Faculty Bibliography

Plerixafor (P), an agent that selectively and reversibly binds to the chemokine receptor CXCR4, has been approved in combination with G-CSF (P + G-CSF) for stem cell (SC) mobilization in patients with multiple myeloma (MM). The goal of this study was to determine the SC collection success rate of P + G-CSF using a clinically relevant outcome defined as the ability to collect at least 5 × 10⁶CD34⁺cells/kg to allow safely two transplants, and identify risk factors impacting SC mobilization. One hundred and thirty-eight patients were mobilized with P + G-CSF upfront following induction. The SC collection success rate was 92.8%. We identified exposure to lenalidomide alone (p = .038), WBC count <4 × 10³/mcL prior to mobilization (p = .01) and non-African American race (p = .019), as risk factors for low efficiency by multivariate analysis. This study demonstrates that P + G-CSF is highly efficient in MM patients and provides strong support for its upfront use in SC collection for MM patients.

BACKGROUND AND AIMS/OBJECTIVE:Preliminary single-institution data suggest that fluorescence in situ hybridization (FISH) may be useful for detecting high-grade dysplasia (HGD) and esophageal adenocarcinoma (EA) in patients with Barrett's esophagus (BE). This multicenter study aims to validate the measurement of polysomy (gain of at least two loci) by FISH as a way to discriminate degrees of dysplasia in BE specimens. METHODS:Tissue specimens were collected from four different hospitals and read by both the local pathology department ("Site diagnosis") and a single central pathologist ("Review diagnosis") at a separate institution. The specimens then underwent FISH analysis using probes 8q24 (MYC), 9p21 (CDKN2A), 17q12 (ERBB2), and 20q13 (ZNF217) for comparison. A total of 46 non-BE, 42 non-dysplastic specialized intestinal metaplasia (SIM), 23 indefinite-grade dysplasia (IGD), 10 low-grade dysplasia (LGD), 29 HGD, and 42 EA specimens were analyzed. RESULTS:We found that polysomy, as detected by FISH, was the predominant chromosomal abnormality present as dysplasia increased. Polysomy was also the best predictor for the presence of dysplasia or EA when comparing its area under the curve to that of other FISH abnormalities. We observed that if at least 10% of cells had polysomy within a specimen, the FISH probe was able to differentiate between EA/HGD and the remaining pathologies with a sensitivity of 80% and a specificity of 88%. CONCLUSIONS:This study demonstrates that using FISH to determine the percentage of cells with polysomy can accurately and objectively aid in the diagnosis of HGD/EA in BE specimens.

Limbic encephalitis presents as altered mood, memory loss and confusion. Clinical features may include psychiatric symptoms and seizures. In contrast to paraneoplastic disorders, non-paraneoplastic autoimmune encephalitis often responds to immunotherapy and sometimes with marked recovery. However, relapse can occur. An 82-year-old male presented with subacute episodes of memory loss over a few days. The patient was unable to recognize his own home and family members. Physical exam was unremarkable. Neuropsychological assessment revealed deficits in cognitive performance that could be consistent with moderate dementia or a more rapidly progressive encephalopathy. Agitated behavior and anxiety were also noted. Laboratory evaluation included hyponatremia, which was corrected with no symptom improvement. B12, TSH, and HIV were normal. CSF analysis revealed 10 WBCs/muL, Glucose-52 mg/dl, Protein-62 mg/dl and was negative for infectious, neoplastic causes, varicella, VDRL, viral cultures, NMDA receptor antibody, GAD 65 antibody and Anti-Hu antibody. Occult malignancy work up with CT scan of chest and abdomen and colonoscopy was normal. Serum for voltage-gated potassium channel antibodies was positive at 849 pmol/l (>88). EEG showed occasional focal left fronto-temporal slowing without epileptiform activity. MRI revealed focal enhancement of the medial left temporal lobe consistent with limbic encephalitis. The patient started high dose steroids with improvement in memory and complete resolution of focal abnormality within the left hippocampal/parahippocampal region suggestive of resolving encephalitis. At seven months after tapering steroids the patient presented with myoclonus and recurrent memory loss. MRI demonstrated recurrent encephalitis with gyral swelling and FLAIR hyperintensity in the left temporal lobe. The patient was restarted on high dose steroids with addition of Rituximab. This case illustrates that limbic encephalitis can present as a rapidly progressive dementia. Differential diagnosis should include more unusual forms of rapidly progressive dementia such as Jakob-Creutzfeldt disease if myoclonus is present, Lewy body dementia if waxing and waning memory, and Alzheimer's dementia with acute delirium if presenting over a period of months. In this patient, MRI changes were crucial to recognizing a potentially reversible limbic encephalitis. Early recognition and treatment may decrease relapse and reduce functional impairment

