External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma: a prospective, randomized study--quality-of-life analysis.

BACKGROUND: A combination of vaginal brachytherapy and external beam radiotherapy was compared with brachytherapy alone in medium-risk endometrial carcinomas. Quality-of-life analysis is an important part of a randomized study to find out the optimal adjuvant treatment for this group of patients. OBJECTIVE: To evaluate the value of adjuvant external beam pelvic radiotherapy in adjunct to vaginal brachytherapy in medium-risk endometrial carcinoma. Quality-of-life evaluation is the main topic of this report. METHODS: A consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study end points were locoregional recurrences and overall survival. Secondary end points were recurrence-free survival, toxicity, and quality-of-life. European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 modules were used to evaluate global health status, functional scales, and symptom scales. RESULTS: Five-year locoregional relapse rates were 1.5% after external beam (ERT) plus vaginal irradiation (VBT) and 5% after vaginal irradiation alone (P = 0.013), and 5-year overall survival (OS) rates were 89% and 90%, respectively. External beam radiotherapy was associated with a higher rate of adverse effects from the intestine and the bladder, and quality-of-life parameters deteriorated at the end of radiotherapy but recovered to normal levels within a few months. There was a significant difference in favor of VBT alone with regard to adverse effects of the bowel and urinary tract, and quality-of-life. CONCLUSIONS: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded; but increased late toxicity from the intestine and the bladder. External beam irradiation decreased global health status during and after treatment, and 3 functional scale items (physical, role, and social). Six of 11 symptom items showed a pattern favoring vaginal brachytherapy alone.

One-pot Eschenmoser episulfide contractions in DMSO: applications to the synthesis of fuligocandins A and B and a number of vinylogous amides.

Practical total syntheses of the natural products fuligocandin A (2a) and fuligocandin B (3) have been achieved through a convergent strategy depending on the Eschenmoser episulfide contraction as a key step. Conducting the reaction in DMSO proved to be an efficient and general method for the synthesis of a variety of vinylogous amides, such as azepan-2-ylidenepropan-2-one.

Thionations using a P4S10-pyridine complex in solvents such as acetonitrile and dimethyl sulfone.

Tetraphosphorus decasulfide (P(4)S(10)) in pyridine has been used as a thionating agent for a long period of time. The moisture-sensitive reagent has now been isolated in crystalline form, and the detailed structure has been determined by X-ray crystallography. The thionating power of this storable reagent has been studied and transferred to solvents such as acetonitrile in which it has proven to be synthetically useful and exceptionally selective. Its properties have been compared with the so-called Lawesson reagent (LR). Particularly interesting are the results from thionations at relatively high temperatures (∼165 °C) in dimethyl sulfone as solvent. Under these conditions, for instance, acridone and 3-acetylindole could quickly be transformed to the corresponding thionated derivatives. Glycylglycine similarly gave piperazinedithione. At these temperatures, LR is inefficient due to rapid decomposition. The thionated products are generally cleaner and more easy to obtain because in the crystalline reagent, impurities which invariably are present in the conventional reagents, P(4)S(10) in pyridine or LR, have been removed.

Synthesis of 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones by addition of Grignard reagents to derivatives of o-aminobenzonitrile.

Addition of organometallics to N-(alpha-haloacyl)-o-aminobenzonitrile resulted in the formation of 2,5-disubstituted 1,4-benzodiazepin-3-ones, whereas N-(beta-haloacyl)-o-aminobenzonitrile gave 2,6-disubstituted 1,5-benzodiazocin-4-ones under similar conditions. Initial cylization of N-(beta-haloacyl)-o-aminobenzonitrile to obtain the corresponding lactam (e.g.alpha,alpha-dimethyl-N-(2-cyanophenyl)-beta-lactam) increased the yield of 1,5-benzodiazocin-4-ones significantly. Somewhat surprisingly, addition of lithium reagents to N-(beta-haloacyl)-o-aminobenzonitrile gave 4,4-disubstituted quinazolines via Grob fragmentation.

The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research.

Swedish health care and national health registers are dependent on the presence of a unique identifier. This paper describes the Swedish personal identity number (PIN) and explores ethical issues of its use in medical research. A ten-digit-PIN is maintained by the National Tax Board for all individuals that have resided in Sweden since 1947. Until January 2008, an estimated 75,638 individuals have changed PIN. The most common reasons for change of PIN are incorrect recording of date of birth or sex among immigrants or newborns. Although uncommon, change of sex always leads to change of PIN since the PIN is sex-specific. The most common reasons for re-use of PIN (n = 15,887), is when immigrants are assigned a PIN that has previously been assigned to someone else. This is sometimes necessary since there is a shortage of certain PIN combinations referring to dates of birth in the 1950s and 1960s. Several ethical issues can be raised pro and con the use of PIN in medical research. The Swedish PIN is a useful tool for linkages between medical registers and allows for virtually 100% coverage of the Swedish health care system. We suggest that matching of registers through PIN and matching of national health registers without the explicit approval of the individual patient is to the benefit for both the individual patient and for society.

External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma--a prospective randomized study.

PURPOSE: To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity. METHODS AND MATERIALS: Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity. RESULTS: Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone. CONCLUSIONS: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.

Description and validation of a four-channel staggered LC-MS/MS system for high-throughput in vitro screens.

A parallel four-channel LC-MS/MS system for quantitative high-throughput in vitro screens is described. The system comprises four pumps, a four-valve autosampler equipped with a nine-port stream selector valve, and a triple quadrupole mass spectrometer. Staggered injections across the sample list are performed by four injector valves onto separate columns in such a manner that the chromatographic window of interest is always eluting from one of the columns into the mass spectrometer. To demonstrate the applicability of the system, three different compounds (verapamil, propanolol, dextromethorphan) were analyzed. The results showed that the sample throughput could be increased more than three times in comparison with a conventional single-column LC-MS/MS system. Validation results for the three compounds showed an accuracy of 85.0-108%, a precision (given as relative standard deviation) of 2.60-10.7%, and a carryover of less than 0.1%.

Differences between children and adults in thiopurine methyltransferase activity and metabolite formation during thiopurine therapy: possible role of concomitant methotrexate.

This study examined the role of thiopurine methyltransferase (TPMT) polymorphism in the metabolism and clinical effects of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease and childhood leukemia. The current hypothesis is that the cytotoxic effects of thiopurines are caused by the incorporation of thioguanine nucleotides into DNA. In this context, S-methylation catalyzed by TPMT can be regarded as a competing metabolic pathway. The authors assayed the TPMT activity in red blood cells from 122 patients treated with azathioprine or 6-mercaptopurine (83 adults with inflammatory bowel disease and 39 children with acute lymphoblastic leukemia) and in 290 untreated controls (219 adult blood donors and 71 children). The concentrations of thioguanine nucleotides and methylthioinosine monophosphate were also assayed in red blood cells from the patients. The TPMT activity and the concentrations of methylthioinosine monophosphate and thioguanine nucleotides were higher in children than in adults. All children but no adult patient received concomitant methotrexate. Interaction between methotrexate and 6-mercaptopurine has been described, and may explain the results. Low TPMT activity in adult patients with inflammatory bowel disease correlated to an increased incidence of adverse drug reactions. However, there was no correlation between TPMT activity and the red blood cell concentrations of methylthioinosine monophosphate or thioguanine nucleotides, or between the concentrations of these metabolites and the occurrence of adverse effects. The results show that the role of thiopurine metabolism for drug effects is complex.