Clinical characteristics of infantile hemangiomas with aggressive, persistent, and destructive ulceration.

BACKGROUND/OBJECTIVES: Ulceration is a common complication of infantile hemangioma (IH). Severe, persistent ulceration occurs in a minority of patients. This study aims to characterize the clinical features of IH with aggressive ulceration (AU). METHODS: Multicenter retrospective study of clinical features of IH with AU. RESULTS: Thirty-five patients with AU were identified and included in the study. The majority of AU occurred in segmental IH (23/35, 65%). Segmental IH with AU were large (≥10 cm2 ; 16/23, 69%, p < .001) with a thin (<3 mm) superficial component (16/23, 69%, p < .001). Localized IH with AU had a thick (>3 mm) superficial component (11/12, 92%, p < .001). All diaper area IH with AU (9/35) were segmental with thin superficial component (100%, p = .02). IH with AU in the head/neck (10/35) were more commonly localized (67%) and mixed (62.5%), while segmental, thick superficial morphology was more common on trunk (9/35) and upper extremities (7/35). CONCLUSIONS: IH resulting in AU differ in clinical features by anatomic site. Those in the diaper area are nearly always segmental with thin superficial component, whereas other sites tend to be localized, mixed, with thick superficial component. These distinct phenotypes may prove useful in the clinical setting for physicians to identify patterns of IH ulceration with increased risk of aggressive, persistent ulceration.

Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma.

18F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging with background signal suppression (DWIBS) are 2 powerful functional imaging modalities in the evaluation of malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET ("PET false-negative"). The aim of this study was to describe the proportion of PET false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET false-negativity to be 11%. Neither tumor load-associated parameters, such as degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P < .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers.

Bacteremias following autologous stem cell transplantation for multiple myeloma: Risk factors and outcomes.

BACKGROUND: Autologous stem cell transplantation (ASCT) is a commonly used treatment for multiple myeloma (MM). This retrospective cohort study characterizes the risk factors and outcomes associated with bacteremia following ASCT at a single center. METHODS: We conducted a retrospective analysis in subjects who underwent ASCT for multiple myeloma and other malignancies from May 2014 to March 2015 at a single center. The control cohort included all subjects undergoing ASCT in the same time period who did not develop bacteremia. RESULTS: During the study period, 363 ASCTs were completed in 282 discrete patients. Bacteremia was documented in 13% of all transplants. Enterococcus faecium was the most frequent species overall (14/62, 23%). Vancomycin resistance was present in 93% of E faecium isolates. Bacteremia was associated with a significantly decreased survival in patients who received their transplant after the first year of myeloma treatment. Overall survival (OS) was not significantly different in the two cohorts among patients undergoing ASCT within the first year of myeloma treatment. Survival analysis showed a significantly decreased OS in patients who developed Enterococcus bacteremia as compared to the non-bacteremia cohort. Enterococcal bacteremia was associated with significantly longer duration of neutropenia (mean 14 vs 9.7 days, P = 0.01), hospitalization (mean 61.7 vs 20.4 days, P = 0.0006), and higher mortality (69% vs 25%, P = 0.01) as compared to other bacteremias. CONCLUSION: We found a high incidence of E faecium and a low incidence of MRSA and Pseudomonas bacteremias following ASCT in our patient population. Survival analysis in our cohort suggests that the effect of underlying disease status and cumulative chemotherapy is critically important in determining outcomes related to bacteremia. Enterococcal bacteremias following ASCT were associated with significantly higher morbidity and mortality than non-enterococcal bacteremias.

Distinct kratom user populations across the United States: A regional analysis based on an online survey.

OBJECTIVE: Kratom preparations have raised concerns of public health and safety in the United States. This paper analyzed the patterns and predictors of kratom use by four U.S. regions according to the U.S. Census. METHOD: An anonymous cross-sectional online survey yielded 8,049 valid responses. The data were categorised by regions (Northeast, South, Midwest, and West) and analyzed for the following predictors: age, gender, marital status, ethnicity, employment status, insurance coverage, education, and household income. RESULTS: After adjusting for state population, the survey response rates were highest from Oregon, Idaho, and Florida. Kratom use was significantly lower for both prescription drug dependency and acute or chronic pain in the Northeast region than the rest of the country. Multiple logistic regression models found that gender, employment, and education were significant on the regional level. Higher education was associated with lower kratom use for an illicit drug dependency (p = .002) independent of region whereas men were less likely to use kratom for acute or chronic pain in the Northeast (p < .001) but more likely in the Midwest (p = .041). CONCLUSIONS: The regional pattern of kratom use differed from opioid use data in both demographics and trend direction warranting further investigation.

