Richard F. Raubertas

Hypothalamic-Pituitary Dysfunction after Radiation for Brain Tumors

Background Patients with brain tumors who are treated with radiation frequently have growth hormone deficiency, but other neuroendocrine abnormalities are presumed to be uncommon. Methods We studied endocrine function in 32 patients (age, 6 to 65 years) 2 to 13 years after they had received cranial radiotherapy for brain tumors. The doses of radiation to the hypothalamic-pituitary region ranged from 3960 to 7020 rad (39.6 to 70.2 Gy). Nine patients also received 1800 to 3960 rad (18.0 to 39.6 Gy) to the craniospinal axis. Serum concentrations of thyroid, gonadal, and pituitary hormones were measured at base line and after stimulation. Results Nine patients (28 percent) had symptoms of thyroid deficiency, and 20 patients (62 percent) had low serum total or free thyroxine or total triiodothyronine concentrations. Of the 23 patients treated only with cranial radiation, 15 (65 percent) had hypothalamic or pituitary hypothyroidism. Of the nine patients who also received spinal (and thus direct thyroid) radiati...

Impact craters and Venus resurfacing history

Venusian impact crater size-frequency distributions, locations, and preservation states were analyzed to reconstruct the history of resurfacing by tectonism and volcanism. An atmospheric transit model for meteoroids demonstrates that for craters larger than about 30 km, the size-frequency distribution is close to the atmosphere-free case. With this result, and assuming that the surface records a crater production population (a catastrophic resurfacing model, CRM), an age of cessation of rapid resurfacing of ∼ 500 Ma is obtained. Crater locations are widely dispersed across Venus and the hypothesis that they are completely spatially random (CSR) cannot be rejected. However, craters that show embayment by plains materials or modification by throughgoing faults (i.e., tectonized) are preferentially found in areas with relatively few craters overall. The primary region where these modified craters are found is the Aphrodite volcanotectonic zone, extending from Ovda Regio on the west to the region east of Atla Regio. These results, together with the appearance of plains material on most crater floors and evidence for complex volcanic stratigraphy, imply that a range of surface ages are recorded by the impact crater population; e.g., the Aphrodite zone is relatively young. An end-member model (equilibrium resurfacing model, ERM) was developed to quantify resurfacing scenarios. In the ERM, Venus has been resurfacing at an average rate of approximately 1 km2 yr−1. However, the CRM and ERM are idealized end-member representations of possible resurfacing histories. For both models, the resurfacing rate can be expressed as the product of resurfacing patch area a (normalized by planetary surface area) and the frequency ω of resurfacing events. Numerical simulations of resurfacing showed that there are two solution branches that satisfy the CSR constraint: a 0.1 (74° diameter circle). The former range corresponds to resurfacing diameters smaller than the average intercrater distance, whereas the latter is associated with large, infrequent events, resurfacing 10% of the planet every 50 Ma to 100% every 500 Ma. The observed fraction of embayed and tectonized craters further constrains values of a and only values near 0.0003 are admissible. The resurfacing model that best fits all of the statistical and geological constraints has resurfacing with small patches that occurs, in any given geological episode, in only a limited number of regions on the planet.

Differential Effects of Paroxetine on Fatigue and Depression: A Randomized, Double-Blind Trial From the University of Rochester Cancer Center Community Clinical Oncology Program

PURPOSE Fatigue and depression typically occur together in cancer patients, suggesting a common etiology, perhaps based on serotonin. This randomized clinical trial tested whether paroxetine, a selective serotonin reuptake inhibitor antidepressant known to modulate brain serotonin, would reduce fatigue in cancer patients and whether any reduction was related to depression. PATIENTS AND METHODS Cancer patients undergoing chemotherapy for the first time were assessed for fatigue. Of 704 patients who reported fatigue at their second chemotherapy cycle, 549 patients were randomly assigned to receive either 20 mg of oral paroxetine hydrochloride daily or placebo for 8 weeks. The assessments of fatigue and depression were performed at cycles 3 and 4 of chemotherapy. RESULTS A total of 244 patients treated with paroxetine and 235 patients treated with placebo provided assessable data. No difference was detected in fatigue between patient groups. At the end of the study, there was a difference between groups in the mean level of depression (Center for Epidemiologic Studies Depression scores, 12.0 v 14.8, respectively; P <.01). CONCLUSION Paroxetine had no influence on fatigue in patients receiving chemotherapy. A possible explanation is that cancer-related fatigue does not involve a reduction in brain 5-HT levels.

