Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial.

BACKGROUND: Critically ill patients suffer from physiological sleep deprivation and have reduced blood melatonin levels. This study was designed to determine whether nocturnal melatonin supplementation would reduce the need for sedation in patients with critical illness. METHODS: A single-center, double-blind randomized placebo-controlled trial was carried out from July 2007 to December 2009, in a mixed medical-surgical Intensive Care Unit of a University hospital, without any form of external funding. Of 1158 patients admitted to ICU and treated with conscious enteral sedation, 82 critically-ill with mechanical ventilation >48 hours and Simplified Acute Physiology Score II>32 points were randomized 1:1 to receive, at eight p.m. and midnight, melatonin (3+3mg) or placebo, from the third ICU day until ICU discharge. Primary outcome was total amount of enteral hydroxyzine administered. RESULTS: Melatonin treated patients received lower amount of enteral hydroxyzine. Other neurological indicators (amount of some neuroactive drugs, pain, agitation, anxiety, sleep observed by nurses, need for restraints, need for extra sedation, nurse evaluation of sedation adequacy) seemed improved, with reduced cost for neuroactive drugs. Post-traumatic stress disorder prevalence did not differ between groups, nor did ICU or hospital mortality. Study limitations include the differences between groups before intervention, the small sample size, and the single-center observation. CONCLUSION: Long-term enteral melatonin supplementation may result in a decreased need for sedation, with improved neurological indicators and cost reduction. Further multicenter evaluations are required to confirm these results with different sedation protocols.

Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial.

BACKGROUND: Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy. PATIENTS AND METHODS: We carried out a multicenter, randomized phase III study. Women aged 65-79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m(2) days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires. RESULTS: From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 [95% confidence interval (CI) 0.83-1.76, P = 0.32]; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80-2.22, P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items. CONCLUSIONS: Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity. CLINICALTRIALSGOV: NCT00331097.

Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study.

BACKGROUND: To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. PATIENTS AND METHODS: A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. RESULTS: Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P<0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole+zoledronic acid versus letrozole comparison (P<0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P=0.004 and 0.47, respectively). CONCLUSIONS: In the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.

Hepatoprotective activity of Trichilia roka on carbon tetrachloride-induced liver damage in rats.

Trichilia roka Chiov. (Meliaceae) is a tree widely distributed in tropical Africa. It has been used in Mali folk medicine for the treatment of various illnesses. A decoction of the roots is taken as a remedy for colds and pneumonia, and it is used as a diuretic and in hepatic disorders. We have evaluated the hepatoprotective effects of a decoction of Trichilia roka root on CCl4-induced acute liver damage in rats. Treatment with the decoction showed a significant protective action made evident by its effect on the levels of glutamate oxalacetate transaminase and glutamate pyruvate transaminase in the serum, on the protein content and lipid peroxidation levels in the liver homogenate. Histopathological changes produced by CCl4, such as necrosis, fatty change, ballooning degeneration and inflammatory infiltration of lymphocytes around the central veins, were clearly recovered by the treatment with Trichilia root decoction. On fractionating this extract into diethyl ether-soluble and water-soluble fractions, the activity was retained in the diethyl ether-soluble fraction. Moreover, the administration of decoction prevented a preferential deposition of collagen around the sinusoidal cell layer, which is responsible for the perisinusoidal fibrosis in the early stage of CCl4 damage. This study showed that treatment with Trichilia roka extracts or silymarin (as reference) appeared to enhance the recovery from CCl4-induced hepatotoxicity. The hepatoprotective properties of Trichilia roka may be correlated to polyphenol content of the decoction and its diethyl ether-soluble fraction.

Angiogenesis sustains tumor dormancy in patients with breast cancer treated with adjuvant chemotherapy.

