Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors.

BACKGROUND: Temozolomide has shown activity and limited toxicity in patients with primary brain tumors at doses of 150-200 mg/m(2)/day on days 1-5 every 4 weeks. In this study, a new alternative dose-dense regimen of temozolomide was explored in patients with recurrent brain tumors. PATIENTS AND METHODS: In this study, we evaluated the safety, dose-limiting toxicity, maximum tolerated dose, recommended dose and activity of temozolomide given on days 1-3 and 14-16 every 28 days (one cycle). The starting daily dose was 200 mg/m(2) in a group of at least six patients, with subsequent increments of 50 mg/m(2) in groups of at least 12 patients until unacceptable toxicity was reached. Oral ondansetron (8 mg) was given 1 h prior to temozolomide administration. McDonald's criteria were used to evaluate antitumor activity. RESULTS: Seventy patients with brain tumors entered this study. The median number of prior chemotherapy treatments was two (range 1-3). Patients were assigned to one of four groups to receive temozolomide at daily doses of 200 (seven patients), 250 (13 patients), 300 (38 patients) and 350 mg/m(2)/day (12 patients). The absence of dose-limiting toxicity at cycle 1 led us to establish dose recommendations based on toxicity after repeated cycles. A total of 23, 72, 192 and 83 cycles were given at daily doses of 200, 250, 300 and 350 mg/m(2), respectively. Grade 3-4 thrombocytopenia was observed in 0/7, 1/13, 5/38 and 4/12 patients treated at doses of 200, 250, 300 and 350 mg/m(2)/day, respectively. Grade 3-4 neutropenia was observed in 1/7, 0/13, 3/38 and 4/12 patients treated with 200, 250, 300 and 350 mg/m(2)/day temozolomide, respectively. At a dose of 350 mg/m(2), sustained grade 2-3 thrombocytopenia did not allow treatment to be resumed at day 14 in >40% of patients, and this dose was considered to be the maximum tolerated dose. Thus, a dose of 300 mg/m(2)/day that was associated with <20% treatment delay due to sustained hematological toxicity was considered as the recommended dose. Objective responses were reported in 13 patients. CONCLUSIONS: Temozolomide can be given safely using a dose-dense regimen of 300 mg/m(2)/day for 3 consecutive days every 2 weeks in patients with recurrent brain tumors.     

Etiology of nonresponsive celiac disease: results of a systematic approach

OBJECTIVES: Nonresponse or relapse of symptoms is common in patients with celiac disease treated with gluten free diet. Refractory sprue (RS) is defined as initial or subsequent failure of a strict gluten-free diet to restore normal intestinal architecture and function in patients who have celiac-like enteropathy. The aims of this study were: 1) to identify causes of persistent symptoms in patients referred with presumed diagnosis of nonresponsive celiac disease (NCD); and 2) to characterize patients with true RS. METHODS: Patients were identified who had been systematically evaluated for NCD between January 1997, and May 2001. Patient records and small bowel biopsy results were reviewed. RESULTS: A total of 55 patients were referred with a presumed diagnosis of NCD. Six did not have celiac disease and had other diseases responsible for their symptoms. Diarrhea, abdominal pain, and weight loss were the most common reasons for evaluation in cases of NCD, whereas weight loss, steatorrhea, and diarrhea were the most common presenting features of RS (nine patients). Of the 49 patients with celiac disease, 25 were identified as having gluten contamination. Additional diagnoses accounting for persistent symptoms included: pancreatic insufficiency, irritable bowel syndrome, bacterial overgrowth, lymphocytic colitis, collagenous colitis, ulcerative jejunitis, T-cell lymphoma, pancreatic cancer, fructose intolerance, protein losing enteropathy, cavitating lymphadenopathy syndrome, and tropical sprue. CONCLUSIONS: Based on this study, we conclude the following: 1) gluten contamination is the leading reason for NCD; 2) of NCD cases, 18% are due to RS; and 3) alternative diseases or those coexistent with celiac disease and gluten contamination should be ruled out before a diagnosis of RS is made.     

Effect of piezocision corticotomy on en-masse retraction:: A randomized controlled trial

ObjectivesTo compare the amount of en-masse retraction with or without piezocision corticotomy, to assess the type of tooth movement, to evaluate root integrity after retraction, and to record reported pain levels.Materials and MethodsThis randomized, controlled clinical trial included 26 orthodontic patients requiring premolar extraction. The patients were divided into two groups: (1) an extraction with piezocision corticotomy group (PCG) and (2) an extraction-only group, which served as the control group (CG). Cone-beam computed tomography images were acquired before and 4 months after the initiation of en-masse retraction utilizing miniscrews. The following variables were assessed: the amount of en-masse retraction, incisor inclination, incisor and canine root resorption, and patient-reported pain.ResultsTwelve and 11 participants completed the entire study in the PCG and CG, respectively. The amount of en-masse retraction was significantly greater in the PCG compared to the CG (mean = 4.8 ± 0.57 mm vs 2.4 ± 0.33 mm, respectively [P < .001]). There was also significantly less tipping and root resorption of incisors in the PCG (P < .05). The reported pain was significantly higher on the first day in the PCG compared to the CG (P < .001); however, it became similar between the groups after 24 hours.ConclusionsPiezocision corticotomy enhanced the amount of en-masse retraction two times more with less root resorption. However, future studies are required to assess the long-term effects of this technique.     