Group psychotherapy for recently diagnosed breast cancer patients: a multicenter feasibility study.

As many as 80% of breast cancer patients report significant distress during initial treatment, yet there is little in the way of systematic psychotherapeutic interventions for women coping with the stress of a recent diagnosis of breast cancer. The literature on psychotherapeutic treatment of cancer patients provides uniform evidence for an improvement in mood, coping and adjustment as a result of group therapy. The present study examined the feasibility of implementing a manualized treatment, supportive–expressive group psychotherapy, in busy oncology practices across the US. This intervention was applied to women with primary breast cancer in a manner which tests not only the efficacy of the approach but also its accessibility to group therapists not previously experienced in its use. One hundred and eleven breast cancer patients within 1 year of diagnosis were recruited from ten geographically diverse sites of the National Cancer Institutes Community Clinical Oncology Program (CCOP) and two academic medical centers. Two therapists from each site were trained in supportive–expressive group psychotherapy. Training consisted of participation in a workshop, reading a treatment manual, and viewing explanatory videotapes. Each patient participated in a supportive–expressive group that met for 12 weekly sessions lasting 90 min. Assessment of mood disturbance was made at entry, 3, 6, and 12 months. Results indicated a significant 40% decrease in the Total Mood Disturbance (TMD) scores of the Profile of Mood States (POMS) (ANOVA F [2,174]=3.98, p<0.05). The total symptom score of the Hospital Anxiety and Depression Scale (HADS) was likewise significantly reduced over the 6‐month period (F [2,174]=5.2, p<0.01). Similarly, the total score of the Impact of Event Scale (IES) was significantly reduced (F [2,174]=4.0, p<0.05). There was substantial uniformity of treatment effect across sites. Outcome was independent of stage of disease (I vs. II). We conclude that this treatment program can be effectively implemented in a community setting and results in reduced distress among breast cancer patients. Copyright

Analysis of Factors That Correlate With Mucositis in Recipients of Autologous and Allogeneic Stem-Cell Transplants

PURPOSE To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy. PATIENTS AND METHODS Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea. Potential covariates included patient age, sex, diagnosis, treatment protocol, transplantation type, stem-cell source, and rate of neutrophil recovery. The three selected end points were also examined for correlation with blood infections and transplant-related mortality. RESULTS A diagnosis of leukemia, use of total body irradiation, allogeneic transplantation, and delayed neutrophil recovery were associated with increased oral mucositis and longer parenteral nutritional support. No factors were associated with diarrhea. Also, moderate to severe oral mucositis (MUCPEAK > or = 18 on a scale of 8 to 24) was correlated with blood infections and transplant-related mortality: 60% of patients with MUCPEAK > or = 18 had positive blood cultures versus 30% of patients with MUCPEAK less than 18 (P =.001); 24% of patients with MUCPEAK > or = 8 died during the transplantation procedure versus 4% of patients with MUCPEAK less than 18 (P =.001). CONCLUSION Gastrointestinal toxicity is a major cause of transplant-related morbidity and mortality, emphasizing the need for corrective strategies. The peak oral mucositis score and the duration of parenteral nutritional support are useful indices of gastrointestinal toxicity because these end points are correlated with clinically significant events, including blood infections and treatment-related mortality.

