BCNU-mediated DNA damage in humans.

We conducted a Phase II study to determine the efficacy of cisplatin, doxorubicin, mitomycin C, and 5-fluorouracil in patients with untreated non-small cell lung cancer. Patients were accrued through the Connecticut Oncology Association (COA), an organization composed of community and university oncologists. Thirteen COA oncologists enrolled 30 patients over 12 months and 26 were eligible for the final analysis. Patients received cisplatin 75 mg/m2, doxorubicin 30 mg/m2, mitomycin C 6.5 mg/m2, and 5-fluorouracil 750 mg/m2 on day 1. The treatment was repeated every 4 weeks, with mitomycin C given during the first 3 cycles and then every other cycle. There were 5 (19%) partial responses, lasting 1.3-7.3 months. The median time to progression was 10.3 months (0.3-12.5 months). Median survival was 7.5 months (0.3-34 months). The major toxicities were related to myelosuppression and there was one septic death. This study demonstrates the limited efficacy of an aggressive regimen using "active" agents in patients with advanced non-small cell lung cancer.

Cyclosporine (cyclosporin A, CSA) prolongs the survival of transplanted organs by reducing the transcription of cytokines, especially interleukin-2, that are thought to mediate T-cell expansion and subsequent graft rejection. Recently, CSA has been suggested as a potentially effective agent in the treatment of T-cell neoplasms. As a result, a Phase II trial of CSA was done in patients with refractory T-cell lymphomas.Patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who had disease progression after at least one previous therapy were eligible for participation. CSA was administered orally at a dose of 7.5 mg/kg twice daily, and the patients were followed for disease response and toxicity.A total of 16 patients were treated. Five patients had PTCL, and 11 had CTCL. Most patients were pretreated extensively with chemotherapy and/or radiation therapy. No responses occurred in patients with PTCL. Two of 11 patients with CTCL responded to therapy. Both patients who responded to CSA had recurrent disease that approached baseline levels within 1 week of discontinuing therapy. A second response occurred in both patients after reinstitution of therapy. Although most patients were removed from the study because of disease progression, renal toxicity was significant.Most patients with refractory T-cell lymphomas did not respond to CSA, suggesting that these malignancies are not interleukin-2 dependent or, alternatively, that CSA did not reach its intracellular target. In the two responding patients, the pattern of repeated rapid regression of disease after CSA administration and subsequent rapid recurrence after a temporary halt in therapy suggested that CSA was cytostatic rather than cytocidal or that the clinical remissions were mediated by the antiinflammatory effects of the drug.

We conducted a study evaluating the efficacy of simultaneous administration of 5-fluorouracil, mitomycin C, and X-irradiation in unresectable Stage III non-small cell lung cancer. Radiation was delivered in a split course to a total of 55 Gy. In the first course, radiation was administered daily in 250 cGy fractions for 12 treatments. Following a two week rest, an additional 10 treatments of 200 cGy fractions were delivered. Chemotherapy consisted of 10 mg/M2 of mitomycin C on day 1, and 1000 mg/M2 per day of 5-fluorouracil by continuous infusion on days 1 through 5 and 29 through 33. Twenty-one enrolled patients were evaluable. The overall response rate was 52% (95% confidence intervals 31-73%), with a median duration of response of 42 weeks. There were 5 complete responders (24%) and four of these patients remain disease-free with follow-up between 24-54 months. The median survival time for all patients was 59 weeks. For the complete responders the median survival time has not yet been reached, but is in excess of 42 months. Toxicity consisted of moderate stomatitis and myelosuppression. The sustained remissions obtained by 4 of 21 patients (18%) treated with concurrent mitomycin C, 5-fluorouracil and x-irradiation are encouraging and deserve further study.