Prevalence of a Cefazolin Inoculum Effect Associated with blaZ Gene Types among Methicillin-Susceptible Staphylococcus aureus Isolates from Four Major Medical Centers in Chicago.

The efficacy of cefazolin with high-inoculum methicillin-susceptible Staphylococcus aureus (MSSA) infections remains in question due to therapeutic failure inferred as being due to an inoculum effect (InE). This study investigated the local prevalence of a cefazolin InE (CInE) and its association with staphylococcal blaZ gene types among MSSA isolates in the Chicago area. Four medical centers in Chicago, IL, contributed MSSA isolates. Cefazolin MICs (C-MIC) were determined at 24 h by the broth microdilution method using a standard inoculum (SI; 5 × 105 CFU/ml) and a high inoculum (HI; 5 × 107 CFU/ml). The CInE was defined as (i) a ≥4-fold increase in C-MIC between SI and HI and/or (ii) a pronounced CInE, i.e., a nonsusceptible C-MIC of ≥16 µg/ml at HI. PCR was used to amplify the blaZ gene, followed by agarose gel electrophoresis and sequencing to determine the gene type. Approximately 269 MSSA isolates were included. All but one isolate were susceptible to cefazolin at SI, and 97% remained susceptible at HI. A total of 196 isolates (73%) were blaZ positive, with the blaZ types led by gene type C (40%). CInE was seen in 45 blaZ-positive isolates (23%), with 44 (22%) presenting a ≥4-fold increase in C-MIC (SI to HI) and 5 (3%) a pronounced CInE. Four of the five met both definitions of CInE, two of which expressed the type A gene. The prevalence of a pronounced CInE associated with the type A blaZ gene from MSSA isolates in Chicago is low. Our predilection for cefazolin use, even early in the management of hospitalized MSSA infections, is tenable.

MAF protein mediates innate resistance to proteasome inhibition therapy in multiple myeloma.

Multiple myeloma (MM) patients with the t(14;16) translocation have a poor prognosis, and unlike other molecular subgroups, their outcome has not improved with the introduction of bortezomib (Bzb). The mechanism underlying innate resistance of MM to Bzb is unknown. In the present study, we have investigated how MAF overexpression impacts resistance to proteasome inhibitor (PI) therapy (Bzb and carfilzomib). High levels of MAF protein were found in t(14;16) cell lines; cell lines from the t(4;14) subgroup had intermediate levels, whereas cell lines from the other subgroups had low levels. High expression of MAF protein in t(14;16) was associated with significantly higher PI half-maximum inhibitory concentration values compared with other molecular subgroups. PI exposure abrogated glycogen synthase kinase 3ß (GSK3ß)-mediated degradation of MAF protein, resulting in increased MAF protein stability and PI resistance. Subsequent studies using loss-of-function and gain-of-function models showed that silencing MAF led to increased sensitivity to PIs, enhanced apoptosis, and activation of caspase-3, -7, -8, -9, poly (ADP-ribose) polymerase, and lamin A/C. In contrast, overexpression of MAF resulted in increased resistance to PIs and reduced apoptosis. These results define the role of MAF and GSK3 in the resistance of t(14;16) MM to PIs and identifies a novel mechanism by which MAF protein levels are regulated by PIs, which in turn confers resistance to PIs.

Efficacy of Intravenous Acetaminophen for Postoperative Analgesia in Primary Total Knee Arthroplasty.

