Cerebrovascular reactivity after cessation of menopausal hormone treatment.

OBJECTIVE: Women who are currently using menopausal hormone therapy (MHT) have higher cerebrovascular reactivity when compared with postmenopausal women who are not taking MHT; however, the effect of cessation of MHT on cerebrovascular reactivity is not known. Given that MHT can have structural and activational effects on vascular function, this study was performed to characterize cerebrovascular reactivity following cessation of MHT in women at low risk for cerebrovascular disease. METHODS: Cerebrovascular reactivity was measured in a subset of women from the Kronos Early Estrogen Prevention Study (KEEPS) 3 years after cessation of the study drug (oral conjugated equine estrogen, transdermal 17ß-estradiol, or placebo [PLA]). RESULTS: Age, body mass index, and blood pressure were comparable among groups. At rest, the middle cerebral artery velocity (MCAv), cerebrovascular conductance index, mean arterial pressure, and cerebral pulsatility index did not differ among groups. Slope-based summary measures of cerebrovascular reactivity did not differ significantly among groups. However, utilizing repeated-measures modeling, there was a significant upward shift in MCAv responses (p = 0.029) in the combined MHT group compared with the PLA group. CONCLUSION: MHT has a marginal sustained effect on cerebrovascular reactivity when measured 3 years after cessation of hormone treatment.

A randomized, double-blind, placebo-controlled trial of valacyclovir prophylaxis to prevent zoster recurrence from months 4 to 24 after BMT.

Reactivation of latent VZV remains a significant cause of morbidity after SCT. Twenty-five percent or more of patients undergoing SCT will experience zoster within the first year after transplant. Short-course (<1 year) prophylaxis with acyclovir has been shown to be effective, but compliance with five times daily dosing may be problematic. We conducted a randomized, double-blind, placebo-controlled trial of valacyclovir (VACV) 1000 mg twice daily from 4 through 24 months after SCT for the prevention of VZV. Fifty-three VZV-seropositive transplant recipients (17 auto-SCT, 36 allo-SCT) were randomized at a median of 163 days after SCT. In a modified intent-to-treat analysis of 49 patients who took study drug, 0 of 22 in the VACV arm experienced zoster reactivation, compared with 6 of 26 (23%) in the placebo arm (P=0.025). Thirty-two subjects completed therapy through the second year post transplant or first episode of zoster. Adverse events resulting in discontinuation were more frequent in the placebo group (5 of 26 vs 3 of 27 for placebo and study drug, respectively). VACV at a dose of 1000 mg twice daily through 24 months after transplant is well tolerated and effective in suppressing shingles after SCT.

Cognitive-behavioral therapy for subthreshold bulimia nervosa: A case series.

The extent to which cognitive-behavioral therapy (CBT) is helpful in treating individuals with bulimic symptoms who do not meet full criteria for bulimia nervosa is unclear. The purpose of this investigation was to examine the potential efficacy of CBT for eating disorder individuals with bulimic symptoms who do not meet full criteria for bulimia nervosa. Twelve participants with subthreshold bulimia nervosa were treated in a case series with 20 sessions of CBT. Ten of the 12 participants (83.3%) completed treatment. Intent-to-treat abstinent percentages were 75.0% for objectively large episodes of binge eating (OBEs), 33.3% for subjectively large episodes of binge eating (SBEs), and 50% for purging at end of treatment. At one year follow-up, 66.7% were abstinent for OBEs, 41.7% for SBEs, and 50.0% for purging. The majority also reported improvements in associated symptoms. This case series provides support for the use of CBT with individuals with subthreshold bulimia nervosa.

Preservation of cocoa antioxidant activity, total polyphenols, flavan-3-ols, and procyanidin content in foods prepared with cocoa powder.

