Non-abstinent treatment outcomes for cannabis use disorder.

BACKGROUND: Abstinence remains a standard outcome for potential treatment interventions for Cannabis Use Disorder (CUD). However, there needs to be validation of non-abstinent outcomes. This study explores reductions in self-reported days of use as another viable outcome measure using data from three completed randomized placebo-controlled clinical trials of pharmacological interventions for CUD. METHODS: The three trials tested the effect of quetiapine (QTP, n = 113); dronabinol (DRO, n = 156); and lofexidine + dronabinol (LFD, n = 122). Self-reported cannabis use was categorized into three use-groups/week: heavy (5-7 days/week), moderate (2-4 days/week) and light use (0-1 days/week). Multinomial logistic regressions analyzed the treatment by time effect on the likelihood of light and moderate use compared to heavy use in each study. RESULTS: Across the three trials, there was no significant overall time-by-treatment interaction (QTP: p = .06; DRO: p = .15; LFD: p = .21). However, the odds of moderate compared to heavy use were significantly higher in treatment than in placebo groups starting around the midpoint of each trial. No treatment differences were found between the odds of light compared to heavy use. CONCLUSIONS: While study-end abstinence rates have been a standard treatment outcome for CUD trials, reduction from heavy to moderate use has not been standardly assessed. During the last several weeks of each trial, those on active medication were more likely to move from heavy to moderate use, which suggests that certain medications may be more impactful than previously assessed. Future studies should determine if this pattern is associated with less CUD severity and/or improved quality of life.

Quetiapine treatment for cannabis use disorder.

BACKROUND: Pharmacotherapy for cannabis use disorder (CUD) is an important unmet public health need. METHODS: In a 12-week randomized double-blind placebo-controlled trial, the efficacy of quetiapine (300 mg nightly) for the treatment of CUD was tested in 130 outpatients. Weekly cannabis use was categorized into three groups: heavy use (5-7 days), moderate use (2-4 days) and light use (0-1 days). RESULTS: At baseline both groups were considered heavy users (using days per week: median = 7.0; interquartile range (IQR): 6.5-7.0; daily dollar value: median = $121.4; IQR: 73.8-206.3). The week-by-treatment interaction was marginally significant (χ2(2) = 5.56, P = .06). With each week, the odds of moderate compared to heavy use significantly increased in the quetiapine group (OR=1.17, P < .0001), but not significantly in the placebo group (OR=1.05, P = .16). The odds of light versus heavy use did not significantly differ over time (P = .12). Treatment was also associated with reduced cannabis withdrawal symptoms by 10.4% each week (95% CI: 8.9-11.8). No serious adverse events occurred during the study and no evidence of development of a movement disorder was detected. Adverse effects were not significantly different between the quetiapine and placebo treatment arms. CONCLUSIONS: The use of quetiapine to treat CUD was associated with an increased likelihood of heavy frequency use transitioning to moderate use, but not light use. The clinical significance of reductions in cannabis use, short of abstinence warrants further study.

Effects of a Mindfulness-based Intervention on diurnal cortisol pattern in disadvantaged families: A randomized controlled trial.

OBJECTIVE: The present study examined the psychophysiological effects of Family-based Mindfulness Intervention (FBMI) on children and parents from disadvantaged families. METHODS: This randomized controlled trial recruited parents and their children from 51 disadvantaged families in Hong Kong and randomized them into FBMI (n = 26) and waitlist control (n = 25) groups. The parent intervention included 6 sessions and the child intervention included 8 sessions with 2 half-hour joint programs. Both interventions lasted 9 hours in total each. All participants completed four salivary cortisol measures after wakeup, before lunchtime, late-afternoon, and before sleep at baseline and end of the intervention. The diurnal cortisol pattern was summarized by the morning cortisol, evening cortisol, mean cortisol, and diurnal cortisol slope. RESULTS: Compared to the control group, children in the FBMI group showed significant increases in morning cortisol (d = 0.50, p =  0.03) and significant decreases in diurnal cortisol slopes (d = 0.50, p =  0.04) at the end of intervention. Parents in the FBMI group displayed significant decreases in evening cortisol (d = 0.50, p =  0.04) compared to the control group at the end of intervention. No significant treatment effects were found on the mean cortisol. DISCUSSION: The present findings suggest that FBMI could improve the diurnal cortisol slope and cortisol levels of the children and parents from disadvantaged families, respectively. Future studies should elucidate its potential benefits on neuroendocrine functioning.