BACKGROUND: The use of intravenous acetaminophen has seen recent enthusiasm as one component of a multimodal approach to pain management. However, there is a lack of literature examining the efficacy of intravenous acetaminophen for pain control in total joint arthroplasty. The purpose of this study was to evaluate the efficacy of intravenous acetaminophen following primary total knee arthroplasty. METHODS: This is a retrospective review of 38 patients undergoing primary total knee arthroplasty by a single surgeon at one institution. Twenty-five patients received 1 gram of intravenous acetaminophen every 6 hours for 24 hours postoperatively. Thirteen patients received no additional intervention. Exclusion criteria were bilateral or concomitant procedures, allergy to medications included in the standard postoperative protocol, neuropathy or sensory disturbances, history of opioid dependence or abuse, deviations from protocol, revision procedures, and incomplete data. Primary outcomes were change in patient-reported visual analog scale (VAS) pain score, overall opioid consumption measured in morphine milligram equivalents, and hospital length of stay. RESULTS: We found no difference in length of stay, at 3.3 days in the control group and 2.9 days in the intervention group. There was a significant difference in VAS score between 16 and 24 hours. There was a statistically significant decrease in overall opioid consumption in the intravenous acetaminophen group 37.6 vs 18.6 morphine milligram equivalents. CONCLUSION: Intravenous acetaminophen is effective in significantly reducing opioid requirements in the first 24 hours following primary total knee arthroplasty. Additionally, there is a clinically significant decrease in VAS pain scores in patients receiving this intervention.

Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease.

Light chain deposition disease (LCDD) is characterized by monotypic immunoglobulin depositions which will eventually lead to loss of organ function if left untreated. While the kidney is almost always affected, the presence and degree of LCDD in other organs vary. Ten to thirty percent of LCDD patients have underlying Multiple Myeloma (MM), yet outcome and prognostic markers in this particular patient group are still lacking. Here, we analyzed 69 patients with MM and biopsy proven LCDD and report on renal and extra-renal involvement and its impact on prognosis as well as renal response depending on hematologic response. Coexisting light chain diseases such as AL amyloid and cast nephropathy were found in 30% of patients; those with LCDD and concurrent amyloid tended to have shorter survival. Cardiac involvement by LCDD was seen in one-third of our patients and was associated with shorter overall survival; such patients also had a significantly higher risk of treatment-related mortality (TRM) after stem cell transplant (SCT) compared to LCDD patients without cardiac involvement. This study highlights that MM patients with LCDD present with different clinical features compared to previously reported LCDD cohorts. Rapid initiation of treatment is necessary to prevent progressive renal disease and worse outcome. Coexisting light chain diseases and cardiac involvement are more common than previously reported and confer worse clinical outcome, emphasizing the need for careful patient careful patient evaluation and treatment selection.

Variations in Inpatient Rehabilitation Functional Outcomes Across Centers in the Traumatic Brain Injury Model Systems Study and the Influence of Demographics and Injury Severity on Patient Outcomes.

OBJECTIVE: To compare patient functional outcomes across Traumatic Brain Injury Model Systems (TBIMS) rehabilitation centers using an enhanced statistical model and to determine factors that influence those outcomes. DESIGN: Multicenter observational cohort study. SETTING: TBIMS centers. PARTICIPANTS: Patients with traumatic brain injury (TBI) admitted to 19 TBIMS rehabilitation centers from 2003-2012 (N=5505). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional outcomes of patients with TBI. RESULTS: Individuals with lower functional status at the time of admission, longer duration of posttraumatic amnesia, and higher burden of medical comorbidities continued to have worse functional outcomes at discharge from inpatient rehabilitation and at the 1-year follow-up, whereas those who were employed at the time of injury had better outcomes at both time periods. Risk-adjusted patient functional outcomes for patients in most TBIMS centers were consistent with previous research. However, there were wide performance differences for a few centers even after using more recently collected data, improving on the regression models by adding predictors known to influence functional outcomes, and using bootstrapping to eliminate confounds. CONCLUSIONS: Specific patient, injury, and clinical factors are associated with differences in functional outcomes within and across TBIMS rehabilitation centers. However, these factors did not explain all the variance in patient outcomes, suggesting a role of some other predictors that remain unknown.

Removing batch effects from purified plasma cell gene expression microarrays with modified ComBat.

