New Collaborative Research on Suicide Prevention, Practice, and Policy With American Indian and Alaska Native Communities Holds Promise for All Peoples.

Youth suicide is increasing in the United States, with deaths among younger people of color driving this upward trend. For more than four decades, American Indian and Alaska Native (AIAN) communities have suffered disproportionate rates of youth suicide and years of productive life lost compared to other U.S. Races. The National Institute of Mental Health (NIMH) recently funded three regional Collaborative Hubs to carry out suicide prevention research, practice, and policy development with AIAN communities in Alaska and rural and urban areas of the Southwestern United States. The Hub partnerships are supporting a diverse array of tribally-driven studies, approaches, and policies with immediate value for increasing empirically driven public health strategies to address youth suicide. We discuss unique features of the cross-Hub work, including: (a) long-standing Community-Based Participatory Research processes that led to the Hubs' innovative designs and novel approaches to suicide prevention and evaluation, (b) comprehensive ecological theoretical approaches that contextualize individual risk and protective factors in multilevel social contexts; (c) unique task-shifting and systems of care approaches to increase reach and impact on youth suicide in low-resource settings; and (d) prioritization of strengths-based approaches. The work of the Collaborative Hubs for AIAN youth suicide prevention is generating specific and substantive implications for practice, policy, and research presented in this article at a time when youth suicide prevention is a dire national priority. Approaches also have relevance for historically marginalized communities worldwide.

Sustaining suicide prevention programs in American Indian and Alaska Native communities and Tribal health centers.

Background: Research on sustaining community-based interventions is limited. This is particularly true for suicide prevention programs and in American Indian and Alaska Native (AIAN) settings. Aiming to inform research in this area, this paper sought to identify factors and strategies that are key to sustain suicide prevention efforts in AIAN communities. Methods: We used a modified Nominal Group Technique with a purposeful sample of N = 35 suicide prevention research experts, program implementors and AIAN community leaders to develop a list of prioritized factors and sustainability strategies. We then compared this list with the Public Health Program Capacity for Sustainability Framework (PHPCSF) to examine the extent the factors identified aligned with the existing literature. Results: Major factors identified included cultural fit of intervention approaches, buy in from local communities, importance of leadership and policy making, and demonstrated program success. Strategies to promote these factors included partnership building, continuous growth of leadership, policy development, and ongoing strategic planning and advocacy. All domains of the PHPCF were representative, but additional factors and strategies were identified that emerged as important in AIAN settings. Conclusions: Sustaining effective and culturally informed suicide prevention efforts is of paramount importance to prevent suicide and save lives. Future research will focus on generating empirical evidence of these strategies and their effectiveness at promoting program sustainability in AIAN communities.

Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors.

BACKGROUND: While patient-derived xenografts (PDXs) offer a powerful modality for translational cancer research, a precise evaluation of how accurately patient responses correlate with matching PDXs in a large, heterogeneous population is needed for assessing the utility of this platform for preclinical drug-testing and personalized patient cancer treatment. PATIENTS AND METHODS: Tumors obtained from surgical or biopsy procedures from 237 cancer patients with a variety of solid tumors were implanted into immunodeficient mice and whole-exome sequencing was carried out. For 92 patients, responses to anticancer therapies were compared with that of their corresponding PDX models. RESULTS: We compared whole-exome sequencing of 237 PDX models with equivalent information in The Cancer Genome Atlas database, demonstrating that tumorgrafts faithfully conserve genetic patterns of the primary tumors. We next screened PDXs established for 92 patients with various solid cancers against the same 129 treatments that were administered clinically and correlated patient outcomes with the responses in corresponding models. Our analysis demonstrates that PDXs accurately replicate patients' clinical outcomes, even as patients undergo several additional cycles of therapy over time, indicating the capacity of these models to correctly guide an oncologist to treatments that are most likely to be of clinical benefit. CONCLUSIONS: Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

