Publications

The contribution of sleep disturbance to persistent cognitive symptoms following a mild traumatic brain injury (mTBI) remains unclear. Obstructive sleep apnea (OSA) is very common, yet its relationship between risk factors for developing OSA and cognitive performance in those with history of mTBI has not been investigated. The current study examined OSA risk levels and its association with cognitive performance in 391 combat-exposed, post-911 veterans and service members (median age = 37 years) enrolled in the Chronic Effects of Neurotrauma Consortium (CENC) prospective multi-center study. Participants included those with and without mTBI (n = 326 and 65, respectively). When using clinical cut-offs, those with history of mTBI were more likely to be categorized as high risk for OSA (mTBI positive = 65% vs. mTBI negative = 51%). After adjustment for TBI status and demographic variables, increased OSA risk was significantly associated with worse performance on measures of complex processing speed and executive functioning (Wechsler Adult Intelligence Scale Fourth Edition Coding, Trail Making Test, part B) and greater symptom burden (Neurobehavioral Symptom Inventory). Thus, OSA, a modifiable behavioral health factor, likely contributes to cognitive performance following mTBI. Accordingly, OSA serves as a potential point of intervention to improve clinical and cognitive outcomes after injury.

INTRODUCTION: Waldenström macroglobulinemia (WM) is an IgM-producing lymphoproliferative disorder that remains incurable. Patients with high-risk disease have an overall survival (OS) of less than 3 years. Both autologous (AHCT) and allogeneic (allo-HCT) hematopoietic cell transplantation (HCT) are prescribed for treatment of WM despite a lack of randomized controlled studies.

MATERIALS AND METHODS: We performed a comprehensive literature search using PubMed/Medline and EMBASE on September 10, 2019. Data on clinical outcomes related to benefits and harms was extracted independently by 3 authors. Fifteen studies (8 AHCT [n = 278 patients], 7 allo-HCT [n = 311 patients]) were included in this systematic review/meta-analysis.

RESULTS: Pooled OS, progression-free survival (PFS), and nonrelapse mortality (NRM) rates post AHCT were 76% (95% confidence interval [CI], 65%-86%), 55% (95% CI, 42%-68%), and 4% (95% CI, 1%-7%), respectively. Pooled OS, PFS, and NRM rates post allografting were 57% (95% CI, 50%-65%), 49% (95% CI, 42%-56%), and 29% (95% CI, 23%-34%), respectively. OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies. Pooled ORR (at day 100) post AHCT and allo-HCT were 85% (95% CI, 72%-94%) and 81% (95% CI, 69%-91%), respectively. Pooled complete response rates post AHCT and allo-HCT were 22% (95% CI, 17%-28%) and 26% (95% CI, 7%-50%), respectively. Relapse rates post AHCT and allo-HCT were 42% (95% CI, 30%-55%) and 23% (95% CI, 18%-28%), respectively.

CONCLUSIONS: Our results show that both AHCT and allo-HCT are effective in the treatment of WM. A 2-fold lower relapse rate but a 7-fold higher NRM was noted for allo-HCT compared with AHCT. The role of transplant in WM needs to be addressed in the era of novel agents.

OBJECTIVE: A recent randomized controlled trial of repetitive transcranial magnetic stimulation (TMS) for major depressive disorder (MDD) in veterans raised the question of whether comorbid posttraumatic stress disorder (PTSD) negatively impacted the outcome of TMS in veterans. To address this, a quality database was analyzed to compare outcomes of MDD treated with TMS in veterans with and without comorbid PTSD.

METHODS: The clinical outcomes of all consecutive veterans with MDD treated with TMS at the James A. Haley Veterans' Hospital as outpatients from October 2013 through September 2018 were included. Patients were initially evaluated by an experienced psychiatrist, and the diagnosis of MDD was made by clinical evaluation per DSM-IV-TR/DSM-5 criteria. At the start of treatment, after every 5 treatments, and at the end of treatment, patients were assessed with self-report and clinician-rated scales of depression. All data were abstracted from an existing quality database.