Guanfacine extended-release for cannabis use disorder: a pilot feasibility trial.

Background: Currently, there are no established pharmacotherapies for cannabis use disorders (CUDs). As a long-acting alpha-2-adrenergic receptor agonist, guanfacine extended-release (G-XR) could be useful in the treatment of CUDs by mitigating withdrawal and improving behavioral control.Objectives: To evaluate the feasibility and tolerability of G-XR as a treatment for CUDs.Methods: In an eight-week open-label outpatient pilot trial, we evaluated the safety and tolerability of G-XR in 22 cannabis dependent individuals. Using 2 different titration schedules, G-XR was gradually titrated to a dose of 4 mg or the highest dose tolerated. All participants received standard medication management.Results: Retention at week eight was 41%. Average daily amount of cannabis use (in grams: F1,86 = 8.74, p = .004; in dollars: F1,86 = 16.67, p < .0001) and cannabis using days (F1,86 = 7.67, p = .007) significantly reduced over the course of study participation. There were no significant differences between the titration schedules on emergence of side effects (Fisher exact test, p = .378) or retention (Log-Rank Test X21 = 0.021, p = .886). A total of 3 participants achieved 3 weeks or greater of total abstinence.Conclusions: G-XR is a feasible treatment for CUDs, and should be evaluated further in an efficacy trial.

A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial.

OBJECTIVE: Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention. METHODS: Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout). RESULTS: Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events. CONCLUSIONS: A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.

Abstinence and reduced frequency of use are associated with improvements in quality of life among treatment-seekers with cannabis use disorder.

BACKGROUND AND OBJECTIVE: Many patients with cannabis use disorder (CUD) do not achieve or do not have abstinence as a goal of treatment, rather they reduce their use. Assessing outcome measures as they relate to functioning and reductions in cannabis use is an important area of study. Quality of life (QoL) shows promise as one such measure. Past studies have demonstrated gender differences in QoL and CUD. We aim to assess (1) the relationship between cannabis use and QoL and (2) gender effects in an outpatient medication treatment study for CUD. METHODS: Data from an 11-weeks, double-blind, placebo-controlled trial of lofexidine and dronabinol for CUD (n = 62) was analyzed. Pearson's correlations between baseline QoL as measured with the Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form (QLES-Q-SF) and cannabis use assessed with modified timeline follow-back (TLFB) were examined. Multiple linear regression models of cannabis use on end of study QLES-Q-SF were analyzed, while adjusting for baseline QLES-Q-SF, study arm, and gender. Moderation effects with gender were also tested. RESULTS: No significant association between baseline cannabis use and QoL was found. End of study abstinence (F1,47 = 8.34, p = .006) and reduced proportion of using days (F1,47 = 9.48, p = .004) were each significantly associated with end of study QoL. Reduction in grams (F1,27 = 0.25, p = .62) was not associated with QoL at end of study. Gender was not a significant moderator. DISCUSSION AND CONCLUSIONS: Abstinence and lower frequency of use are associated with higher QoL, regardless of gender. SCIENTIFIC SIGNIFICANCE: This is the first time QoL has been demonstrated to change over the course of CUD medication treatment. QoL is an important outcome in CUD treatment. TRIAL REGISTRATION: NCT01020019. (Am J Addict 2018;27:101-107).

Open-label pilot study of injectable naltrexone for cannabis dependence.