Little is known about the effects of common cooking processes on cocoa flavanols. Antioxidant activity, total polyphenols (TP), flavanol monomers, and procyanidin oligomers were determined in chocolate frosting, a hot cocoa drink, chocolate cookies, and chocolate cake made with natural cocoa powder. Recoveries of antioxidant activity, TP, flavanol monomers, and procyanidins ranged from 86% to over 100% in the chocolate frosting, hot cocoa drink, and chocolate cookies. Losses were greatest in the chocolate cake with recoveries ranging from 5% for epicatechin to 54% for antioxidant activity. The causes of losses in baked chocolate cakes were investigated by exchanging baking soda with baking powder or combinations of the 2 leavening agents. Use of baking soda as a leavening agent was associated with increased pH and darkening color of cakes. Losses of antioxidant activity, TP, flavanol monomers, and procyanidins were associated with an increased extractable pH of the baked cakes. Chocolate cakes made with baking powder for leavening resulted in an average extractable pH of 6.2 with essentially complete retention of antioxidant activity and flavanol content, but with reduced cake heights and lighter cake color. Commercially available chocolate cake mixes had final pHs above 8.3 and contained no detectable monomeric flavanols after baking. These results suggest that baking soda causes an increase in pH and subsequent destruction of flavanol compounds and antioxidant activity. Use of an appropriate leavening agent to moderate the final cake pH to approximately 7.25 or less results in both good leavening and preservation of cocoa flavanols and procyanidins.

Blood stream infection after hematopoietic stem cell transplantation is associated with increased mortality.

Blood stream infection (BSI) is a serious complication of hematopoietic stem cell transplantation (HSCT). The aim of this retrospective cohort analysis was to describe BSI after HSCT, and to assess the predictors and outcomes of BSI after HSCT using multivariable modeling. Of the 243 subjects transplanted, 56% received allogeneic HSCT and 106 (43.6%) developed BSI. Of the 185 isolates, 68% were Gram-positive cocci, 21% were Gram-negative bacilli (GNR) and 11% were fungi. Type of allogeneic HSCT was an independent risk factor for BSI (hazard ratio (HR) 3.26, 95% confidence interval (CI) 1.50, 7.07, P = 0.01), as was the degree of HLA matching (HR 1.84, 95% CI 1.00, 3.37, P = 0.05). BSI was a significant independent predictor of mortality after HSCT (HR 1.79, 95% CI 1.18, 2.73, P = 0.007), after adjusting for acute graft-versus-host disease (GVHD) and allogeneic HSCT (both predicting death < or = 3 months after HSCT). In contrast to the effects of acute GVHD and allogeneic HSCT, the effect of BSI was evident throughout the post-HSCT period. GNR BSI and vancomycin-resistant enterococcal BSI also were significantly associated with death. We concluded that BSI is a common complication of HSCT associated with increased mortality throughout the post-HSCT period.

Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors.

We enrolled 25 patients with extensive, steroid-refractory chronic graft-versus-host disease (cGVHD) in a prospective trial evaluating the efficacy of extracorporeal photophoresis (ECP) in both skin and visceral cGVHD. The median time from transplant to initiation of ECP was 790 days. ECP was administered for 2 consecutive days every 2 weeks in 17 patients and once a week in eight patients until best response or stable disease. The median duration of therapy was 9 months (range 3-24 months). In all, 20 patients had improvement in cutaneous GVHD and six had healing of oral ulcerations. Steroid sparing or discontinuation of immunosuppressive medications was possible in 80% of patients. Response rates were similar between patients receiving treatment weekly vs every 2 weeks and in patients commencing ECP less than vs greater than 18 months from transplant (70 vs 66%). When patients were stratified based on the Akpek prognostic score, there was no difference in overall response between the favorable (Akpek score<2.5) and unfavorable risk groups, but patients with progressive onset cGVHD tended to have a higher response than those with de novo onset. In summary, we report improvement in skin and/or visceral cGVHD in 71% overall and 61% of high-risk patients.

A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease.

