Maximum tolerable doses of intravenous zidovudine in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer patients

Background: Experimental studies have demonstrated that 5-fluorouracil(5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity.Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZTis 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU +l-leucovorin (LV), and that this combination has promising antitumor activity.The purpose of this study was therefore to evaluate the antitumor activity ofweekly bolus 5-FU + LV + AZT, administered at its MTD, and to determinewhether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells.Patients and methods: Twenty-nine chemotherapy-naïve metastaticcolorectalcancer patients with measurable disease entered the study to evaluate theactivity of a weekly 5-FU 500 mg/m² i.v. bolus + LV 250mg/m² i.v. two-hour infusion + AZT 8000mg/m² i.v. two-hour infusion. In 10 different patients, whoduring three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNAstrand breaks in blood nuclear cells were determined by a fluorescent analysisof DNA unwinding.Results: Treatment was generally well tolerated and WHO grades III–IVtoxicities, consisting mostly of diarrhea (17%), were uncommon. Onepatient died of severe diarrhea with consequent hypokalemia and cardiacarrhythmia. All patients were considered evaluable for response, and 3(10%) complete and 10 (35%) partial responses were observed, foran objective response rate of 45% (95% confidence limit interval26%–64%). Both 5-FU + LV and AZT decreased the percentageof double stranded DNA in nuclear blood cells. The greatest effect wasobserved with 5-FU + LV + AZT, which reduced the percentage of double strandedDNA to 50% and 36% after 24 and 48 hours, respectively, and thisinteraction between 5-FU + LV and AZT was found to be cumulative.Conclusions: These studies demonstrate that the present dose and scheduleof AZT in combination with 5-FU + LV has significant activity in metastaticcolorectal cancer and that the combination of 5-FU + LV with AZT increases theamount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrantsfurther study in colorectal cancer.     

Über Konstitutionelle Eosinophilie bei chronischen Arthritiden

Ohne Zusammenfassung     

Peripartale Blutungen,Diagnostik und Therapie

Die Anaesthesiologie - Anhand einer fiktiven Kasuistik wird die aktuelle Leitlinie „Peripartale Blutungen, Diagnostik und Therapie“ mit einem Schwerpunkt auf die anästhesiologische...     

The proteome of Saccharomyces cerevisiae mitochondria

We performed a comprehensive approach to determine the proteome of Saccharomyces cerevisiae mitochondria. The proteins of highly pure yeast mitochondria were separated by several independent methods and analyzed by tandem MS. From >20 million MS spectra, 750 different proteins were identified, indicating an involvement of mitochondria in numerous cellular processes. All known components of the oxidative phosphorylation machinery, the tricarboxylic acid cycle, and the stable mitochondria-encoded proteins were found. Based on the mitochondrial proteins described in the literature so far, we calculate that the identified proteins represent approximately 90% of all mitochondrial proteins. The function of a quarter of the identified proteins is unknown. The mitochondrial proteome will provide an important database for the analysis of new mitochondrial and mitochondria-associated functions and the characterization of mitochondrial diseases.     

Insight in obsessive-compulsive disorder: a study of an Italian sample

Insight is a complex phenomenon that can be interpreted according to a dimensional model. Given the controversial data of insight in obsessive-compulsive disorder (OCD), our study aimed to investigate insight in an Italian sample of patients with OCD by means of the specific item on the Yale-Brown obsessive-compulsive scale (Y-BOCS) and to explore the possible correlations between it and clinical features. One hundred and seventeen out-patients with a DSM-IV diagnosis of OCD and different comorbid psychiatric disorders were included in the study and assessed by means of the Y-BOCS, Hamilton rating scale for depression (HRSD) and the global clinical impression. The results showed that almost 50% of the patients had an excellent level of insight and 15% had a little or no insight. No correlation between levels of insight and clinical features was observed, except for a negative trend with the presence of somatic obsessions. In addition, a trend towards a lower level of insight was observed in those bipolar patients with a positive history of repeated manic or hypomanic episodes. Further studies seem to be necessary in order to establish whether or not OCD patients with poor insight represent a distinct sub-group of patients.     