Previous studies reported a higher prevalence of venous-thromboembolic events among patients with Cushing disease (CD) compared to those with ACTH-independent Cushing syndrome (CS) from adrenal sources. The objective of the current study was to evaluate the coagulation profile of patients with CS from different etiologies. A prospective observational study was conducted at a clinical research center. The study included adult patients admitted for evaluation of suspected CS (n=85), that were divided into 3 groups: CD (n=22), ACTH-independent CS from an adrenal tumor/hyperplasia (adrenal CS, n=21), and a control group consisting of subjects with negative screening for CS (rule-out CS, n=42). Coagulation profiles were drawn before and 8.5±4.3 months after surgery (trans-sphenoidal or adrenalectomy, n=18), and included fibrinogen, Factor VIII (FVIII), von Willebrand factor antigen (vWF:Ag), plasminogen activator inhibitor-1 (PAI-1), antithrombin III (ATIII), Protein C (PC), Protein S (PS), α2-antiplasmin (α2AP), and aPTT measurements. Patients with CD had higher baseline mean cortisol levels, ATIII activity and vWF:Ag levels compared with adrenal CS. Differences in ATIII activity and vWF:Ag levels remained even after controlling for BMI, and ATIII after also controlling for 24-h urinary free cortisol collections. Our study showed for the first time the differences in coagulation profiles between various etiologies of CS. We assume that the higher cortisol burden among CD patients may explain the differences found in the coagulation profile as well as the higher risk for VTE compared with primary adrenal CS patients.

Thiazolyl peptides are a class of natural products with potent Gram-positive antibacterial activities. Lack of aqueous solubility precluded this class of compounds from advancing to clinical evaluations. Nocathiacins and thiazomycins are sub-classes of thiazolyl peptides that are endowed with structural features amenable for chemical modifications. Semi-synthetic modifications of nocathiacin led to a series of analogs with improved water solubility, while retaining potency and antibacterial spectrum. We studied the activities of a selection of two natural products (nocathiacin and thiazomycin) as well as seven polar semi-synthetic analogs against twenty clinical strains of Mycobacterium tuberculosis with MDR phenotypes. Two compounds show useful activity against H37Rv strain with MIC values ⩽1 μM, two (⩽0.5 μm) and three (⩽10 μm). These two derivatives showed MIC values ⩽2.5 μm against most of the 20 MDR strains regardless their resistance profile. Specifically, these lack cross-resistance to rifampicin, isoniazid and moxifloxacin.

Ceftazidime-avibactam resistance is mediated by bla_KPC-3 mutations, which restore carbapenem susceptibility. We subjected Klebsiella pneumoniae isolates with different bla_KPC-3 mutations (n = 5) or wild-type bla_KPC-3 (n = 2) to serial passages with meropenem. The meropenem MIC against each isolate increased. Mutations in the ompK36 porin gene evolved in 5 isolates. Among isolates with D179Y substitutions in KPC-3, bla_KPC-3 mutations reverted to wild type, were replaced by new mutations, or were retained. Carbapenem treatment of ceftazidime-avibactam-resistant K. pneumoniae infections may select for carbapenem resistance.