Women not in cardiology: where are we going wrong? A survey of the perceptions and barriers to training

In the UK, there is a difference between the medical specialties and cardiology in recruitment of women. Research, thus far, has concentrated on women already in cardiology. Although invaluable in understanding barriers to training, these studies fail to provide insight into why other trainees chose an alternative. Therefore, we designed a survey aimed at medical personnel, evaluating why higher trainees in other specialties overlooked cardiology.An online survey was distributed via email to non-cardiology higher trainees in Wales. Questions covered previous clinical experiences of cardiology, interactions with cardiologists, and tried to identify deterrent factors.There were 227 responses received over six weeks: 61.7% (n=137) female respondents, 23.5% (n=52) less than full-time. Of these, 49% completed a cardiology placement previously. Bullying was witnessed and experienced equally among genders, females witnessed and experienced sexism, 24% (n=24) and 13% (n=13), respectively. In contrast, male trainees witnessed and experienced sexism 14% (n=7) and 0%. There were 62% (n=133) who felt cardiologists and registrars were unapproachable. Work-life balance ranked first (40%), as the most important factor influencing career choice. The negative attitudes of cardiologists and registrars was ranked top 3 for not pursuing cardiology.In conclusion, many barriers exist to cardiology training including poor worklife balance, sexism and lack of less than full-time opportunities. However, this survey highlights that the behaviour of cardiologists and registrars has the potential to impact negatively on trainees. It is, therefore, our responsibility to be aware of this and encourage change.     

Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease

BACKGROUND/AIMS: The aims were to study: 1) the prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic liver disease, 2) viral and host immunogenetic factors that may predispose to diabetes, and 3) liver transplantation outcome in patients with or without diabetes. METHODS: Fasting blood glucose values of patients who underwent liver transplantation because of hepatitis C-related cirrhosis (73 patients) were compared with those of patients with cirrhosis due to cholestatic (78 patients) or alcoholic liver disease (53 patients) and to a general population. Data on diabetes prevalence in a population without liver cirrhosis was based on the prevalence of diabetes in Olmsted County, Minnesota, residents. HLA was determined using serologic assays. Hepatitis C virus genotypes were determined with polymerase chain reaction amplification and direct sequencing. Hepatitis G RNA was detected with polymerase chain reaction. Liver transplantation outcome in patients with or without diabetes was determined with rejection, retransplantation, or death at 1 year after transplantation as end points. RESULTS: Of 64 patients with hepatitis C alone, 16 (25%) had diabetes before transplantation compared with 1 of 78 (1.3%) with cholestatic liver disease (p= 0.0001) and 10 of 53 (19%) with alcoholic liver disease (p=0.36). Nine patients had hepatitis C plus cholestatic liver disease; one of these (11%) had diabetes. The prevalence of diabetes in patients with cholestatic liver cirrhosis was not different from that of the general population. The frequency of hepatitis G virus coinfection, HLA-DR3, or HLA-DR4 in hepatitis C and diabetes was not different from that of hepatitis C alone. The distribution of hepatitis C virus genotype was similar in those with and those without diabetes. Diabetes was not associated with increased risk of rejection, retransplantation, or death at 1 year after transplantation, and had no impact on overall survival after transplantation. CONCLUSIONS: 1) The risk of diabetes is not increased in patients with liver cirrhosis due to cholestatic liver disease but is in patients with liver cirrhosis due to hepatitis C or alcoholic liver disease; 2) cofactors (age, sex, body mass index, hepatitis G virus coinfection, hepatitis C virus genotype, or HLA-DR3/DR4) did not explain the increased risk of diabetes in patients with hepatitis C; 3) diabetes before liver transplantation did not change the outcome at 1 year after transplantation or survival.     

AML transformation in 56 patients with Ph− MPD in two well defined populations

The Philadelphia chromosome‐negative (Ph?) chronic myeloproliferative disorders (MPD) have an inherent tendency for transformation into acute myelogenous leukaemia (AML). The long‐term rate of leukaemic transformation in unselected MPD patients was studied in well‐defined MPD populations in Gothenburg, Sweden and the Côte d′Or area, Burgundy, France, respectively. Over a median observation time of 15 yr, 56 subjects (7%) out of a total of 795 patients with Ph? MPD transformed to AML. The yearly incidence of AML transformation was 0.38% in polycythaemia vera (PV), 0.37% in essential thrombocythaemia (ET) and 1.09% in idiopathic myelofibrosis (IMF). The incidence of AML development was significantly higher in IMF as compared with both PV and ET (P = 0.002 and P = 0.02, respectively). Six of the patients who developed AML had never been treated with cytoreductive agents and two had only been exposed to interferon. In IMF, the average time from diagnosis to AML transformation was 42 ± 33 months, which was significantly shorter than for both PV and ET (88 ± 56 and 76 ± 57 months; P = 0.0075 and P = 0.027, respectively). The time from diagnosis to AML transformation appears to be a continuous event as regards all three MPD entities. It was shown that 17 out of the 18 patients with PV who developed AML were females; this was true despite the fact that the male/female ratio for the whole PV group was 146/171 (0.85). As regards ET and IMF patients who transformed to AML, the gender ratio showed slight male predominance (1.33 and 1.13, respectively). The average survival time for the 56 MPD patients who developed AML was 4.6 ± 5.5 (range 0–28) months and did not differ with respect to the three subtypes of pre‐AML MPD.