A case report of concurrent embryonal rhabdomyosarcoma and diffuse large B-cell lymphoma in an adult without identifiable cancer predisposition.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. Rhabdomyosarcoma, the most common soft tissue sarcoma of childhood. makes up less than 1% of solid malignancies in adults with around 400 new cases each year in the United States. They have not previously been reported concurrently. CASE PRESENTATION: A 37 year old woman presented with painful enlarging leg mass. Biopsy of the mass was consistent with embryonal rhabdomyosarcoma. Staging imaging revealed a PET avid anterior mediastinal lymph node. Excisional biopsy of this mass was consistent with diffuse large B-cell lymphoma. Hybridization capture-based next-generation DNA sequencing did not reveal shared somatic tumor mutations. Germline analysis did not show identifiable aberrations of TP53 or other heritable cancer susceptibility genes. She was treated with a personalized chemotherapy regimen combining features of R-CHOP and Children's Oncology Group ARST 0331. CONCLUSIONS: This case illustrates a unique clinical entity successfully treated with a personalized chemotherapeutic regimen.

Seasonality of suicide behavior in Northwest Alaska: 1990-2009.

OBJECTIVES: Suicide is a leading cause of death worldwide, and disproportionately affects Indigenous populations. Seasonal suicide patterns are variable in the literature, and could offer novel approaches to the timing and focus of prevention efforts if better understood. With a suicide surveillance system in place since 1989, this study offers an unprecedented opportunity to explore seasonal variations in both fatal and non-fatal suicide behavior in an Indigenous Arctic region. STUDY DESIGN: Cross-sectional. METHODS: In this descriptive study, we analyzed data collected from 1990 to 2009 in the rural northwest region of Alaska, both graphically and using the chi-squared test for multinomials. RESULTS: We found a significant monthly variation for suicide attempts, with a peak in suicide behavior observed between April and August (P = 0.0002). Monthly variation was more pronounced among individuals ≤29 years of age, and was present in both males and females, although the seasonal pattern differed by sex. CONCLUSIONS: Our findings of a significant seasonal pattern in suicide behavior, with monthly variation (summer peak) in non-fatal suicide behavior among younger age groups, and among both males and females can assist planners in targeting subpopulations for prevention at different times of the year.

Insulin-like growth factor type 1 (IGF-1) and IGF binding protein-3 in patients with Ewing sarcoma family of tumors.

BACKGROUND: Ewing sarcoma family of tumors (ESFTs) are the second most common bone tumor, that most often affects persons ages 3-40 years. The ESFTs rely on signaling through the insulin-like growth factor-1 receptor (IGF-1R) for growth and transformation. The current studies were performed to determine the levels of IGF-1 and IGF binding protein-3 (IGFBP-3) in patients with ESFT. The authors then performed an exploratory analysis to evaluate whether IGF parameters could differentiate event free or overall survival in ESFT patients. METHODS: The authors measured serum levels of IGF-1 and IGFBP-3 by using a radioimmunoassay from 111 patients with ESFT with a median follow-up of 13 years from diagnosis. RESULTS: The IGF-1 levels were lower among patients with metastatic disease to the bones or the bone marrow compared with patients without metastasis to these sites (p2 = 0.021 and 0.0038, respectively). IGFBP-3 is known to sequester IGF-1; the ratios of IGFBP-3 to IGF-1 were evaluated. Patients with metastatic disease to any site had higher IGFBP-3 to IGF-1 ratios than patients with localized disease (p2 = 0.0067). There was a trend toward increased survival in patients with localized disease who had high IGFBP-3 to IGF-1 levels. Metastatic patients showed a similar trend. CONCLUSIONS: Levels of IGF-1 and IGFBP-3 in ESFT patients can identify patients with the most widespread disease. The IGFBP-3 to IGF-1 ratio in patients with either localized or metastatic disease identified patients with a trend toward increased survival. Further prospective evaluation with higher patient numbers might show a prognostic role for the IGFBP-3 to IGF-1 ratio in patients with ESFT.

Lack of correlation of functional scintigraphy with (99m)technetium-methoxyisobutylisonitrile with histological necrosis following induction chemotherapy or measures of P-glycoprotein expression in high-grade osteosarcoma.

