High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

Clinicians’ Attitudes toward Patients with Disorders of Consciousness: A Survey

Notwithstanding fundamental methodological advancements, scientific information about disorders of consciousness (DOCs)—e.g. Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) and Minimally Conscious State (MCS)—is incomplete. The possibility to discriminate between different levels of consciousness in DOC states entails treatment strategies and ethical concerns. Here we attempted to investigate Italian clinicians’ and basic scientists’ opinions regarding some issues emerging from the care and the research on patients with DOCs. From our survey emerged that Italian physicians working with patients with DOCs give a central role to ethics. Current Italian regulation regarding basic research conducted in patients with DOCs apparently risks to be inadequate to support scientific advancement, and would deserve a different assessment compared to ordinary treatments. We think the results of our survey deserve attention from an international audience because they exemplify the difficulty to define a shared approach to the issues related to patients with DOCs and the necessity to better assess both the ordinary and experimental treatment of patients with DOCs at the ethical and legal level.     

Association of Intraprocedural Blood Pressure and End Tidal Carbon Dioxide with Outcome After Acute Stroke Intervention

Background

General anesthesia (GA) for acute stroke interventions may be associated with inferior functional outcomes. Our goal was to identify physiologic parameters that mediate this association.

Methods

Consecutive patients treated at our institution between August 2007 and December 2010 were identified from a prospective database. Clinical data were then extracted by retrospective chart review. Variables significantly associated with outcome in univariate analysis were also examined in multivariate analysis, controlling for well-established prespecified predictors of functional outcome.

Results

Of the 106 patients identified, 20 were excluded (17 due to the absence of 90-day mRS and 3 due to insufficient anesthetic records). Blood pressure (BP) decreased significantly after induction of GA, but there was no association between BP and outcome. End tidal carbon dioxide values (ETCO2) at 60 and 90 min, however, were significantly associated with outcomes in both univariate and multivariate analyses. Mean ETCO2 in patients with favorable outcomes (modified Rankin Scale (mRS) 0–3) was higher than in those with unfavorable outcomes (mRS 4–6): 35.2 mmHg versus 32.2 (p = 0.03) at 60 min and 34.9 versus 31.9 (p = 0.04) at 90 min. The adjusted odds ratios for poor outcomes for each 1 mmHg decrease in ETCO2 were the same: 0.76 (95 % CI 0.65–0.92; p = 0.004) at 60 min and 0.76 (95 % CI 0.61–0.93; p = 0.01) at 90 min.

Conclusions

While BP decreased significantly in patients undergoing GA for acute stroke intervention, it did not correlate with patient outcome. Decreases in ETCO2 at 30 and 60 min, however, were associated with 90-day mRS.     

Gender Abuse,Depressive Symptoms,and Substance Use Among Transgender Women: A 3-Year Prospective Study