Experimental studies performed in Folkman laboratories suggest that angiogenesis is involved in the biology of tumor dormancy. We determined the vascular index in a series of 190 women operated of node-positive invasive breast cancer treated with adjuvant chemotherapy (CMF schedule) and we studied the relationship between vascularity of primary tumors with the behaviour in time of metastasis. The study of the hazard function of recurrence (in any site) was performed resorting to a generalized linear modelling approach with a binominal error according to Efron. A total of 80 cases developed recurrences during the period of observation. We found that the hazard function of metastasis in time presented two peaks of incidence at 20 and 60 months, respectively. We also plotted the curves of the hazard function by considering three values of microvessel counts corresponding to the quartiles of their distribution. The risk of first recurrence was associated with vascular index, and the patients of the third quartile of distribution of microvessels had the highest risk. In the final full model for the risk of recurrence at 5 years vascular index provided the highest prognostic contribution followed by the number of involved axillary lymph nodes. The observation that the patients with highly angiogenic tumors are at high risk of recurrence coupled with the identification of the second peak of incidence after 5 years which was also mainly sustained by angiogenic tumors suggest that a fraction of breast cancers promote metastasis after a period of tumor dormancy. The clinical and therapeutic implications of our results are discussed.

Multi-institutional phase II randomized trial of integrated therapy with cisplatin, dacarbazine, vindesine, subcutaneous interleukin-2, interferon alpha2a and tamoxifen in metastatic melanoma. BREMIM (Biological Response Modifiers in Melanoma).

The aim of this study was to evaluate the toxicity and efficacy of a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with metastatic melanoma. Consecutive patients with metastatic melanoma were enrolled in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon 3 MU subcutaneously three times a week and tamoxifen 20 mg orally were given throughout. Ninety-two patients were included in this study. Patient characteristics in the three groups were well balanced. The three regimens were delivered on an outpatient basis without major toxicity. The toxicities that did occur consisted primarily of flu-like symptoms in the IL-2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No grade IV toxicities were encountered and no treatment-related deaths occurred. The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The median duration of response was 6 months and the median survival was 11 months. According to this phase II randomized trial polychemoimmunotherapy with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has a response rate of 13%.

Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy.

PURPOSE: To determine the role of the two angiogenic peptides, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) (the latter also being a target enzyme for cytotoxicity of 5-fluorouracil and methotrexate), and conventional prognostic factors in predicting relapse-free survival (RFS) and overall survival (OS) probabilities in two cohorts of patients with node-positive breast cancer (NPBC) treated with either adjuvant chemotherapy (CMF [cyclophosphamide, methotrexate, 5-fluorouracil] schedule) or hormone therapy (tamoxifen). PATIENTS AND METHODS: We studied two groups of 137 and 164 patients with NPBC, median follow-up of 72 months for both, treated with adjuvant chemotherapy or hormone therapy, respectively. The cytosolic levels of VEGF and TP were determined in the primary tumor by original immunometric methods. The association between VEGF and TP and of these angiogenic peptides with other prognostic indicators were tested by using the Spearman correlation coefficient (for continuous variables) or the Kolmogorov-Smirnov test (for dichotomous variables). Results of the clinical outcome were analyzed by both univariate and multivariate (for RFS only) Cox regression models in which VEGF and TP were treated as continuous variables. RESULTS: In the CMF group, the concentrations of VEGF and TP ranged from 5.8 to 7798 pg/mg of protein (median, 87.5 pg/mg) and from 1.2 to 904 U/mg (median, 138.2 U/mg), respectively. There was no significant association between the two angiogenic peptides. VEGF was not associated with any other variable, whereas TP showed a positive association with age and an inverse association with the number of involved nodes. In the tamoxifen group, the concentrations of VEGF (5.9-2482; median, 79.3 pg/mg protein) and TP (6.1-1542; median, 146.5 U/mg) were similar to those of the CMF group, and the two angiogenic peptides were not correlated. VEGF was positively associated with age and was inversely associated with estrogen receptor and progesterone receptor, whereas TP was not associated with any other variable. Univariate analysis in the CMF group showed that VEGF and TP were significantly predictive of both RFS and OS. Likewise, the number of involved axillary nodes was significantly associated with both RFS and OS. Univariate analysis in the tamoxifen group showed that TP did not significantly influence either RFS or OS. On the contrary, VEGF levels were significantly predictive of both RFS and OS, as were the number of involved nodes, estrogen receptor concentrations, and progesterone receptor concentration. In the multivariate analysis on RFS in the CMF group, VEGF, TP, their first-order interaction term, and age were significant and independent predictive factors. In the tamoxifen group, only VEGF and the number of involved nodes were significant and independent predictive factors. DISCUSSION: The results of our study suggest that high levels of TP and low levels of VEGF characterize the patients with NPBC treated with adjuvant CMF who have the highest likelihood of favorable outcome. Low levels of VEGF and the presence of less than three involved axillary nodes characterize the patients with NPBC treated with adjuvant tamoxifen who have the highest likelihood of favorable outcome. This information may be useful to plan future studies to better select the patients with NPBC for conventional adjuvant treatments as well as to monitor the efficacy of novel therapeutic strategies of adjuvant therapy based on inhibition of angiogenesis.