SUMMARY: In all, 55 patients at high risk or ineligible for a conventional allogeneic hematopoietic stem cell transplant (HSCT) received a regimen consisting of extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation. The median age was 49 years (18-70 years); 44 received a sibling and 11 an unrelated HSCT; 44% were over the age of 50 years and 31% had undergone a prior HSCT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Full donor chimerism was documented in 98% by day +100. The 1000-day nonrelapse mortality was 11%. The median follow-up is 502 days (154-1104 days). The 1- and 2-year overall survival (OS) and event-free survival (EFS) are 67, 58 and 55%, and 47%, respectively. Patients who had not received a prior HSCT or had less than three prior chemotherapy regimens had a 71% OS and 67% EFS at 1 year. Greater than grade II aGVHD developed in 9% and chronic GVHD (cGVHD) in 43%, and extensive in 12% and limited in 31%. Of the patients, 86% who engrafted had a disease response, 72% had complete and 14% partial responses. This novel reduced intensity preparative regimen was well tolerated and associated with a low incidence of transplant-related mortality and serious acute and cGVHD.

A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation.

Oral mucositis is a complication common to many cancer therapies and produces considerable pain and morbidity. The present study reports a double-blind, prospective, randomized clinical trial testing the efficacy of a calcium phosphate mouth rinse (Caphosol) with fluoride treatments vs a standard regimen of fluoride rinsing and placebo tray treatments in 95 patients undergoing hematopoietic stem cell transplantation (HSCT). The days and severity of mucositis were prospectively evaluated. There were statistically significant decreases in days of mucositis (3.72 vs 7.22 P=0.001), duration of pain (2.86 vs 7.67, P=0.0001), dose of morphine (34.54 mg vs 122.78 mg), days of morphine (1.26 vs 4.02, P=0.0001) and days to the onset of engraftment ANC (absolute neurotrophil count)>200 mm(3) (11.12 vs 12.56) in the Caphosol and fluoride treatment group vs fluoride-rinse group, respectively. Caphosol, a neutral, supersaturated, Ca(2+)/PO(4)(3-) mouth rinse, used in combination with topical fluoride treatments, is superior to fluoride rinse alone in reducing the frequency, intensity and duration of oral mucositis in patients undergoing HSCT.

Extracorporeal photopheresis in chronic graft-versus-host disease.

Despite significant advances in stem cell manipulation and post-transplant immunosuppression, chronic graft-versus-host disease (cGVHD) remains a cause of major long-term morbidity in survivors of allogeneic stem cell transplantation. Extracorporeal photopheresis (ECP) is a novel therapeutic intervention which has demonstrated efficacy in patients with refractory acute and chronic GVHD. Clinical responses have been reported in skin and visceral GVHD. While the long-term immunomodulatory effects of ECP in cGVHD are unknown, recent studies of patients undergoing a 6- to 12-month course of ECP treatment demonstrated an attenuation of Th1-mediated cytokine secretion by activated T-helper cells, a shift in the DC1/DC2 ratio favoring plasmacytoid rather than monocytoid dendritic cell profiles, and a decrease in antigen responsiveness by dendritic cells. The implications of these immunomodulatory effects of ECP on pathogenesis and clinical outcome remains a fertile area for future research.

Randomized trial of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation.

Peripheral blood cell (PBC) rescue has become the mainstay for autologous transplantation in patients with lymphoma, multiple myeloma, and solid tumors. Different methods of hematopoietic progenitor cell (HPC) mobilization are in use without an established standard. Forty-seven patients with relapsed or refractory lymphoma received salvage chemotherapy and were randomized to have HPC mobilization using filgrastim [granulocyte-colony-stimulating factor (G-CSF)] alone for 4 days at 10 microg/kg per day (arm A) or cyclophosphamide (5 g/m(2)) and G-CSF at 10 microg/kg per day until hematologic recovery (arm B). Engraftment and ease of PBC collection were primary outcomes. All patients underwent the same high-dose chemotherapy followed by reinfusion of PBCs. There were no differences in median time to neutrophil engraftment (11 days in both arms; P =.5) or platelet engraftment (14 days in arm A, 13 days in arm B; P =.35). Combined chemotherapy and G-CSF resulted in higher CD34(+) cell collection than G-CSF alone (median, 7.2 vs 2.5 x 10(6) cells/kg; P =.004), but this did not impact engraftment. No differences were found in other PBC harvest outcomes or resource utilization measures. A high degree of tumor contamination, as studied by consensus CDR3 polymerase chain reaction of the mobilized PBCs, was present in both arms (92% in arm A vs 90% in arm B; P = 1). No differences were found in overall survival or progression-free survival at a median follow-up of 21 months. This randomized trial provides clinical evidence that the use of G-CSF alone is adequate for HPC mobilization, even in heavily pretreated patients with relapsed lymphoma.

Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease.

Extracorporeal photochemotherapy (ECP) has been associated with clinical improvement in several patients with acute and chronic graft-versus-host disease (cGVHD) after allogeneic bone marrow transplantation, but the mechanism of action is unknown. This study tested the hypothesis that in patients with cGVHD, ECP modulates alloreactivity by affecting activated lymphocyte populations or by altering the interaction between effector lymphocytes and antigen-presenting cells (APCs). Ten patients who had refractory cGVHD were treated with ECP, and the clinical response to and immunologic effects of this therapy were assessed. Seven patients had a response and 3 had no change in clinical manifestations of cGVHD. One patient died from catheter-related sepsis. Immunologic effects observed after ECP included normalization of inverted ratios of CD4 to CD8 cells, an increase in the number of CD3-CD56+ natural killer (NK) cells, and a decrease in CD80+ and CD123+ circulating dendritic cells. The results suggest that ECP modulates both NK cells and APC populations in patients with cGVHD.

A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation.

Intravenous immunoglobulin is approved for use in allogeneic bone marrow transplant recipients for prevention of graft-versus-host disease (GVHD) and infections, but the minimally effective dose has not been established. In this multicenter, randomized, double-blind trial, patients undergoing allogeneic marrow transplantation were randomized to receive 100 mg/kg, 250 mg/kg, or 500 mg/kg doses of intravenous immunoglobulin. Each dose was given weekly for 90 days and then monthly until 1 year after transplant. Six hundred and eighteen patients were evaluated. Acute GVHD (grades 2-4) occurred in 39% of the patients (80 of 206) in the 100 mg/kg group, 42% of the patients (88 of 208) in the 250 mg/kg group, and in 35% of the patients (72 of 204) in the 500 mg/kg group (P = 0.344). Among patients with unrelated marrow donors, a higher dose of intravenous immunoglobulin (500 mg/kg) was associated with less acute GVHD (P = 0.07). The incidences of chronic GVHD, infection and interstitial pneumonia were similar for all three doses of intravenous immunoglobulin. The dose of intravenous immunoglobulin also had no effect on the types of infection, relapse of hematological malignancy or survival. Except for more frequent chills (P = 0.007) and headaches (P = 0.015) in patients given the 500 mg/kg or 250 mg/kg dose of immunoglobulin, adverse events were similar for all three doses. These results suggest that 100 mg/kg, 250 mg/kg, and 500 mg/kg doses of intravenous immunoglobulin are associated with similar incidences of GVHD and infections in most allogeneic marrow transplants. These results should be considered when designing cost-effective strategies for the use of intravenous immunoglobulin in allogeneic marrow transplants receiving other current regimens for prophylaxis of GVHD and infection.

Phase II study of combination human recombinant GM-CSF with intermediate-dose cytarabine and mitoxantrone chemotherapy in patients with high-risk myelodysplastic syndromes (RAEB, RAEBT, and CMML): an Eastern Cooperative Oncology Group Study.

A Phase II study of GM-CSF with intermediate-dose cytarabine and mitoxantrone was conducted in patients with high-risk myelodysplastic syndrome. It was designed to evaluate if priming with growth factor could increase the efficiency of chemotherapy. In this older population only two of 10 patients achieved a bone marrow CR, including one patient whose leukemic blasts had an "S" phase increase of 2.55x at 48 hr. Unexpected hepatotoxicity was noted. This regimen cannot be recommended for this elderly population of patients.