RESULTS: Among the 118 patients treated with TMS for depression, 55 (47%) had comorbid PTSD and 63 (53%) had no comorbid PTSD. Response and remission rates by score on the Montgomery-Asberg Depression Rating Scale were similar between patients with PTSD (52.5% and 40.9%, respectively) and without PTSD (53.8% and 35.6%, respectively). No seizures or persistent adverse effects were observed or reported in either group.

CONCLUSIONS: Comorbid PTSD did not impact the outcome of TMS for depression in this sample of veterans. Future studies should include formal ratings of PTSD to determine if the severity of PTSD affects the outcome.

In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent [14.4 months) vs high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65; P =0.004], low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62; P<0.0001), and supportive care (2.1 months, hazard ratio 2.94, 95%CI: 2.39-3.61; P<0.0001). Our results indicate a significant survival benefit with hypomethylating agents compared to high-intensity, low-intensity, or supportive care. Additionally, high-intensity chemotherapy resulted in superior overall outcomes compared to low-intensity therapy and supportive care. Results from this study highlight the need for novel therapeutic approaches besides utilization of intensive chemotherapy in this specific aged population.

Mycosis fungoides and Sézary syndrome are the most common types of primary cutaneous T cell lymphomas. The clinical presentation of mycosis fungoides is generally indolent, whereas Sézary syndrome represents a more aggressive disease variant. Stage at diagnosis is the most important determinant of long-term survival outcome. Although most patients present with early-stage disease, those who develop progressive disease or have an advanced stage represent a therapeutic challenge because of a lack of effective therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) has been used as a potentially curative treatment modality with encouraging long-term outcomes. However, a lack of randomized controlled data remains, and the published literature is limited to mostly retrospective studies. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 13, 2018. We extracted data on clinical outcomes related to benefits (overall [OS] and progression-free [PFS] survival) and harms (relapse and nonrelapse mortality [NRM]) independently by 2 authors. Our search strategy identified 289 references. Five studies (266 patients) were included in this systematic review and meta-analysis. Reduced-intensity and nonmyeloablative regimens were more commonly prescribed (76%). Mobilized peripheral blood stem cells were the preferred graft source (78%). The pooled OS and PFS rates were 59% (95% confidence interval [CI], 50% to 69%) and 36% (95% CI, 27% to 45%), respectively. Pooled relapse rate was 47% (95% CI, 41% to 53%) and pooled NRM rate 19% (95% CI, 13% to 27%). Results of this systematic review and meta-analysis show that allo-HCT yields encouraging OS and PFS rates; however; relapse remains a significant cause of allo-HCT failure. Novel strategies to further improve outcomes should focus on offering allo-HCT before the development of resistant disease and reducing relapse by incorporating post-transplant maintenance therapies.

PURPOSE: Our objective was to provide regionally appropriate, resource-conscious recommendations for the diagnosis and treatment of pediatric patients with febrile neutropenia.

METHODS: A multinational panel of Central American and Caribbean clinicians who deliver pediatric oncology care prioritized clinically important questions and then used the Grading of Recommendations Assessment, Development and Evaluation methodology to provide recommendations on the selected topics.

RESULTS: Twenty-two questions and 2 definitions were included in the guideline, which was intended to establish minimum care standards for pediatric patients treated in regional centers. Of all the included studies, 6.9% were conducted in low- and middle-income countries, and no studies were performed in countries represented on the panel.

CONCLUSION: The panel made recommendations on the basis of existing evidence but identified important gaps in knowledge from the region and from resource-limited settings that may affect the clinical applicability of these recommendations. These deficiencies suggest a research agenda that will enable future guidelines to be more responsive to the local context.

BACKGROUND: Research output/efforts in a country should be reflective of the disease burden. India is a site for several national and multinational clinical trials. However, whether clinical trials performed in India reflect the disease burden is not well known.

OBJECTIVES: The aim of this study was to evaluate the relationship between disease burden and clinical trials performed in India.

MATERIALS AND METHODS: We extracted data on the disease burden from the World Health Organization (WHO) website and on characteristics of clinical trials performed in India from the Clinical Trial Registry of India (CRTI). The correlation between disease burden parameters of overall mortality, disability-adjusted life years (DALYs), years lost due to disability (YLD) and years of life lost (YLL), and the frequency of clinical trials associated with a particular disease was assessed. Additional subgroup analysis according to the number of trial centers, study phase, and medicine type was also performed.