Tailored therapy for aggressive non-Hodgkin's lymphoma: results of a phase II study with a long-term follow-up.

Aim of the study was to improve cure rate and survival of aggressive non-Hodgkin's lymphoma (NHL) with a tailored program of therapy based on histologic type, prognostic characteristics of patients and response to therapy, and with the use of differentiating or cytostatic agents such as Ara-C at low doses and alphaIFN. Fifty-four consecutive patients with aggressive NHL were treated in the induction phase with 4 sequential courses of a third generation regimen (modified CODBLAM IV), followed in responsive patients by 1 cycle of doxorubicin and cyclophosphamide and 1 cycle of high dose methotrexate with folinic acid rescue (AC-MTX). Patients who achieved partial response (PR) were treated with the combination of CCNU + vinblastine if affected by high grade NHL, or with low dose Ara-C plus alphaIFN if affected by intermediate grade NHL. Patients who obtained complete response (CR) with basal adverse prognostic factors were treated with alphaIFN as maintenance therapy for two years. Radiotherapy and surgery were effected in selected cases. Thirty-four patients (62.9%) achieved CR and 12 patients (22.2%) showed PR after induction therapy. Among the 12 patients who achieved PR, 6 prolonged CRs were obtained in 7 patients treated with Ara-C at low doses plus alphaIFN and 4 CRs were obtained in 5 patients treated with CCNU + vinblastine. After completion of treatment, 44 patients (81.5%) obtained CR, 2 patients (3.7%) showed PR and 8 patients (14.8%) presented progression of disease (PD). Fifteen patients received alphaIFN as maintenance therapy. The overall survival and failure-free survival rates are 53.7% and 50% respectively, with a median follow-up of 82 months: 27 patients remain alive, disease-free without relapses, and can be considered cured. This tailored program of therapy resulted effective and moderately toxic and may improve the outcome in aggressive NHL.

Change in major amputation rate in a center dedicated to diabetic foot care during the 1980s: prognostic determinants for major amputation.

From 1990 to 1993, 115 diabetic patients were consecutively hospitalized in our diabetologic unit for foot ulcer and 27 (23.5%) major amputations were carried out. The major amputation rate of this series of cases was compared with that occurring in diabetic subjects taken into our hospital for foot ulcer in two previous periods: 1979-1981 (17 major amputations in 42 inpatients or 40.5%) and 1986-1989 (26 major amputations in 78 inpatients or 33.3%). The comparison shows a progressive reduction in major amputation rate [Odds ratio 0.66, 95% confidence interval (CI) 0.46-0.96]. Univariate and multivariate analysis, carried out in the population of the 1990-1993 period, in order to detect the independent factors associated with major amputation show the following prognostic determinants of major amputation: Wagner grade (odds ratio 7.69, CI 1.58-37.53), prior stroke (odds ratio 35.05, CI 3.14-390.53), prior major amputation (odds ratio 3.49, CI 1.26-9.38), transcutaneous oxygen level (odds ratio 1.06, CI 1.01-1.12), and ankle-brachial blood pressure index (odds ratio 4.35, CI 1.58-12.05), while an independent protective role was attributed to hyperbaric oxygen treatment (odds ratio 0.15, CI 0.03-0.64). In accordance with other studies, we, therefore, conclude that a comprehensive protocol as well as a multidisciplinary approach in a dedicated center can assure a decrease in major amputation rate. The parameters of limb perfusion were the modifiable prognostic determinants most strongly predictive for amputation.

Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study.

OBJECTIVE: To evaluate the effectiveness of systemic hyperbaric oxygen therapy (s HBOT) in addition to a comprehensive protocol in decreasing major amputation rate in diabetic patients hospitalized for severe foot ulcer. RESEARCH DESIGN AND METHODS: From August 1993 to August 1995, 70 diabetic subjects were consecutively admitted into our diabetologic unit for foot ulcers. All the subjects underwent our diagnostic-therapeutic protocol and were randomized to undergo s-HBOT. Two subjects, one in the arm of the treated group and one in the arm of nontreated group, did not complete the protocol and were therefore excluded from the analysis of the results. Finally, 35 subjects received s-HBOT and another 33 did not. RESULTS: Of the treated group (mean session = 38.8 +/- 8), three subjects (8.6%) underwent major amputation: two below the knee and one above the knee. In the nontreated group, 11 subjects (33.3%) underwent major amputation: 7 below the knee and 4 above the knee. The difference is statistically significant (P = 0.016). The relative risk for the treated group was 0.26 (95% CI 0.08-0.84). The transcutaneous oxygen tension measured on the dorsum of the foot significantly increased in subjects treated with hyperbaric oxygen therapy: 14.0 +/- 11.8 mmHg in treated group, 5.0 +/- 5.4 mmHg in nontreated group (P = 0.0002). Multivariate analysis of major amputation on all the considered variables confirmed the protective role of s-HBOT (odds ratio 0.084, P = 0.033, 95% CI 0.008-0.821) and indicated as negative prognostic determinants low ankle-brachial index values (odds ratio 1.715, P = 0.013, 95% CI 1.121-2.626) and high Wagner grade (odds ratio 11.199, P = 0.022, 95% CI 1.406-89.146). CONCLUSIONS: s-HBOT, in conjunction with an aggressive multidisciplinary therapeutic protocol, is effective in decreasing major amputations in diabetic patients with severe prevalently ischemic foot ulcers.

CMF vs alternating CMF/EV in the adjuvant treatment of operable breast cancer. A single centre randomised clinical trial (Naples GUN-3 study).

The aim of this study was to test the hypothesis of Goldie and Coldman that the use of non-cross-resistant regimens of chemotherapy could lead to maximal anti-tumour effect. We compared standard CMF (cyclophosphamide, methotrexate, fluorouracil) with alternating CMF/EV (epirubicin, vincristine) in the adjuvant therapy of early breast cancer. Stage II premenopausal node-positive or post-menopausal node-positive oestrogen receptor-negative and stage III breast cancer patients were eligible for the study. From January 1985 to December 1990, 220 patients were randomised (115 to CMF and 105 to CMF/EV). Toxicity was mild; neurotoxicity, vomiting and hair loss were more frequent in the CMF/EV group, while permanent amenorrhoea, diarrhoea, stomach ache and minor infections occurred more often in the CMF arm. At a follow-up of 48 months, 113 patients (51.4%) had had recurrence (62 on CMF and 51 on CMF/EV) and 54 (24.5%) had died (30 on CMF and 24 on CMF/EV). There was no significant difference in disease-free and overall survival between the two arms. After adjusting for menopausal status and stage, the relative risk (RR) of recurrence for CMF/EV patients was 0.93 (95% CL 0.64-1.35), while the RR of death was 0.85 (95% CL 0.49-1.47). In conclusion, the Goldie-Coldman model of alternating therapy is not confirmed in this trial of adjuvant therapy of early breast cancer, although in view of its design a difference of less than 20% in 3 year disease-free survival could not be excluded.