Genetic and environmental influences on anorexia nervosa syndromes in a population-based twin sample.

BACKGROUND: Genetic and environmental influences on broadly-defined anorexia nervosa (AN) syndrome were examined in a population-based twin sample. METHODS: AN syndrome was assessed in 672 female 17 year-old twins using structured interviews and a self-report questionnaire. RESULTS: Twenty-six probands with AN syndrome were identified. Biometrical model-fitting analyses indicated that genetic and non-shared environmental factors accounted for 74% and 26% of the variance in AN syndrome, respectively. CONCLUSIONS: Findings support previous research indicating significant genetic and non-shared environmental influences on AN syndromes.

Treatment of primary resistant or relapsed multiple myeloma with high-dose chemoradiotherapy, hematopoietic stem cell rescue, and granulocyte-macrophage colony-stimulating factor.

In this prospective, multicenter, phase 2 study, multiple myeloma (MM) patients with primary resistant disease or recurrent chemosensitive disease, in chemoresistant relapse, or in second or subsequent remission were treated with high-dose chemoradiotherapy followed by autologous peripheral blood stem cell (PBSC) rescue. PBSCs were collected using granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 microg/kg per day subcutaneously for 3 days. Patients underwent high-dose chemoradiotherapy consisting of melphalan (140 mg/m2 x 1 day), cyclophosphamide (60 mg/kg per day x 2 days), methylprednisolone (2 g/d x 7 days), and total body radiation (150 cGy bid x 3 days) followed by peripheral blood stem cell reinfusion (> or = 1.2 x 10(9) mononucleated cells per kg) and GM-CSF support (5 microg/kg per day) and were evaluated for response, survival, and toxicity. Thirty-six patients, median age 53.4 years, completed the study. The mean pretransplantation cumulative melphalan dose was 464 +/- 72 mg. Excluding the 3 patients (8.3%) who failed to engraft, the median times to engraftment and platelet recovery were 10 days (range, 8-39 days) and 17 days (range, 7-67 days), respectively. Four patients (11.1%) died of complications related to the regimen (main causes of death, sepsis and acute respiratory distress syndrome) within the first 100 days. Twenty-two patients (61.1%) achieved complete response (CR), 8 (22.2%) partial response, and 2 (5.5%) no response. Two patients developed myelodysplastic syndrome after achieving CR. For all 36 patients, the probability of overall survival at 5 years was 27.3%. Median survival was 31 months (range, 0.3-81 months) in all patients and 42 months (range, 3.4-81 months) in those with CR. The probabilities of overall and disease-free survival at 5 years for the 22 patients who achieved CR were 43.6% and 15.7%, respectively. This high-dose chemotherapy regimen coupled with PBSC rescue is associated with a high CR rate and is capable of inducing long-term survival in a subset of heavily pretreated patients with primary resistant or recurrent MM.

High dietary manganese lowers heart magnesium in pigs fed a low-magnesium diet.

Young pigs were fed a diet moderately high or low in manganese (Mn) (0.95 +/- 0.10 mmol Mn/kg, n = 8 or 0.040 +/- 0.003 mmol Mn/kg, n = 6) and deficient in magnesium (Mg) (4.1 mmol Mg/kg) for 5 wk. All eight pigs consuming the high Mn diet died following convulsive seizures, whereas only two of six died in the group fed low Mn. In an attempt to determine the cause of death, a subsequent study examined the interactive effect of deficient dietary Mg and Mn on the tissue distribution of Mg and Mn. Pigs were individually fed, for 5 wk, diets that contained: 4.1 mmol Mg/kg and 36.0 micromol Mn/kg, 4.1 mmol Mg/kg and 0.91 mmol Mn/kg, 4.1 mmol Mg/kg and 0.91 mmol Mn/kg with added ultratrace minerals, or 41.1 mmol Mg/kg and 0. 91 mmol Mn/kg, and ultratrace minerals. Liver and skeletal muscle Mn concentrations were significantly elevated by increased dietary Mn. Increased dietary Mn did not affect heart Mn, but heart Mg concentrations were significantly depressed by high, as compared to low, dietary Mn (38.7 +/- 3.3 vs. 32.7 +/- 2.6 mmol Mg/kg). These data suggest high dietary Mn may exacerbate Mg deficiency in heart muscle and thus may be a complicating factor in the deaths observed in Mg-deficient pigs.

