Faculty Bibliography

Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by strong and uniform expression of CD30. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate has been approved by the U.S. FDA for relapsed/refractory systemic ALCL and achieves improved outcomes. We report a 44-year-old African-American man who presented with lymphadenopathy, lip and chest nodules diagnosed as CD30+, ALK-negative ALCL. The patient was treated with BV upon recurrence. While on treatment, the patient developed new-onset nodules on the chest and back. Skin biopsy showed a diffuse dermal infiltrate of medium-to-large atypical lymphocytes with frequent mitosis and scattered eosinophils. Immunohistochemically, the atypical cells displayed the same immunophenotype as previous specimens (CD3+, CD4-/CD8-, CD56-, ALK- and TCR γ-), except for lack of CD30 expression which was attributed to BV treatment effect. The diagnosis was thought to be consistent with ALK-negative ALCL and the patient was continued on BV along with total skin electron beam radiation and the lesions cleared. The patient relapsed 2 months later with extensive disease and expired. In summary, this is the first report in the literature of loss of CD30 expression in ALCL after BV therapy. Awareness of this may prevent a mistaken diagnosis of a CD30-negative secondary T-cell lymphoma.

INTRODUCTION/BACKGROUND:The aim of this systematic review was to assess the efficacy of Saline load tests (SLTs) to evaluate extension of periarticular wounds into capsule in emergent settings. METHODS:We systematically reviewed the literature to evaluate the accuracy of the SLT in diagnosing penetrating joint injuries in the elbow, wrist, shoulder, knee, or ankle. RESULTS:The SLT values to determine knee arthrotomies vary from 73.8 mL to 194 mL with sensitivities ranging between 91% and 99% depending on the size of the laceration. A SLT of 30 mL in the ankle yields sensitivities ranging from 95% to 99% in assessing joint penetration. A SLT of 45 mL in the elbow yields a sensitivity of 95% in assessing joint penetration. The addition of methylene blue does not change the sensitivity of the SLT. CONCLUSION/CONCLUSIONS:Several studies have demonstrated the utility of the SLT as a diagnostic modality for penetrating joint injuries. However, the literature analyzed in this study was inconclusive and more studies are required to make definitive recommendations. In addition, more studies will be needed on joints other than the knee, pediatric patients, and the use of methylene blue dye in conjunction with SLT. LEVEL OF EVIDENCE/METHODS:Level II, Diagnostic study.

OBJECTIVE: Adults with serious psychological distress have a high likelihood of mental health problems severe enough to cause serious impairment in social and occupational functioning requiring treatment. These adults visit doctors frequently yet have poor health compared to adults without serious psychological distress. This study examined associations between emotional states of serious psychological distress in relationship to healthcare utilization indicators. A guiding hypothesis was that somatization underlying emotional states contributes to excessive healthcare seeking among adults with serious psychological distress. METHODS: Using 2006-2014 National Health Interview Survey, in adults with serious psychological distress (n=9271), the six states: unable to make efforts, nervousness, hopelessness, sadness, worthlessness and restlessness were assessed in multivariate models in relation to four healthcare utilization indicators: change in the usual place of healthcare, change due to insurance, having seen a healthcare provider in the last 6months and having 10 or more doctor visits in the last 12months. Models were adjusted for sociodemographic variables, having seen a mental health provider, and health conditions. RESULTS: Adults feeling unable to make efforts were more likely to seek healthcare in the last 6months and at least ten times in the last twelve months. Adults feeling hopeless were less likely to be heavy healthcare utilizers. CONCLUSIONS: Predisposing medical conditions do not fully explain healthcare utilization in adults with serious psychological distress. Educating healthcare providers about the emotional states motivating healthcare seeking, and integrating mental healthcare into primary care, may improve the health of adults with serious psychological distress.

OBJECTIVE: Measurement error in self-reported total sugars intake may obscure associations between sugars consumption and health outcomes, and the sum of 24 h urinary sucrose and fructose may serve as a predictive biomarker of total sugars intake. DESIGN: The Study of Latinos: Nutrition & Physical Activity Assessment Study (SOLNAS) was an ancillary study to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort. Doubly labelled water and 24 h urinary sucrose and fructose were used as biomarkers of energy and sugars intake, respectively. Participants' diets were assessed by up to three 24 h recalls (88 % had two or more recalls). Procedures were repeated approximately 6 months after the initial visit among a subset of ninety-six participants. SETTING: Four centres (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA) across the USA. SUBJECTS: Men and women (n 477) aged 18-74 years. RESULTS: The geometric mean of total sugars was 167.5 (95 % CI 154.4, 181.7) g/d for the biomarker-predicted and 90.6 (95 % CI 87.6, 93.6) g/d for the self-reported total sugars intake. Self-reported total sugars intake was not correlated with biomarker-predicted sugars intake (r=-0.06, P=0.20, n 450). Among the reliability sample (n 90), the reproducibility coefficient was 0.59 for biomarker-predicted and 0.20 for self-reported total sugars intake. CONCLUSIONS: Possible explanations for the lack of association between biomarker-predicted and self-reported sugars intake include measurement error in self-reported diet, high intra-individual variability in sugars intake, and/or urinary sucrose and fructose may not be a suitable proxy for total sugars intake in this study population.