In an attempt to increase the antitumor effect of cisplatin (50 mg/m2) and dacarbazine (350 mg/m2), each repeated on days 1 to 3 every 4 weeks in patients with metastatic melanoma, tamoxifen was added to the regimen. Before the first course of chemotherapy, the patients received a loading dose of tamoxifen (100 mg orally twice a day for 7 days), followed by a maintenance dose of 10 mg orally twice a day and continued throughout the treatment. Aspirin (325 mg orally every other day) was administered at the same time as the tamoxifen in an attempt to reduce the risk of thromboembolic events. The activity of high-dose cisplatin with dacarbazine and tamoxifen was disappointing. Of 23 evaluable patients, only three responded--an overall response rate of 13% (95% confidence limits, 0% to 27%). These responses consisted of one pathologic complete remission in a patient with nodal metastases, one clinical complete remission in a patient with a very large pelvic mass, and one partial response in another patient with nodal metastases. The duration of responses was 12+, 4, and 4 months, respectively. These data do not support a significant interaction between tamoxifen and cisplatin or dacarbazine. Assuming that tamoxifen is important in the cisplatin, dacarbazine, and carmustine combination, as suggested by others, the most relevant interaction may be between tamoxifen and carmustine.

Cyclosporin A (CSA) is an immunosuppressive agent that in experimental models has antiproliferative activity against colon cancer and other human neoplasms. A phase II trial was conducted to evaluate CSA in refractory colorectal malignancies. CSA was administered at a starting dose of 7.0 mg/kg twice daily (total dose, 14 mg/kg/day) and escalated to tolerance. Of 18 patients with measurable disease, 17 were evaluable. All had been treated with one fluorouracil-containing regimen. The European Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 17 of the 18 patients. No objective responses were seen. Four patients maintained stable disease lasting from 10 to 75+ weeks. Significant toxicity occurred in 9 of 17 (53%) patients. Dose reduction was necessary in 10 of 17 (59%). Sustained escalation beyond the initial dose was possible in only two cases. Toxicities included nausea and vomiting (71%), nephrotoxicity (41%), fatigue (35%), flu-like symptoms (29%), and neurotoxicity (18%). In the dose and schedule employed in this trial, CSA is ineffective in refractory colorectal cancer and produces significant toxicity.

Nine patients with metastatic malignant melanoma were entered onto a phase II trial consisting of WR-2721, 740 mg/m2 i.v. over 15 min, followed 15 min after completion by cisplatin, 100 mg/m2 i.v. over 30 min in 250 cc of 3% saline, on days 1 and 8 every 4 weeks. Six patients received two full courses of chemotherapy and were considered evaluable for response. No patients obtained a response. Toxicity, assessed according to the National Cancer Institute Common Toxicity Criteria, was acceptable and usually transient. However, fatigue, which manifested as a decrease in performance status, was significant in six of eight patients in whom this side effect could be evaluated. This subjective toxicity was most likely due to the high-dose cisplatin therapy. The lack of response in six fully evaluable patients allowed us to conclude with greater than 95% confidence that the combination of high-dose cisplatin and WR-2721 in a split-course day 1 and 8 schedule has a true response rate of less than 40%. In view of the relatively high subjective toxicity observed in our study and the more encouraging results observed by other groups using a different dose schedule of WR-2721 plus cisplatin, we do not recommend the use of high-dose cisplatin plus WR-2721 as employed in this trial.

The combination of cisplatin plus dacarbazine (DTIC) is active in metastatic melanoma with response rates reported between 10% and 55%. To optimize this regimen, a Phase II study was conducted employing a dose intensity of cisplatin higher than previously reported. Twenty-two patients were treated. Eight patients received cisplatin 100 mg/m2 on days 1 and 8 combined with DTIC 300 mg/m2 on days 1, 2, 8 and 9 (regimen A). Because of excessive toxicity, the protocol was modified so that cisplatin was given at 50 mg/m2 per day and DTIC 350 mg/m2 per day on days 1 through 3 (regimen B). The overall response rate was 32% and consisted of four partial and three complete responses (CR). The median duration of response was 6 months. Two of the CR remain in sustained, unmaintained remission in excess of 1.5 years. All seven patients that responded were treated on regimen B. High-dose cisplatin plus DTIC on a 3-day schedule represents an effective, well-tolerated therapy for metastatic melanoma.