The short-form McGill Pain Questionnaire in chronic cancer pain

A short form of the McGill Pain Questionnaire (SF-MPQ) was previously developed. It was found to correlate highly with and demonstrate differences due to treatment in a manner similar to the long form of the McGill Pain Questionnaire (LF-MPQ). The LF-MPQ was previously found to be a valid measurement of pain in the cancer population. The present study demonstrated that the sensory, affective, and total scores of the SF-MPQ correlated highly with the LF-MPQ on three administrations, each 3-4 wk apart in 24 patients with chronic pain due to cancer. Both the long and short total scores correlated highly with the visual analogue scale (VAS) and present pain intensity (PPI) scale. The SF-MPQ demonstrated changes over time in a manner similar to the LF-MPQ in this patient group. These observations support the value of the SF-MPQ as a tool for studying interventions in patients with chronic pain due to cancer.

A Randomized Study of Tracking With Outreach and Provider Prompting to Improve Immunization Coverage and Primary Care

Objective. To compare and measure the effects and cost-effectiveness of two interventions designed to raise immunization rates. Settings. Nine primary care sites serving impoverished and middle-class children. Subjects. Complete birth cohorts (ages 0 to 12 months; n = 3015) from these sites. Interventions. Two 18-month duration interventions: 1) tracking with outreach [tracking/outreach] to bring underimmunized children to their primary care provider office, and 2) a primary care provider office policy change to identify and reduce missed immunization opportunities (prompting). Design. Randomized, controlled trial, randomizing within sites using a two-by-two factorial design. Subjects were allocated to one of four study groups: control, prompting only, tracking/outreach only, and combined prompting with tracking/outreach. Outcomes were obtained by blinded chart abstraction. Measures. Immunization status for age; number of days of delay in immunization; primary care utilization; and rates of screening for occult disease. Results. Out of 3015 subjects, 274 subjects (9%) transferred out of the participating sites or had incomplete charts and were excluded. The 2741 (91%) remaining subjects were assessed. At baseline, study groups did not differ in age, gender, insurance type, or immunization status. Of the remaining subjects, 63% received Medicaid. Final series-complete immunization coverage levels were: control, 74%; prompting-only, 76%; tracking/outreach-only 95%; and combined tracking/outreach with prompting, 95%. Analysis of variance showed that: 1) tracking/outreach increased immunization rates 20 percentage points; 2) tracking/outreach decreased mean immunization delay 63 days; 3) tracking/outreach increased mean health supervision visits 0.44 visits per child; 4) tracking/outreach increased mean anemia screening 0.17 screenings per child and mean lead screenings 0.12 screenings per child; 5) impact of tracking/outreach was greatest for uninsured and impoverished patients; and 6) the prompting intervention had no impact on the studied outcomes, and its failure was caused by inconsistent use of prompts and failure to vaccinate ill children when prompted. Using tracking/outreach, the cost per additional child fully immunized was

Prevalence of Hereditary Hemochromatosis in 16 031 Primary Care Patients

474. Each

Observer variation in interpretation of magnetic resonance images of the temporomandibular joint.

1000 spent on the tracking/outreach intervention resulted in: 2.1 additional fully vaccinated children and 668 fewer child-days of delayed immunization; 4.6 additional health supervision visits and 5.9 additional other visits to the primary care provider; and 1.8 additional anemia screenings and 1.3 additional lead screenings. Conclusions. Outreach directed toward children not up-to-date on immunizations improves not only immunization status, but also health supervision visit attendance and screening rates. The cost per additional child immunized was high, but should be interpreted in view of the spillover benefits that accompanied improved immunization. Effective means to improve coverage by reducing missed immunization opportunities still need to be identified. immunization, primary care, randomized, controlled trial, missed immunization opportunities, outreach.

Autotransplantation for relapsed or refractory Hodgkin's disease : long-term follow-up and analysis of prognostic factors