Objectives. We examined the effects of gender abuse (enacted stigma), depressive symptoms, and demographic, economic, and lifestyle factors on substance use among transgender women.Methods. We conducted a 3-year prospective study (December 2004 to September 2007) of 230 transgender women aged 19 to 59 years from the New York Metropolitan Area. Statistical techniques included generalized estimating equations with logistic and linear regression links.Results. Six-month prevalence of any substance use at baseline was 76.2%. Across assessment points, gender abuse was associated with alcohol, cannabis, cocaine, or any substance use during the previous 6 months, the number of days these substances were used during the previous month, and the number of substances used. Additional modeling associated changes in gender abuse with changes in substance use across time. Associations of gender abuse and substance use were mediated 55% by depressive symptoms. Positive associations of employment income, sex work, transgender identity, and hormone therapy with substance use were mediated 19% to 42% by gender abuse.Conclusions. Gender abuse, in conjunction with depressive symptoms, is a pervasive and moderately strong risk factor for substance use among transgender women. Improved substance abuse treatment is sorely needed for this population.Previous studies and reports have pointed to a high prevalence of substance use among transgender women.1,2 In surveys of this population in large US cities, self-reports of alcohol, cannabis, cocaine, amphetamine, methamphetamine, and opiate use have been 4 to 10 times as high as corresponding reports in the general population.3–6 A recent study of this population in the New York Metropolitan Area observed prevalence estimates of these substances that were, for the most part, marginally higher than previous reports (60.4% for heavy alcohol use, 40.0% for cannabis, 21.7% for cocaine, 3.9% for amphetamines and methamphetamines, and 3.5% for opiates).7Early clinical studies of this population attributed such high percentages of substance use to a gender identity at odds with sexual anatomy,8 with later reports emphasizing more socially based conflict described as “gender-variant living in an often hostile world.”9^(p88) Following minority stress theory,10 the use of alcohol and other drugs in lesbian, gay, bisexual, and transgender populations is now often understood as resulting from internalized stigma (including transgender phobia directed at oneself) or enacted stigma in the forms of discrimination or psychological or physical abuse by others.11–13Enacted stigma and substance use have been described in a few studies of lesbian, gay, bisexual, and transgender populations,14–16 but longitudinal investigations of these associations are rare,17 the findings have not been consistent,18 and no empirical research has focused on stigma and substance use among transgender women.19Recent prospective studies of transgender women by our research team have pointed to gender abuse (enacted stigma) as a pervasive risk factor for a range of interrelated adverse health outcomes. In one study, gender abuse was associated with incident HIV and sexually transmitted infection in part because of the mediating effect of depressive symptoms.20 A subsequent study showed moderately strong associations of psychological and physical gender abuse with incident major depression.21In this study, we furthered this line of inquiry by systematically examining gender abuse, depressive symptoms, and demographic, economic, and lifestyle variables as interrelated risk factors for substance use. We hypothesized that psychological and physical gender abuse (enacted stigma) would be associated with substance use across time. We also hypothesized that these associations would be partially mediated by depressive symptoms (i.e., gender abuse causes depression, which then causes substance use). We have observed associations of gender abuse and depression in our previous studies, and depression, in turn, has been linked to substance use in numerous clinical and population studies.22 One interpretation of the latter link, the self-medication hypothesis, suggests that depressed individuals use certain substances in an attempt to temporarily ameliorate their symptomatology.23Against the background of the previous study,21 which linked 4 background variables (employment income, sex work, social presentation of transgender identity, and hormone therapy) to depression in part because of the mediated effects of gender abuse, we hypothesized that these same background variables would likewise affect substance use in part because of the mediated effects of gender abuse. The link between employment income and gender abuse may reflect the social scrutiny of transgender women’s behavior in a formal workplace environment. Sex work (especially in public venues), social presentation of transgender identity, and physical feminization associated with hormone therapy may increase the public visibility of gender nonconformity and increase the odds of gender abuse as a result.     

Immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children

Objective: To determine the immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children in north Queensland.
Methodology: A cross-sectional survey of immunity in a sample of children; 101 fully vaccinated Aboriginal and Torres Strait Island children, with a median age of 24.5 months, from 10 communities in North Queensland participated in this study. The main outcome measures were the prevalence of adequate antibody levels against hepatitis B, poliomyelitis and measles.
Results: Only 54% (95% Cl 44–63%) of the children had adequate immunity (10 m iu/mL) to hepatitis B, and one child had been infected despite vaccination. Although all the children (95% Cl 96–100%) had adequate immunity (i.e. neutralizing antibodies at a dilution of 1:8) to poliovirus 2, only 93% (95% Cl 86–96%) and 60% (95% Cl 50–69%) had adequate immunity to polioviruses 1 and 3, respectively. Nearly all (96%; 95% Cl 90–98%) of the children had adequate immunity (i.e. detectable IgG antibody) to measles.
Conclusions: Although a relatively low proportion of the children had adequate antibody levels against hepatitis B the clinical significance of this observation is uncertain. Further studies are needed to determine whether fully vaccinated Torres Strait Island children have been adequately protected and whether they require a booster dose of hepatitis B vaccine. A substantial proportion of fully vaccinated Aboriginal and Torres Strait Island children are inadequately protected against poliomyelitis, and therefore any such child with acute flaccid paralysis should be investigated fully for poliomyelitis. Vaccinated Aboriginal and Torres Strait Island children are well protected against measles, as are other Australian children.     

New treatment strategies for malignant gliomas

Malignant gliomas are the most prevalent type of primary brain tumor in adults. Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. The median survival of patients with glioblastoma muhiforme, the most common grade of malignant glioma, is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Essentially, tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required. Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy.     

Maternal healthcare needs assessment survey at Rabia Balkhi Hospital in Kabul, Afghanistan

OBJECTIVE: Since the Department of Health and Human Services chose Rabia Balkhi Hospital (RBH) in Kabul, Afghanistan, as a site for intervention in 2002, the status of women's health there has been of interest. This study created a tool to assess accessibility and quality of care of women admitted from May to July, 2005. METHODS: A 39-item questionnaire was created in English and translated into Dari. Hospital staff administered the survey to 292 women admitted to RBH for obstetric and gynecological complaints. RESULTS: Approximately 40% of the women traveled between 1 and 5 hours to reach RBH. Only 54% (158/292) of women reported having their blood pressure monitored during their pregnancy. About one-third of women reported that they had never received an immunization. CONCLUSIONS: This survey tool ascertained that women who received care at RBH traveled great lengths to reach the facility. Preventative measures such as blood pressure checks and immunizations are areas that need improvement.