BACKGROUND: There are no FDA-approved pharmacotherapies for cannabis use disorders (CUD), despite the evaluation of numerous medications. Notably, chronic dosing of oral naltrexone decreases self-administration of cannabis in human laboratory studies. OBJECTIVES: To test the feasibility of long-acting injectable naltrexone for the treatment of CUD, while obtaining preliminary safety and efficacy data. METHODS: Twelve adult participants (seven male) meeting DSM-IV-TR criteria for cannabis dependence enrolled into an 8-week, open-label pilot study conducted at an academic treatment research clinic. They received 380 mg intramuscular injections of long-acting naltrexone on study day 1 and at the start of study week 5. Outcome measures included percentages of study completers and participants who received the second injection, frequency of adverse events (AEs), and cannabis consumption measured by average daily grams, dollars, and using days per week as measured by timeline follow-back and urine oral delta-9-tetrahydrocannabinol (THC) concentrations. RESULTS: Of the 12 participants enrolled in the study, 9 completed the study and 6 received the second injection. There were no severe AEs but an unexpected AE led to the addition of supportive medications to the protocol. Number of cannabis use days per week significantly decreased over the course of the study (p = .001). Creatinine-corrected urine THC concentrations and average daily cannabis use per study week in grams and in dollars did not decrease over the course of the study. CONCLUSIONS: Long-acting injectable naltrexone is a feasible intervention for CUD worthy of further study in a placebo-controlled, double-blinded randomized clinical trial.

Oral administration of Lactobacillus plantarum CJLP133 and CJLP243 alleviates birch pollen-induced allergic rhinitis in mice.

AIMS: In this study, we evaluated the therapeutic efficacy of selected probiotics in a mouse model of birch pollen (BP)-induced allergic rhinitis. METHODS AND RESULTS: Oral administration of Lactobacillus plantarum CJLP133 and CJLP243 ameliorated the symptoms of BP-induced allergic rhinitis by reducing airway hyperresponsiveness, and both the histological scores and the number of infiltrated cells in the nasal cavities and lungs. Compared with those from vehicle-treated mice, bronchoalveolar lavage fluid and draining lymph node samples from CJLP133 and CJLP243-administrated mice showed diminished numbers of immune cells, increased secretion of a Th1-type cytokine (IFN-γ) and decreased production of Th2-type cytokines (IL-4, IL-5 and IL-13). Consistent with these results, levels of IL-4, IL-5, IL-13, serum IgE and BP-specific serum IgG1 were decreased, whereas secretion of IFN-γ and BP-specific serum IgG2a was augmented upon administration of CJLP133 and CJLP243 in mice. CONCLUSION: Oral administration of L. plantarum CJLP133 and CJLP243 alleviates symptoms of BP-induced allergic rhinitis in mice by recovering Th1/Th2 balance via enhancement of the Th1-type immune response. SIGNIFICANCE AND IMPACT OF THE STUDY: Lactobacillus plantarum CJLP133 and CJLP243 have therapeutic effects on BP-induced allergic rhinitis in an animal model.

Phylogenetic group distributions, virulence factors and antimicrobial resistance properties of uropathogenic Escherichia coli strains isolated from patients with urinary tract infections in South Korea.