Several recent studies [1-6] support a high prevalence of hereditary hemochromatosis (2 to 5 per 1000) in the U.S. population. Nationally representative data are available on the proportion of persons in the United States who have elevated serum iron measures (serum ferritin level and serum transferrin saturation) on initial testing [7], but the proportion of persons with hemochromatosis can be determined only through further diagnostic follow-up, such as that provided by screening studies. A meta-analysis of screening studies done throughout the world and a recent study done in a health maintenance organization [5, 6] suggest that hemochromatosis is relatively common among white and Hispanic persons. A gene for hemochromatosis was discovered in 1996 [8], but many questions remain unanswered about the accuracy of genetic testing for hemochromatosis. Experts currently do not advocate widespread population screening done by using genetic methods [9]. Serum transferrin saturation is thought to be a sensitive marker for hemochromatosis [1]. The threshold transferrin saturation value used for screening has ranged from 45% to 70% [4, 10-18]. Some authorities suggest that a persistently elevated serum transferrin saturation with no other explanation is enough to predict homozygosity for the hemochromatosis allele. It has been suggested that the threshold value for serum transferrin saturation screening should be lower for women than for men because a threshold value of 62% failed to detect 40% of suspected female homozygotes in one study [1]. We report our experience with serum transferrin saturation screening for hemochromatosis in primary care patients. Our goal was to estimate the prevalence of hemochromatosis and to establish the feasibility of screening for hemochromatosis in a large primary care population. Methods We enrolled 22 primary care practices from the Rochester, New York, area. These urban and suburban practices included 63 physicians, nurse practitioners, and physician assistants and ranged in type from solo practices to large clinics. Practice size varied from 1500 to 13 000 patients. Participating physicians were asked to offer screening to all adult patients ( 18 years of age) seen during their enrollment period. Patients with previously diagnosed hemochromatosis were excluded. Patient enrollment rates varied from 19% to 94%. After each participant had given signed informed consent, about 10 mL of venous blood was obtained. Serum was separated, and serum transferrin saturations were analyzed with a Hitachi 747 analyzer (Hitachi, Tokyo, Japan). A standard Boehringer-Mannheim system (Boehringer-Mannheim, Indianapolis, Indiana) was used with FerroZine (Boehringer-Mannheim) as the reactive chromogen read at 570 nm. Serum ferritin levels were measured on the Ciba-Corning Automated Chemiluminescence System (Ciba-Corning, Medfield, Massachusetts) by using a two-site chemiluminometric sandwich immunoassay with acridinium ester as the luminescent tag. The subsequent screening protocol is outlined in Figure 1. Patients with a screening serum transferrin saturation of 45% or more were recalled so that a second transferrin saturation test could be given under fasting conditions and the serum ferritin level could be measured. All patients with a fasting serum transferrin saturation of 45% or more were evaluated by the investigators. Patients with a fasting serum transferrin saturation of 55% or more and a serum ferritin level of 200 g/L or more who had no apparent secondary cause of abnormal iron status, such as iron-loading anemias or other causes of chronic liver disease, were offered liver biopsy with quantitative iron estimation to confirm the diagnosis of hereditary hemochromatosis. First-degree relatives of these patients were offered screening for hemochromatosis. Patients with suspected hemochromatosis who declined liver biopsy were offered therapeutic phlebotomy. Mobilizable iron stores were determined on the basis of the blood volume removed before iron depletion (serum ferritin level < 25 g/L) was achieved. The following formula was used: g of iron = (hematocrit/3) weight of blood 0.0035. Figure 1. Screening protocol. The diagnosis of hemochromatosis was based on liver biopsy findings when possible. Patients with quantitative hepatic iron concentrations of 50 mol per g or more or a hepatic iron index score (quantitative hepatic iron concentration in mol per g dry weight divided by age) of 1.9 or more were classified as having biopsy-proven hemochromatosis. Among patients in whom biopsy could not be done, those with a serum transferrin saturation of 55% or more on initial testing and on repeated testing done under fasting conditions, a serum ferritin level of 200 g/L or more, and no identifiable secondary cause of iron overload were classified as having clinically proven hemochromatosis. These patients were advised to undergo therapeutic phlebotomy and to have their first-degree relatives screened