The importance of the interval between methotrexate (MTX) and fluorouracil (5-FU) was studied in 168 patients with previously untreated, measurable, advanced colorectal cancer. They were randomized to receive MTX 200 mg/m2, followed by 5-FU 600 mg/m2 either 24 hours (arm A) or 1 hour (arm B) after MTX. All patients received leucovorin (LV) 24 hours after MTX, 10 mg/m2 orally every 6 hours for six doses. The regimen was repeated every 2 weeks, with 5-FU escalation as tolerated. Arm A was significantly better than arm B with respect to overall response rate (29% v 14.5%, P = .026), time to progression (TTP; median, 9.9 months v 5.9 months, P = .009), and survival (median, 15.3 months v 11.4 months, P = .003). Significant differences between arms were not found in response rate, median TTP, or median survival for the subgroup of patients with rectal primaries who comprised 20% of the patients in each arm. Significant factors prognostic for survival were performance status and number of metastases, as well as treatment. Age did not influence survival. Toxicity was similar in both arms and was primarily gastrointestinal. More mucositis was seen in arm A. There were four toxic deaths secondary to neutropenia and infection (one from arm A and three from arm B) and three other deaths (two from arm A and one from arm B) that were possibly drug-related. The combination of MTX with LV rescue and 5-FU is an active regimen in advanced colorectal cancer; its efficacy is increased in colon, but not rectal cancer, when the interval between MTX and 5-FU is long (24 hours) rather than short (1 hour).

Glioblastoma multiforme is a fatal malignancy of the central nervous system, demanding new methods of treatment. The combination of a calmodulin antagonist with bleomycin has shown synergistic activity in several preclinical models and has been evaluated in a Phase I clinical trial. Since phenothiazines reach high concentrations in the central nervous system, and bleomycin has been reported to have antitumoral activity as well, we studied this combination in a Phase II clinical trial. In addition, we purified calmodulin from normal brain and malignant gliomas to determine its biochemical and pharmacological characteristics. Seventeen patients were entered onto this study and all were evaluable. There were no partial or complete responses. There was one case of fatal pulmonary toxicity in a patient showing an objective tumor response. Otherwise, the treatment was well tolerated. Calmodulin purified from the normal brain and gliomas of patients undergoing resection was identical to each other and to calmodulin prepared from rat cerebrum and glioma. These characteristics included elution from a TSK phenyl high pressure liquid chromatography column, migration on 16% sodium dodecyl sulfate gels, amino acid composition, and inhibition by drugs. Therefore, the failure of this combination therapy was not due to a difference in human glioma calmodulin as compared to previously reported studies with calmodulin from murine sources.

SUMMARY:We report a clinical and biochemical survey of 23 patients with Friedreich's ataxia from southern Italy. They were studied clinically and by means of a clinical rating scale devised by us (Inherited Ataxias Clinical Rating Scale). Laboratory tests, based on the Quebec Cooperative Study, were also performed on our patients. No major clinical or biochemical differences were found between Italian and Canadian patients. Investigation of CSF monoamine metabolites showed that HVA decreased after probenecid and metoclopramide loading

Calmodulin antagonists, such as trifluoperazine, can enhance the cytotoxic effects of bleomycin both in tissue culture and in vivo. Therefore, we evaluated the effects of combination treatment with these drugs in a phase I clinical trial. Patients with objectively measurable or evaluable cancer refractory to conventional treatment who had an acceptable performance status (ECOG 0-2) and acceptable laboratory studies were eligible. All patients gave written informed consent. A cycle of therapy consisted of three weekly treatments with trifluoperazine (days 1-4) and 30 IU bleomycin (day 3). After three patients completed a cycle of therapy without experiencing dose-limiting toxicity, new patients were entered in the study and received a higher dose of trifluoperazine. The dose of bleomycin remained constant. Evaluable patients received at least 2 weeks of treatment and survived for 6 weeks; of 19 patients, 2 were unevaluable. The major toxicities were neurological and pulmonary and included one case of fatal pneumonia with interstitial pulmonary fibrosis. There was no hematologic toxicity. Two patients underwent partial responses (PRs) and two had complete responses (CRs). We conclude that trifluoperazine can safely be given with bleomycin and that further study of the potential efficacy of this treatment is indicated.