Varicella zoster virus infections following allogeneic bone marrow transplantation: frequency, risk factors, and clinical outcome.

Reactivation of varicella zoster virus (VZV) is a common event in patients undergoing allogeneic bone marrow transplantation (BMT) and may lead to life-threatening complications. We retrospectively analyzed the incidence, clinical outcome, and risk factors for VZV infections occurring within the first 5 years of transplantation in 100 consecutive adults undergoing allogeneic BMT between 1992 and 1997. Forty-one patients (41%) developed VZV reactivation a median of 227 days (range 45-346 days) post-transplantation. Twelve percent of VZV reactivation occurred in the first 100 days and 88% within the first 24 months. Among those who survived for 2 or more years after transplantation (n = 47), 59% developed VZV infection. Forty percent of patients with VZV reactivation required admission with a mean hospital stay of 7.2 days. Two patients developed encephalitis, and 1 died despite antiviral therapy. The most frequent complications were post-herpetic neuralgia and peripheral neuropathy (68%). Thoracic dermatomal zoster represented 41% of the infections; disseminated cutaneous involvement was observed in 17% of patients. No clinical or epidemiologic risk factors were associated with recurrence. Administration of ganciclovir for prevention of cytomegalovirus infection delayed the onset of VZV infection beyond 4 months (P = .06). In a further subset analysis, patients with a limited chronic graft-versus-host disease (GVHD) had a lower estimated incidence of VZV reactivation compared with those with extensive chronic GVHD (P = .11). We conclude that complications from reactivation of VZV infection are common and associated with considerable morbidity and mortality in patients undergoing allogeneic BMT.

Predictive validity of bulimia nervosa as a diagnostic category.

OBJECTIVE: The authors sought to investigate the predictive validity of bulimia nervosa as a diagnostic category. METHOD: More than 10 years after they appeared as patients with bulimia nervosa, 177 women (participation rate=79.7%) completed follow-up assessments. RESULTS: Among the women with a current eating pathology, most engaged in recurrent binge eating and purging. Anorexia nervosa and binge eating disorder were relatively uncommon. Eating disorder outcome was significantly related to the presence of mood, substance use, and impulse control disorders but not to the presence of anxiety disorders. CONCLUSIONS: These results support the validity of bulimia nervosa as a diagnostic category that is distinct from anorexia nervosa. Furthermore, these results suggest that bulimic symptoms are associated with disorders involving distress and disinhibition.

Myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders with a variable clinical course and prognosis. Treatment should be individualized based on the patient's age, subtype, percent blasts in the marrow, and cytogenetics. The use of the International Prognostic Scoring Index is helpful in assigning prognosis. The standard of care for low-risk patients is supportive care. Low-risk patients with symptomatic anemia should be considered for a trial of erythropoietin. The serum erythropoietin (EPO) level may help predict response to treatment. The treatment of the symptomatic and high-risk patient is unclear. Low-dose cytarabine, amifostine, and 5-azacitidine can induce responses in selected patients, but the duration of responses is short, and treatment does not appear to prolong survival. Intensive chemotherapy should be reserved for high-risk, younger patients. Topotecan and intermediate cytarabine appear to have an active regimen, but remissions are short. Younger patients who present with high-risk MDS without an antecedent history of MDS should receive intensive acute myeloid leukemia (AML) induction chemotherapy. Younger patients with high-risk MDS and an HLA-compatible donor should be offered an allogeneic stem cell transplant.