PURPOSE/OBJECTIVE:The objective of the study was to compare the psychiatric and behavioral side effect (PBSE) profiles of both older and newer antiepileptic drugs (AEDs) in children and adolescent patients with epilepsy. METHOD/METHODS:We used logistic regression analysis to test the correlation between 83 non-AED/patient related potential predictor variables and the rate of PBSE. We then compared for each AED the rate of PBSEs and the rate of PBSEs that led to intolerability (IPBSE) while controlling for non-AED predictors of PBSEs. RESULTS:922 patients (≤18 years old) were included in our study. PBSEs and IPBSEs occurred in 13.8% and 11.2% of patients, respectively. Overall, a history of psychiatric condition, absence seizures, intractable epilepsy, and frontal lobe epilepsy were significantly associated with increased PBSE rates. Levetiracetam (LEV) had the greatest PBSE rate (16.2%). This was significantly higher compared to other AEDs. LEV was also significantly associated with a high rate of IPBSEs (13.4%) and dose-decrease rates due to IPBSE (6.7%). Zonisamide (ZNS) was associated with significantly higher cessation rate due to IPBSE (9.1%) compared to other AEDs. CONCLUSION/CONCLUSIONS:Patients with a history of psychiatric condition, absence seizures, intractable epilepsy, or frontal lobe epilepsy are more likely to develop PBSE. PBSEs appear to occur more frequently in adolescent and children patients taking LEV compared to other AEDs. LEV-attributed PBSEs are more likely to be associated with intolerability and subsequent decrease in dose. The rate of ZNS-attributed IPBSEs is more likely to be associated with complete cessation of AED.

The prevalence of type 2 diabetes is rising worldwide, especially in older adults. Diet and lifestyle, particularly plant-based diets, are effective tools for type 2 diabetes prevention and management. Plant-based diets are eating patterns that emphasize legumes, whole grains, vegetables, fruits, nuts, and seeds and discourage most or all animal products. Cohort studies strongly support the role of plant-based diets, and food and nutrient components of plant-based diets, in reducing the risk of type 2 diabetes. Evidence from observational and interventional studies demonstrates the benefits of plant-based diets in treating type 2 diabetes and reducing key diabetes-related macrovascular and microvascular complications. Optimal macronutrient ratios for preventing and treating type 2 diabetes are controversial; the focus should instead be on eating patterns and actual foods. However, the evidence does suggest that the type and source of carbohydrate (unrefined versus refined), fats (monounsaturated and polyunsaturated versus saturated and trans), and protein (plant versus animal) play a major role in the prevention and management of type 2 diabetes. Multiple potential mechanisms underlie the benefits of a plant-based diet in ameliorating insulin resistance, including promotion of a healthy body weight, increases in fiber and phytonutrients, food-microbiome interactions, and decreases in saturated fat, advanced glycation endproducts, nitrosamines, and heme iron.

The prevalence of sexually transmitted infections (STIs) and early pregnancy are high among adolescents in Madagascar. We applied a qualitative descriptive approach to evaluate perceptions, attitudes, and misconceptions regarding STIs and contraception among female and male adolescents ages 15-19 years (n = 43) in Northern Madagascar in 2014 using focus group discussions with open-ended questions. Data were coded and analyzed for major themes. Participants were in the 6th to 12th grade in school; 53% were female. Despite high levels of awareness, significant stigma against and misconceptions about STIs, condom use, and sexual practices existed. Many participants did not know how to use condoms and felt uncomfortable suggesting condoms with regular partners, despite acknowledging infidelity as a frequent problem. Male participants were more willing to use condoms as contraception for unwanted pregnancy than for prevention of STIs. Most participants held misconceptions about side effects of contraceptives, including infertility, cancer, and preventing bad blood from leaving the woman's body. Systematic and community-wide health education and formal reproductive health curricula in schools may improve attitudes and stigma regarding STIs and family planning. These strategies need to be developed and employed via collaboration among faith-based, community and non-governmental organizations, schools, and governmental health and social service agencies.