The effects of alpha2-adrenergic antagonists on amphetamine- induced locomotion and stereotypy were studied in mice. Six alpha2-antagonists (i.e., yohimbine, rauwolscine, piperoxan, tolazoline, RX781094, and RS21361) selectively attenuated amphetamine-induced increases in locomotion at doses which did not effect amphetamine-induced stereotypies. Higher doses of the antagonists which attenuated baseline sterotyopies also attenuated amphetamine-induced increases in stereotypies. The effect of the alpha2-antagonists was qualitatively similar to that observed with the atypical antipsychotic clozapine. Furthermore, the in vivo relative potency of the alpha2-antagonists in the present study was comparable to that reported in other studies. These results suggest that alpha2-adrenergic receptors may modulate the effects of amphetamine on locomotion in mice.

Acidification of the urine and urinary excretion of hydrogen was studied in ten gouty subjects (age 24–56, mean 38) with normal renal function. In three gouty patients on low purine intake, urinary pH and net acid excretion were not different from that found in normal controls. Furthermore, the response to ammonium chloride load was similar in both groups. In contrast, gouty patients on high purine intake showed permanent aciduria with lowered ammonium excretion and a diminished response to ammonium chloride load. In the four gouty subjects given ammonium chloride during high purine intake, mean urinary uric acid excretion decreased by 300 mg. day while serum urate did not change. This decrement was closely related to the progressive increase in urinary ammonium. Three gouty subjects given equivalent amount of dilute hydrochloric acid failed to show a similar response. The present study indicates that protein and purine intake may influence urinary acidification in primary gout. The data further suggest a possible relationship between ammonia and uric acid production during high purine intake and ammonium chloride load.

HLA antigen typing was carried out in a family with an autosomal dominant form of spinocerebellar degeneration [possibly olivoponto cerebellar atrophy (O.P.C.A.)--Type 1]. Eleven ataxic patients, three possibly ataxic subjects, two unrelated spouses and 13 clinically normal at risk siblings were typed for ABO and Rh blood groups, HLA-A and HLA-B antigens, C4 component of the complement and a number of other serum proteins (Clq, beta-1A, beta-1C, C5, beta-lipoproteins). No solid evidence for linkage between the ataxia gene and the HLA or C4 loci could be demonstrated in this family. Certain serum proteins, and particularly beta-lipoproteins were found to be significantly reduced in some sub-groups of subjects.

The purpose of this research was to determine whether brain stimulation reward and exploration are induced by activation of the same set of neurons along the medial forebrain bundle. The behavioral version of the collision test was utilized with electrodes in the lateral hypothalamus (LH) and the ventral tegmental area (VTA). A collision effect obtained between LH and VTA in one behavior at the exclusion of the other was treated as evidence of the involvement of two different sets of fibers. In 4 rats, a collision effect was observed only in self-stimulation, whereas in 1 rat, a collision was obtained in exploration at the exclusion of self-stimulation. Three animals showed no collision in either behavior. These data suggest that coexistence of self-stimulation and exploration following medial forebrain bundle stimulation can be explained by current spread on two different sets of fibers.

MILIARESSIS, E., P. P. ROMPRE AND A. DURIVAGE. Psychophysical method for mapping behavioral substrates using a moveable electrode . BRAIN RES. BULL. 8 (6) 693–701, 1982.—With the use of moveable electrodes, 28 rat mesencephalic sites were examined for self-stimulation behavior (SS). The relative importance of each site in SS was established according to (1) a traditional method which consists of comparing sites based on the rates of responding (2) a psychophysical procedure based on the pulse frequency required at each site in order for the stimulation to elicit a criterion behavioral performance. It was shown that anatomical conclusions reached by the use of behavioral output procedures depend purely on the arbitrary choice of stimulation parameters. It was also demonstrated that the combination of moveable electrodes with psychophysical measurements results in enhanced mapping resolution and enables one to trace the boundaries of behaviorally relevant structures and pathways with significantly better confidence.

The effects of an acute injection of synthetic salmon calcitonin (sCT) and human CT (hCT) and of long term (4-month) administration of sCT on serum glucose levels were investigated in eight patients with Paget's disease of bone. The results obtained demonstrate a small but statistically significant rise in serum glucose after a single sc injection of synthetic hCT. However, the serum glucose level was not increased after 4 months of daily administration of synthetic sCT to our pagetic patients. Our results also substantiate the clinical observation that long term administration of CT does not cause clinical diabetes or significantly change fasting blood glucose concentration. Our results are also consistent with the view that the effect of CT administration on glucose metabolism is related to the secondary hypocalcemia.