UNLABELLED: Urinary tract infections (UTIs) are one of the most common diseases by which humans seek medical help and are caused mainly by uropathogenic Escherichia coli (UPEC). Studying the virulence and antibiotic resistance of UPEC with respect to various phylogenetic groups is of utmost importance in developing new therapeutic agents. Thus, in this study, we analysed the virulence factors, antibiotic resistance and phylogenetic groups among various UPEC isolates from children with UTIs. The phylogenetic analysis revealed that majority of the strains responsible for UTIs belonged to the phylogenetic groups B2 and D. Of the 58 E. coli isolates, 79·31% belonged to group B2, 15·51% to group D, 3·44% to group A and 1·72% to B1. Simultaneously, the number of virulence factors and antibiotic resistance exhibited were also significantly high in groups B2 and D compared to other groups. Among the isolates, 44·8% were multidrug resistant and of that 73% belonged to the phylogenetic group B2, indicating the compatibility of antibiotic resistance and certain strains carrying virulence factor genes. The antibiotic resistance profiling of UPEC strains elucidates that the antimicrobial agents such as chloramphenicol, cefoxitin, cefepime, ceftazidime might still be used in the therapy for treating UTIs. SIGNIFICANCE AND IMPACT OF THE STUDY: As the antibiotic resistance pattern of uropathogenic Escherichia coli varies depending on different geographical regions, the antibiotic resistance pattern from this study will help the physicians to effectively administer antibiotic therapy for urinary tract infections. In addition, the frequency of virulence factors and antibiotic resistance genes among various phylogenic groups could be effectively used to draw new targets for uropathogenic Escherichia coli antibiotic-independent therapies. The study emphasizes need of public awareness on multidrug resistance and for more prudent use of antimicrobials.

Focused parathyroidectomy without intra-operative parathyroid hormone monitoring for primary hyperparathyroidism: results in a low-volume hospital.

BACKGROUND: The role of routine intra-operative parathyroid hormone monitoring for sporadic primary hyperparathyroidism is contentious. Satisfactory results can be achieved in high-volume centres. The results of low-volume hospitals are rarely studied. METHODS: A retrospective, non-comparative study was conducted. From November 2002 to October 2012, 105 patients with clinically sporadic primary hyperparathyroidism underwent focused parathyroidectomy without intra-operative parathyroid hormone monitoring. Single adenoma was localised on pre-operative ultrasonography or sestamibi scan. The cure rate, surgical complication rate and pathology findings were evaluated. RESULTS: Most of the operations (63.8 per cent) were performed under local anaesthesia. All but two patients (98.1 per cent) were cured after surgery. There was only one case of double adenomas. No recurrent hyperparathyroidism was observed after a mean follow up of 56.9 months. Surgical complications comprised two cases (1.9 per cent) of transient vocal fold palsy and one case (1.0 per cent) of permanent vocal fold palsy. Seven patients (6.7 per cent) suffered temporary hypocalcaemia. CONCLUSION: Satisfactory results of focused parathyroidectomy without routine intra-operative parathyroid hormone monitoring for appropriately selected primary hyperparathyroidism cases can be attained in a low-volume hospital.

Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.

Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

Investigation on antibacterial and antioxidant activities, phenolic and flavonoid contents of some thai edible plants as an alternative for antibiotics.

This study was aimed to examine the antibacterial and antioxidative properties of seven edible plants from Thailand to develop alternative antibiotics as feed additives. The plants include Citrus aurantifolia Swingle (Lime) fruits and its leaves, Sesbania grandiflora L. (Agati sesbania) leaves, Piper sarmentosum Roxb (Wild betal) leaves, Curcuma domestica Valeton (Turmeric) roots, Morinda citrifolia L. (Beach mulberry) leaves, Cassia siamea britt (Siamea cassia) leaves, and Cocos nucifera L. (Coconut) peels. The plants were extracted by methanol, n-hexane, chloroform, ethyl acetate, butanol and water. Antibacterial activities with minimum inhibitory concentration (MIC) were determined by agar diffusion assay against Escherichia coli, Burkholderia sp., Haemopilus somnus, Haemopilus parasuis, and Clostridium perfringens that were considered pathogenic strains in livestock infection. Methanol extracts of C. aurantifolia Swingle fruits and leaves showed the broadest spectrum of antibacterial activities except for C. perfringens. Butanol extract of S. grandiflora L. leaves showed the strongest activity against Burkholderia sp. with MIC, 135 µg/mL. P. sarmentosum Roxb leaves showed antibacterial activities against E. coli, Burkholderia sp. and H. parasuis. Ethyl acetate and water extracts from C. domesitca Valeton roots showed MIC of 306 µg/mL and 183 µg/mL, respectively against only C. perfringens. Antioxidative activity was determined by 2-diphenyl-2-picryl hydrazyl photometric assay. The methanol extracts of C. aurantifolia Swingle fruits and P. sarmentosum Roxb leaves showed the highest antioxidant activity among all the extracts with 3.46 mg/mL and 2.70 mg/mL effective concentration 50% (EC50) values, respectively. Total contents of phenolics and flavonoids were measured from the plant extracts. Methanol extracts of S. grandiflora L. and chloroform extracts of C. domestica Valeton were found to have the highest amount of total phenolics, 41.7 and 47.8 µg/mL, respectively. Flavonoid content of methanol extracts in S. grandiflora L. T was 22.5 µg/mL and the highest among plant extracts tested. These results indicated that C. aurantifolia Swingle, S. grandiflora L., P. sarmentosum Roxb, and C. domestica Valeton have antibacterial and antioxidant activities and can be used as alternative antibiotics or potential feed additives for the control of animal pathogenic bacteria.