RESULTS: Only 18% of clinical trials addressed top 10 diseases associated with 68.3% of overall mortality, and 8% of clinical trials addressed top 10 diseases associated with 52.3% of DALYs. Similarly, 16% of clinical trials addressed top 10 diseases associated with 53.2% YLDs. Furthermore, top 10 diseases associated with 65.9% of YLLs were addressed in only 8% of ongoing clinical trials. The overall correlation between any disease burden parameters with the diseases being explored in clinical trials was poor.

CONCLUSION: There is a mismatch between diseases for which clinical trials are happening in the India and the disease burden of India. Measures need to be taken to fulfill this gap between demand and need.

OBJECTIVES: The majority of patients with acute myeloid leukemia (AML) are aged 70 and over. However, there is uncertainty about how and whether older patients with AML should receive cytotoxic treatment.

MATERIALS AND METHODS: Medline and Cochrane library search was performed for studies in newly diagnosed AML which enrolled at least 20 patients per arm (for randomized controlled trials), or 50 patients (for non-randomized studies) over the age of 70. References were hand searched for additional eligible studies. Study investigators were contacted to maximize relevant data. Dual independent data extraction was done using standardized data collection forms. Data was collected on study and treatment characteristics, baseline patient information, and outcomes. Study methodological quality was assessed. The primary outcome was 1 year overall survival (OS). Impact of treatment [intensive chemotherapy (INT), low-dose chemotherapy (LOW), hypomethylating agents (HMA), or best supportive care (BSC)], cytogenetics, performance status, and comorbidity were assessed.

RESULTS: The search produced 11,846 references of which 38 randomized controlled trials and 30 non-randomized studies met inclusion criteria, representing 13,381 patients, with a worldwide distribution. One-year OS with INT was 37% (31-42%), with LOW 11% (6-18%), with HMA 35% (18-54%) and with BSC 17%(13-21%). Two-year OS was 22% (18-26%), 11% (7-15%), 22% (16-28%), 6% (2-12%), respectively. We present subgroup data based on the studies including cytogenetics, performance status, and comorbidity. Formal direct comparisons with adjustment for all prognostic factors were not possible.

CONCLUSIONS: In this largest to date series of AML patients aged 70 and older, we provide benchmarks for treatment efficacy and effectiveness that may be used for decision analysis models and for the future development of clinical trials focusing on these patients.

OBJECTIVE: The purpose of this study was to describe incidence and assess predictors of adherence to Positive Airway Pressure (PAP) therapy for Obstructive Sleep Apnea (OSA) in persons with acquired brain injury (ABI).

METHODS: A 2012-2015 retrospective analysis of consecutive ABI patients admitted for neurorehabilitation, referred for polysomnography (PSG), and prescribed PAP for OSA. Univariable linear regressions were conducted to examine predictors of average hours of nightly PAP use. Univariable logistic regressions were conducted to examine predictors of PAP adherence using the conventional clinical definition of ≥4 h per night ≥70% of the time. Persons with traumatic etiology were separately analyzed.

RESULTS: ABI etiology was 51% traumatic, 36% stroke, and 13% other nontraumatic causes. Nearly two-thirds were nonadherent to PAP. For the overall sample, higher average nightly PAP usage was significantly predicted by positive hypertension diagnosis (β = 0.271, p = 0.019). Likewise, greater adherence based on the conventional cutoff was predicted by poorer motor functioning at hospital admission (OR = 0.98, p = 0.001) and lower oxygen saturation nadir (OR = 0.99, p = 0.003). For those with traumatic injuries, greater adherence was predicted by poorer functional status at hospital admission (OR = 0.98, p = 0.010) and positive hypertension diagnosis (OR = 0.16, p = 0.023).

CONCLUSIONS: In this study of hospitalized neurorehabilitation patients with ABI and comorbid OSA, predictors of adherence included lower oxygen saturation, poorer functional status and hypertension diagnosis, perhaps signifying the role of greater severity of illness on treatment adherence. High rates of refusal and nonadherence to frontline PAP therapy for sleep apnea is a concern for persons in recovery form ABI who are at a time of critical neural repair.