Kleptomania in impulse control disorders,obsessive-compulsive disorder,and bipolar spectrum disorder: Clinical and therapeutic implications

This paper aims to critically review currently available data on kleptomania and to analyze the possible future evolution of clinical research and therapeutic strategies.     

Obsessive-compulsive disorder in childhood and adolescence

Obsessive-compulsive disorder (OCD) is a common psychiatric condition during childhood and adolescence, which continues to be underestimated and undertreated. For these reasons, it constitutes a primary cause of major disabilities in those ages and, sometimes, of permanent impairments later on. In these last few years, childhood and adolescence OCD has attracted an increasing focus which has promoted a deeper awareness of this illness, a better recognition with earlier interventions, as well as the set-up of more tailored and specific strategies, including psychotropic drugs. The aim of this paper is to present a critical review of paediatric OCD, with a special attention towards the most compelling reports available up to now and towards the most interesting areas for future research.     

Treatment with 5-Fluorouracil/Folinic Acid, Oxaliplatin, and Irinotecan Enables Surgical Resection of Metastases in Patients With Initially Unresectable Metastatic Colorectal Cancer

Background The prognosis of unresectable metastatic colorectal cancer might be improved if a radical surgical resection of metastases could be performed after a response to chemotherapy. Methods We treated 74 patients with unresectable metastatic colorectal cancer (not selected for a neoadjuvant approach) with irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin (FOLFOXIRI and simplified FOLFOXIRI). Because of the high activity of these regimens (response rate, 72%), a secondary curative operation could be performed in 19 patients (26%). Results Four patients underwent an extended hepatectomy, nine patients underwent a right hepatectomy, three patients underwent a left hepatectomy, and three patients had a segmental resection. In five patients, surgical removal of extrahepatic disease was also performed. In seven patients, surgical resection was combined with intraoperative radiofrequency ablation. The median overall survival of the 19 patients who underwent operation is 36.8 months, and the 4-year survival rate is 37%. The median overall survival of the 34 patients who were responsive to chemotherapy, but who did not undergo operation, is 22.2 months (P = .0114). Conclusions The FOLFOXIRI regimens we studied have significant antitumor activity and allow a radical surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer not selected for a neoadjuvant approach and also those with extrahepatic disease. The median survival of patients with resected disease is promising.     

Kleptomania: clinical features and comorbidity in an Italian sample.

Kleptomania, listed in DSM-IV as an impulse control disorder not elsewhere classified, is a psychiatric condition still poorly understood and subject of only a few systematic studies. The aim of this research was, therefore, to evaluate the clinical features and comorbidity of Italian patients with a DSM-IV diagnosis of kleptomania. Twenty outpatients with a lifetime diagnosis of kleptomania by DSM-IV criteria, were included in the study and underwent a specially designed semistructured interview and the Family History Research Diagnostic Criteria. The majority of patients reported an early and abrupt onset and an episodic course of the disorder, with no gender preponderance. Lifetime comorbidity for other axis I disorders was high, in particular for mood, anxiety, and impulse control disorders. Family history also showed a high prevalence of psychiatric disorders. Our study indicates clear connections between kleptomania and different psychiatric disorders, the exact nature of which has yet to be clarified.     

Infusions of fluorouracil and leucovorin: effects of the timing and semi-intermittency of drug delivery.

Preclinical and clinical studies have demonstrated that the circadian modulation of 5-FU delivery may reduce toxicities and improve antitumor activity. However, the relative importance of the timing of 5-FU delivery has not been clinically addressed. The aims of this study were to determine the toxicities, the maximum tolerable doses and the activity of a regimen with 5-fluorouracil (5-FU) and leucovorin (LV) administered as a 14-day continuous infusion according to a flat or three different chronomodulated rhythms in patients with metastatic gastrointestinal carcinomas. A total of 113 patients entered the study and their characteristics were comparable among the four groups. Toxicities included mainly stomatitis and diarrhea, and a reduced toxicity was observed in all the three chronogroups that allowed the delivery of higher dose intensities. Response rates were not significantly different among the four groups. These results suggest that a reduction in 5-FU+LV toxicity and an increase in 5-FU dose intensity can be obtained by a nonsinusoidally circadian modulated infusion. However, the reduction in toxicity observed seems to be dependent mainly on the quasi-intermittency and not on the timing of 5-FU+LV delivery.