Fatty acid biosynthesis and lipogenic enzyme activities in subcutaneous adipose tissue of feedlot steers fed supplementary palm oil or soybean oil.

We hypothesized that supplementing finishing diets with palm oil would promote adipocyte differentiation in subcutaneous adipose tissue of feedlot steers, and that soybean oil supplementation would depress adipocyte differentiation. Twenty-eight Angus steers were assigned randomly to 3 groups of 9 or 10 steers and fed a basal diet without additional fat (control), with 3% palm oil (rich in palmitic acid), or with 3% soybean oil (rich in polyunsaturated fatty acids), for 10 wk, top-dressed daily. Palm oil had no effect (P > 0.05) on ADG, food intake, or G:F, whereas soybean oil depressed ADG (P = 0.02), food intake (P = 0.04), and G:F (P = 0.05). Marbling scores tended (P = 0.09) to be greater in palm oil-fed steers (Modest(09)) than in soybean oil-fed steers (Small(55)). Subcutaneous adipocyte mean volume was greater in palm oil-fed steers (515.9 pL) than in soybean-supplemented cattle (395.6 pL; P = 0.01). Similarly, glucose and acetate incorporation into total lipids in vitro was greater in subcutaneous adipose tissue of palm oil-fed steers (119.9 and 242.8 nmol·3h(-1)·10(5) cells, respectively) than adipose tissue of soybean oil-fed steers in (48.9 and 95.8 nmol·3h(-1)·10(5) cells, respectively). Glucose-6-phosphate dehydrogenase and NADP-malate dehydrogenase activities were greater (P ≤ 0.05) in subcutaneous adipose tissue of palm oil-fed steers than in adipose tissue of control steers. Palm oil did not increase palmitic acid or decrease oleic acid in subcutaneous adipose tissue or LM, but decreased (P ≤ 0.05) myristoleic, palmitoleic, and cis-vaccenic acid in adipose tissue, indicating a depression in stearoyl-coenzyme A desaturase activity. Soybean oil increased the proportion of α-linolenic acid in adipose tissue and muscle and increased linoleic acid and 18:1trans-10 in muscle. We conclude that palm oil supplementation promoted lipid synthesis in adipose tissue without depressing feed efficiency or increasing the palmitic acid content of beef.

Quantitative PCR and in vivo efficacy of antibiotics in the treatment of Vibrio vulnificus infection in a mouse model.

The Centers for Disease Control and Prevention (CDC) recommend oral or intravenous doxycycline plus a third-generation cephalosporin or fluoroquinolone alone for the treatment of Vibrio vulnificus infections. Until now, no study has compared oral with parenteral administered doxycycline with respect to their in vivo efficacy. In the present work, ICR mice infected with a high dose of V. vulnificus were administered ciprofloxacin, ceftriaxone, and doxycycline. The bacterial DNA copy number in surviving and non-surviving mice was determined using quantitative polymerase chain reaction (qPCR). In this setting, ciprofloxacin was the most effective monotherapeutic drug, but a higher survival rate (50%) was achieved using the combination therapy of intraperitoneal doxycycline plus ceftriaxone. The blood of non-surviving mice at 12 h post-infection contained at least 10(4) DNA copies/µL, in contrast to 10(2) to 10(3) DNA copies/µL in surviving mice. Thus, in the treatment of V. vulnificus infections in humans, when the intravenous form of doxycycline is unavailable, ciprofloxacin might be a better option than oral doxycycline to lower mortality. In addition, our results demonstrate that qPCR can be a useful tool for identifying the V. vulnificus load in infected patients, with the DNA copy number providing a marker of either disease severity or mortality.

Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma.

BACKGROUND: Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS: Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS: The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS: Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.

A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer.

BACKGROUND: Studies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting. PATIENTS AND METHODS: LMCRC patients were randomized to receive every 14 days, FA, 400 mg/m2 infused over 2 h, followed by 5-FU as a 400 mg/m2 i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m2 over 46 h (LV5FUs) with or without irinotecan: 180 mg/m2 infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety. RESULTS: Treated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI [hazard ratio (HR) 0.89, log-rank P = 0.44]. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%). CONCLUSION: FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.

High-dose squalene ingestion increases type I procollagen and decreases ultraviolet-induced DNA damage in human skin in vivo but is associated with transient adverse effects.

BACKGROUND: Evidence for beneficial effects of squalene on ultraviolet (UV)-induced photoageing of the skin is lacking. AIM: To investigate whether squalene supplementation improves signs and molecular markers of photoageing in human skin in vivo. METHODS: In total, 40 female volunteers aged > 50 years received two different doses [13.5 g/day (low-dose group) and 27 g/day (high-dose group)] of squalene for 90 days. At baseline and at the completion of the study, facial wrinkles were measured using skin replicas. Skin samples were taken to compare type I procollagen and matrix metalloproteinase 1 mRNA levels by real-time reverse-transcriptase PCR, and for type I procollagen immunostaining. Skin samples were also taken 24 h after 2 x minimal erythema dose (MED) of UV irradiation before and after squalene intake to assess UV-induced thymine dimer formation and keratinocytic apoptosis. RESULTS: In total, 37 subjects completed the trial. Transient loose stool was experienced by 35% of volunteers in the low-dose group and 55% in the high-dose group. Facial wrinkles decreased significantly (P < 0.05) in the high-dose group, while procollagen type I mRNA levels and MED increased significantly in the low-dose group. Procollagen immunostaining tended to increase in both groups. Facial erythema decreased and pigmentation increased significantly in both groups. UV-induced keratinocytic apoptosis and thymine dimer staining were substantially reduced in both groups. CONCLUSIONS: Daily ingestion of 13.5 or 27 g of squalene per day resulted in antiageing effects in photoaged skin. However, in view of the frequent incidence of loose stool experienced by the subjects, the risk-benefit ratio of high-dose squalene supplementation is too high to recommend it for treating skin ageing.

Major late toxicities after conformal radiotherapy for nasopharyngeal carcinoma-patient- and treatment-related risk factors.

PURPOSE: To retrospectively analyze the factors affecting late toxicity for nasopharyngeal carcinoma. METHODS AND MATERIALS: Between 1998 and 2003, 422 patients were treated with a conformal technique with 2-Gy daily fractions to a total dose of 70 Gy. Conventional fractionation (5 fractions weekly) was used in 232 patients and accelerated fractionation (6 fractions weekly) in 190 patients. One hundred seventy-one patients were treated with the basic radiotherapy course alone (Group 1), 55 patients had an additional boost of 5 Gy in 2 fractions (Group 2), and 196 patients underwent concurrent cisplatin-based chemotherapy (Group 3). RESULTS: The 5-year overall toxicity rate was significantly greater in Group 3 than in Group 1 (37% vs. 27%, p = 0.009). Although the overall rate in Group 2 was not elevated (28% vs. 27%, p = 0.697), a significant increase in temporal lobe necrosis was observed (4.8% vs. 0%, p = 0.015). Multivariate analyses showed that age and concurrent chemotherapy were significant factors. The hazard ratio of overall toxicity attributed to chemotherapy was 1.99 (95% confidence interval, 1.32-2.99, p = 0.001). The mean radiation dose to the cochlea was another significant factor affecting deafness, with a hazard ratio of 1.03 (95% confidence interval, 1.01-1.05, p = 0.005) per 1-Gy increase. The cochlea that received >50 Gy had a significantly greater deaf rate (Group 1, 18% vs. 7%; and Group 3, 22% vs. 14%). CONCLUSION: The therapeutic margin for nasopharyngeal carcinoma is extremely narrow, and a significant increase in brain necrosis could result from dose escalation. The significant factors affecting the risk of deafness included age, concurrent chemoradiotherapy, and greater radiation dose to the cochlea.