In osteosarcoma, some studies have suggested P-glycoprotein expression is a prognostic factor. The clearance of (99m)technetium hexakis-2-methoxyisobutylisonitrile ((99m)Tc-MIBI) has been used in some tumor systems as an in vivo measure of P-glycoprotein-mediated efflux. In this study we explored the correlation between (99m)Tc-MIBI clearance and histological necrosis following induction chemotherapy and P-glycoprotein expression in osteosarcoma. The primary tumors of 20 patients with high-grade osteosarcoma were imaged at diagnosis with (99m)Tc-MIBI, and the uptake ratios and biological half-lives were calculated. P-Glycoprotein expression in the tumor tissue was determined immunohistochemically and by measuring mRNA expression of the multidrug resistance-1 gene. The histological necrosis following induction chemotherapy was assessed by the Huvos grading system. The biological half-life of (99m)Tc-MIBI ranged from 1.4 to 52.5 h. Seven of the 20 tumor samples had a favorable extent of necrosis following induction chemotherapy. The (99m)Tc-MIBI half-life and uptake ratio showed no correlation with histological necrosis following induction chemotherapy. The (99m)Tc-MIBI half-life and uptake ratio did not correlate with either measure of P-glycoprotein expression. The results of this pilot study indicate that (99m)Tc-MIBI imaging is not an effective predictor of histological necrosis following induction chemotherapy in high-grade osteosarcoma. (99m)Tc-MIBI imaging did not correlate with measures of P-glycoprotein expression in the tumor tissue.

Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT).

BACKGROUND: A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies. METHODS AND RESULTS: Our objective was to determine whether treatment aimed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol. The study was a placebo-controlled, randomized trial conducted in 20 Veterans Affairs medical centers. A total of 2531 men with coronary heart disease, with mean HDL cholesterol 0.82 mmol/L (31.5 mg/dL) and mean LDL cholesterol 2.9 mmol/L (111 mg/dL), were randomized to gemfibrozil 1200 mg/d or placebo and were followed up for 5 years. Strokes were confirmed by a blinded adjudication committee. Relative risks were derived from Cox proportional hazards models. There were 134 confirmed strokes, 90% of which were ischemic. Seventy-six occurred in the placebo group (9 fatal) and 58 in the gemfibrozil group (3 fatal), for a relative risk reduction, adjusted for baseline variables, of 31% (95% CI, 2% to 52%, P=0.036). The reduction in risk was evident after 6 to 12 months. Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol. CONCLUSIONS: In men with coronary heart disease, low HDL cholesterol, and low LDL cholesterol, gemfibrozil reduces stroke incidence.

Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.

CONTEXT: A low plasma level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD). A secondary prevention study, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), demonstrated that CHD events were significantly reduced during a median follow-up of 5.1 years by treating patients with the fibric acid derivative gemfibrozil when the predominant lipid abnormality was low HDL-C. OBJECTIVE: To determine if the reduction in major CHD events with gemfibrozil in VA-HIT could be attributed to changes in major plasma lipid levels. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial conducted from September 1991 to August 1998. SETTING: The Department of Veterans Affairs Cooperative Studies Program, in which 20 VA medical centers were participating sites. PARTICIPANTS: A total of 2531 men with a history of CHD who had low HDL-C levels (mean, 32 mg/dL [0.83 mmol/L] ) and low low-density lipoprotein cholesterol (LDL-C) levels (mean, 111 mg/dL [2.88 mmol/L]). INTERVENTION: Participants were randomly assigned to receive gemfibrozil, 1200 mg/d (n = 1264), or matching placebo (n = 1267). MAIN OUTCOME MEASURE: Relation of lipid levels at baseline and averaged during the first 18 months of gemfibrozil treatment with the combined incidence of nonfatal myocardial infarction and CHD death. RESULTS: Concentrations of HDL-C were inversely related to CHD events. Multivariable Cox proportional hazards analysis showed that CHD events were reduced by 11% with gemfibrozil for every 5-mg/dL (0.13-mmol/L) increase in HDL-C (P =.02). Events were reduced even further with gemfibrozil beyond that explained by increases in HDL-C values, particularly in the second through fourth quintiles of HDL-C values during treatment. During gemfibrozil treatment, only the increase in HDL-C significantly predicted a lower risk of CHD events; by multivariable analysis, neither triglyceride nor LDL-C levels at baseline or during the trial predicted CHD events. CONCLUSIONS: Concentrations of HDL-C achieved with gemfibrozil treatment predicted a significant reduction in CHD events in patients with low HDL-C levels. However, the change in HDL-C levels only partially explained the beneficial effect of gemfibrozil.