BACKGROUND:Whole genome sequencing (WGS) has rapidly become an important research tool in tuberculosis epidemiology and is likely to replace many existing methods in public health microbiology in the near future. WGS-based methods may be particularly useful in areas with less diverse Mycobacterium tuberculosis populations, such as New York City, where conventional genotyping is often uninformative and field epidemiology often difficult. This study applies four candidate strategies for WGS-based identification of emerging M. tuberculosis subpopulations, employing both phylogenomic and population genetics methods. RESULTS:M. tuberculosis subpopulations in New York City and New Jersey can be distinguished via phylogenomic reconstruction, evidence of demographic expansion and subpopulation-specific signatures of selection, and by determination of subgroup-defining nucleotide substitutions. These methods identified known historical outbreak clusters and previously unidentified subpopulations within relatively monomorphic M. tuberculosis endemic clone groups. Neutrality statistics based on the site frequency spectrum were less useful for identifying M. tuberculosis subpopulations, likely due to the low levels of informative genetic variation in recently diverged isolate groups. In addition, we observed that isolates from New York City endemic clone groups have acquired multiple non-synonymous SNPs in virulence- and growth-associated pathways, and relatively few mutations in drug resistance-associated genes, suggesting that overall pathoadaptive fitness, rather than the acquisition of drug resistance mutations, has played a central role in the evolutionary history and epidemiology of M. tuberculosis subpopulations in New York City. CONCLUSIONS:Our results demonstrate that some but not all WGS-based methods are useful for detection of emerging M. tuberculosis clone groups, and support the use of phylogenomic reconstruction in routine tuberculosis laboratory surveillance, particularly in areas with relatively less diverse M. tuberculosis populations. Our study also supports the use of wider-reaching phylogenomic and population genomic methods in tuberculosis public health practice, which can support tuberculosis control activities by identifying genetic polymorphisms contributing to epidemiological success in local M. tuberculosis populations and possibly explain why certain isolate groups are apparently more successful in specific host populations.

BACKGROUND:Acute kidney injury (AKI) is common among intensive care unit (ICU) patients. AKI is highly heterogeneous, with variable links to poor outcomes. Current approaches to classify AKI severity and identify patients at highest risk for poor outcomes focus on the maximum change in serum creatinine (SCr) values. However, these scores are hampered by the need for a reliable baseline SCr value and the absence of a component differentiating transient from persistent rises in SCr. We hypothesized that identification of resolving or nonresolving AKI subphenotypes based on the early trajectory of SCr values in the ICU would better differentiate patients at risk of hospital mortality. METHODS:We performed a secondary analysis of two prospective studies of ICU patients admitted to a trauma ICU (group 1; n = 1914) or general medical-surgical ICUs (group 2; n = 1867). In group 1, we tested definitions for resolving and nonresolving AKI subphenotypes and selected the definitions resulting in subphenotypes with the greatest separation in risk of death relative to non-AKI controls. We applied this definition to group 2 and tested whether the subphenotypes were independently associated with hospital mortality after adjustment for AKI severity. RESULTS:AKI occurred in 46% and 69% of patients in groups 1 and 2, respectively. In group 1, a resolving AKI subphenotype (defined as a decrease in SCr of 0.3 mg/dl or 25% from maximum in the first 72 h of study enrollment) was associated with a low risk of death. A nonresolving AKI subphenotype (defined as all AKI cases not meeting the "resolving" definition) was associated with a high risk of death. In group 2, the resolving AKI subphenotype was not associated with increased mortality (relative risk [RR] 0.86, 95% CI 0.63-1.17), whereas the nonresolving AKI subphenotype was associated with higher mortality (RR 1.68, 95% CI 1.15-2.44) even after adjustment for AKI severity stage. CONCLUSIONS:The trajectory of SCr levels identifies AKI subphenotypes with different risks for death, even among AKI cases of similar severity. These AKI subphenotypes might better define the patients at risk for poor outcomes who might benefit from novel interventions.

PURPOSE: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. Based on data showing KIR-ligand mismatched NK-cells reduce the risk of leukemia and multiple myeloma (MM) relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK-cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK-cells, our single-arm phase II clinical trial in patients with smoldering MM was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind lack of clinical efficacy. EXPERIMENTAL DESIGN: Treatment-naive patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and twenty-four hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK-cell phenotype and function was analyzed using high-resolution flow cytometry. RESULTS: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK-cell responsiveness and KIR2D expression on the NK-cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK-cells by trogocytosis, with reductions in NK-cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the anti-myeloma cytotoxicity of remaining KIR2Ddull patient NK-cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK-cells. CONCLUSIONS: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK-cell tumor killing via checkpoint inhibition.