Cellular regulation of bovine intramuscular adipose tissue development and composition.

It is well documented that grain feeding stimulates adipogenesis in beef cattle, whereas pasture feeding depresses the development of adipose tissues, including intramuscular (i.m.) adipose tissue. Additionally, production practices that depress adipocyte differentiation also limit the synthesis of MUFA. Marbling scores and MUFA increase in parallel suggesting that stearoyl-coenzyme A desaturase (SCD) gene expression is closely associated with and necessary for marbling adipocyte differentiation. Similarly, marbling scores and fatty acid indices of SCD activity are depressed in response to dietary vitamin A restriction. In bovine preadipocytes, vitamins A and D both decrease glycerol-3-phosphate dehydrogenase (GPDH) activity, an index of adipocyte differentiation, whereas incubation of bovine preadipocytes with l-ascorbic acid-2-phosphate increases GPDH activity. Exposing bovine preadipocytes to zinc also stimulates adipogenesis, putatively by inhibiting nitric oxide (NO) production. However, incubation of bovine preadipocytes with arginine, a biological precursor of NO, strongly promotes differentiation in concert with increased SCD expression. This suggests that the effect of either arginine or zinc on adipogenesis is independent of NO synthesis in bovine preadipocytes. Enhanced expression of SCD is associated with a greater accumulation of MUFA both in bovine preadipocyte cultures and during development in growing steers. In bovine preadipocytes, trans-10, cis-12 CLA strongly depresses adipocyte differentiation and SCD gene expression, thereby reducing MUFA concentrations. The bovine preadipocyte culture studies suggest that any production practice that elevates vitamins A or D or trans-10, cis-12 CLA in bovine adipose tissue will reduce i.m. adipose tissue development. Conversely, supplementation with vitamin C or zinc may promote the development of i.m. adipose tissue.

Treatment of lipomas assisted with tumescent liposuction.

BACKGROUND: Lipoma is a common soft-tissue tumour of mature fat cells. Although surgical excision is effective, treatments that are less invasive and not associated with disfigurement of scar would be ideal for the treatment of lipomas. Recently, tumescent liposuction has been used for the treatment of lipomas. OBJECTIVE: To evaluate the efficacy of tumescent liposuction in lipoma treatment, we reviewed our experience of lipoma treatment by tumescent liposuction. METHODS: A total of 21 patients presenting with 31 lipomas were treated with tumescent liposuction. After liposuction, remaining stromas were removed by a haemostat through the small incision. Tumour size and post-operative complications were recorded before and after treatment. RESULTS: A total of 31 lipomas of 21 patients were treated by tumescent liposuction. The size of lipomas ranged between 1.2 and 11 cm (mean size, 4.1 cm). In 23 cases, there were no complications. However, remnant lipomas, bruise, haematoma and immediate dimpling were found as complications. CONCLUSION: Tumescent liposuctions with extracting remnant fat tissue and fibrous tissue through the opening for liposuction can be an effective treatment technique in lipoma treatment in the efficacy and cosmetic outcomes and this method can be a substitute for excision in treating large lipomas.