Digital storage phosphor chest radiography: an ROC study of the effect of 2K versus 4K matrix size on observer performance.

PURPOSE: To compare observer performance in the detection of abnormalities on 1,760 x 2,140 matrix (2K) and 3,520 x 4,280 matrix (4K) digital storage phosphor chest radiographs. MATERIALS AND METHODS: One hundred sixty patients who underwent dedicated computed tomography (CT) of the thorax were prospectively recruited into the study. Posteroanterior and lateral computed radiographs of the chest were acquired in each patient and printed in 2K and 4K formats. Six radiologists independently analyzed the hard-copy images and scored the presence of parenchymal (opacities 2 cm, and subtle interstitial), mediastinal, and pleural abnormalities on a five-point confidence scale. With CT as the reference standard, observer performance tests were carried out by using receiver operating characteristic (ROC) analysis. RESULTS: Analysis of averaged observer performance showed 2K and 4K images were equally effective in detection of all three groups of abnormalities. In the detection of the three subtypes of parenchymal abnormalities, there were no significant differences in averaged performance between the 2K and 4K formats (area below ROC curve [A(z)] values: opacities 2 cm, 0.86 +/-.025 and 0.85 +/- 0.030; subtle interstitial abnormalities, 0.73 +/- 0.041 and 0.72 +/- 0.041). Averaged performance in detection of mediastinal and pleural abnormalities was equivalent (A(z) values: mediastinal, 0.70 +/- 0.046 and 0.73 +/- 0.033; pleural, 0.85 +/- 0.032 and 0.86 +/- 0.033). CONCLUSION: Observer performance in detection of parenchymal, mediastinal, and pleural abnormalities was not significantly different on 2K and 4K storage phosphor chest radiographs.

Non-Q-wave myocardial infarction following thrombolytic therapy: a comparison of outcomes in patients randomized to invasive or conservative post-infarct assessment strategies in the Veterans Affairs non-Q-wave Infarction Strategies In-Hospital (VANQWISH) Trial.

OBJECTIVES: We wished to determine the effect of post-infarct management strategy on event rates (death or recurrent nonfatal myocardial infarction [MI]) in patients who evolved non-Q-wave MI (NQMI) following thrombolytic therapy. BACKGROUND: Patients who evolve NQMI following thrombolytic therapy are often considered to be at high risk and are frequently managed with routine early invasive testing despite a lack of data supporting improved outcome. METHODS: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study included 115 patients who evolved NQMI following thrombolytic therapy. We compared the event rates in patients randomized to routine early coronary angiography with those in patients randomized to a conservative strategy of noninvasive functional assessment, with angiography reserved for patients with spontaneous or induced ischemia. RESULTS: During an average follow-up of 23 months, 19 of 58 patients (33%) randomized to the invasive management strategy died or suffered recurrent nonfatal MI, compared with 11 of 57 patients (19%) randomized to the conservative strategy (p = 0.152). Equivalent numbers of patients were subjected to revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass graft). There were more deaths in the invasive management group than in the conservative management group (11 vs. 2). Excess deaths could not be attributed to periprocedural mortality. CONCLUSIONS: Overall event rates (death or recurrent nonfatal MI) are comparable with conservative and invasive strategies in patients who evolve NQMI following thrombolytic therapy. Mortality rate in patients managed conservatively is low (3.5%), and routine invasive management may be associated with an increased risk of death.