for hemochromatosis. Patients with initial and fasting serum transferrin saturations of 55% or more and serum ferritin levels less than 200 g/L were classified as having probable hemochromatosis. They were advised to have serial follow-up of iron studies and to have their first-degree relatives screened for hemochromatosis. The prevalence of hemochromatosis was defined as the probability that a primary care patient screened according to the above protocol would receive a diagnosis of hemochromatosis. At two steps of the protocol (measurement of fasting serum transferrin saturation and evaluation by investigators [Figure 2]), some participants dropped out; these participants provided incomplete information about their hemochromatosis status and represent right-censored observations, in the terminology of life-table analysis. Therefore, the Kaplan-Meier method [19] was used to estimate the prevalence of hemochromatosis and CIs were determined by using the likelihood ratio method [20]. In the analysis, we assumed that at these two screening steps, the likelihood that a participant dropped out was unrelated to his or her true hemochromatosis status. The demographic characteristics of study patients were compared by using chi-square tests. Figure 2. Screened patients. Results Demographic Characteristics of the Study Sample A total of 18 770 patients was enrolled in the study over a 26-month period. The demographic characteristics of these patients are shown in Table 1. The proportion of men in the sample was greater among the white patients than among the nonwhite patients (44% compared with 37% to 39%; P < 0.001), and the white patients were older than the nonwhite patients (median age, 54 years compared with 43 to 45 years; P < 0.001). Of the enrolled patients, 2739 (15%) did not complete the screening protocol; 2499 of these dropouts occurred before the initial serum transferrin saturation test was done. Dropout rates were significantly higher for men than for women (17% compared with 15%; P < 0.001), for nonwhite patients than for white patients (17% for African-American patients, 21% for patients of other or unknown ethnicity, and 15% for white patients; P < 0.001), and for younger patients than for older patients (21% for patients 18 to 39 years of age, 16% for patients 40 to 54 years of age, 11% for patients 55 to 69 years of age, and 9% for patients 70 years of age; P < 0.001). However, because of the large sample sizes, these statistically significant differences may not have had clinical significance. The dropouts did not substantially change the demographic characteristics of the study sample (Table 1). Table 1. Demographic Characteristics of Enrolled and Screened Patients Evaluation of Patients with Serum Transferrin Saturations of 45% or More A total of 932 patients had an initial serum transferrin saturation of 45% or more (Figure 2). Of 311 patients who subsequently had a fasting serum transferrin saturation of 45% or more, we could evaluate 255. The disposition of these patients is shown in Figure 3. Eighty-two patients persistently had a serum transferrin saturation of 55% or more; of these, 50 had a serum ferritin level of 200 g/L or more and 32 had a serum ferritin level less than 200 g/L. Of the 50 patients whose serum ferritin level was 200 g/L or more, 35 had no secondary explanation for their iron status and no contraindications for liver biopsy. Thus, they met our protocol criteria for liver biopsy. Of these 35 patients, 14 declined biopsy and 21 underwent biopsy. Of the 21 who had biopsy, 18 had biopsy-proven hemochromatosis (defined as a hepatic iron index score 1.9 or a quantitative hepatic iron concentration 50 mol per g dry weight). All biopsy specimens that met these criteria had a grade of at least 2+ on Prussian blue staining. One patients specimen had a grade of 2+ but was inadequate for quantitative iron determination. This patient also had a sister with biopsy-proven hemochromatosis and was classified as having clinically proven hemochromatosis. Of the remaining 2 patients who underwent biopsy, 1 had chronic hepatitis C and the other had drug-induced hepatitis. An additional 13 patients had liver biopsy at the clinical discretion of the investigators but were not eligible for biopsy according to the protocol because one or both of their serum transferrin saturations were less than 55% (Figure 3). Seven of the 13 had biopsy-proven hemochromatosis (of the other 6, 3 had steatohepatitis, 1 had chronic hepatitis C, 1 had drug-induced hepatitis, and 1 had nonspecific hepatitis). Thus, a total of 25 study patients had biopsy-proven hemochromatosis (Table 2). Figure 3. Evaluated patients. Table 2. Demographic and Clinical Characteristics of Patients with Biopsy-Proven Hemochromatosis Seventeen patients met our study criteria for liver biopsy and had no identifiable secondary cause of iron overload but did not have biopsy, either because they refused it (n = 14) or because the invest