BACKGROUND: Gene expression profiling (GEP) via microarray analysis is a widely used tool for assessing risk and other patient diagnostics in clinical settings. However, non-biological factors such as systematic changes in sample preparation, differences in scanners, and other potential batch effects are often unavoidable in long-term studies and meta-analysis. In order to reduce the impact of batch effects on microarray data, Johnson, Rabinovic, and Li developed ComBat for use when combining batches of gene expression microarray data. We propose a modification to ComBat that centers data to the location and scale of a pre-determined, 'gold-standard' batch. This modified ComBat (M-Combat) is designed specifically in the context of meta-analysis and batch effect adjustment for use with predictive models that are validated and fixed on historical data from a 'gold-standard' batch. RESULTS: We combined data from MIRT across two batches ('Old' and 'New' Kit sample preparation) as well as external data sets from the HOVON-65/GMMG-HD4 and MRC-IX trials into a combined set, first without transformation and then with both ComBat and M-ComBat transformations. Fixed and validated gene risk signatures developed at MIRT on the Old Kit standard (GEP5, GEP70, and GEP80 risk scores) were compared across these combined data sets. Both ComBat and M-ComBat eliminated all of the differences among probes caused by systematic batch effects (over 98% of all untransformed probes were significantly different by ANOVA with 0.01 q-value threshold reduced to zero significant probes with ComBat and M-ComBat). The agreement in mean and distribution of risk scores, as well as the proportion of high-risk subjects identified, coincided with the 'gold-standard' batch more with M-ComBat than with ComBat. The performance of risk scores improved overall using either ComBat or M-Combat; however, using M-ComBat and the original, optimal risk cutoffs allowed for greater ability in our study to identify smaller cohorts of high-risk subjects. CONCLUSION: M-ComBat is a practical modification to an accepted method that offers greater power to control the location and scale of batch-effect adjusted data. M-ComBat allows for historical models to function as intended on future samples despite known, often unavoidable systematic changes to gene expression data.

Self-reported Health Diagnoses and Demographic Correlates With Kratom Use: Results From an Online Survey.

OBJECTIVES: To determine whether diagnosed pre-existing health conditions correlate with Kratom demographics and use patterns. METHODS: A cross-sectional, anonymous US national online survey was conducted among 8049 Kratom users in October, 2016 to obtain demographic, health, and Kratom use pattern information. RESULTS: People who use Kratom to mitigate illicit drug dependence self-reported less pain and better overall health than individuals who used Kratom for acute/chronic pain. Self-reported improvements in pre-existing mental health symptoms (attention deficit and hyperactivity disorder/attention deficit disorder, anxiety, bipolar disorder, post-traumatic stress disorder, and depression) attributed to Kratom use were greater than those related to somatic symptoms (back pain, rheumatoid arthritis, acute pain, chronic pain, fibromyalgia). Demographic variables, including female sex, older age, employment status, and insurance coverage correlated with increased likelihood of Kratom use. CONCLUSIONS: Kratom use may serve as a self-treatment strategy for a diverse population of patients with pre-existing health diagnoses. Healthcare providers need to be engaging with patients to address safety concerns and potential limitations of its use in clinical practice for specific health conditions.

FRAX is a robust predictor of baseline vertebral fractures in multiple myeloma patients.

FRAX is a commonly used tool to evaluate patient fracture risk based on individual patient models that integrate the risks associated with clinical risk factors with or without bone mineral density (BMD) at the femoral neck. Retrospectively, factors identified by the FRAX scoring algorithm were used to predict the risk for vertebral compression fractures at baseline in newly diagnosed multiple myeloma patients. The data were derived from myeloma patients enrolled in Total Therapy Protocols (TT4 & TT5) between 8/2008 and 9/2017. FRAX scores were calculated and baseline PET and MRI imaging obtained. Univariate and multivariate logistic regression analyses determined the association between FRAX components and the existence of vertebral compression fractures, both pathologic and osteoporotic. The patient population had a median age of 61 years (43-76), 37% female, and 87% white. The median major osteoporotic score (MOS) and Hip fracture scores (HFS) for TT4 patients (low-risk myeloma) were 5.6 and 0.5, respectively, while median MOS and HFS for TT5 (high risk myeloma) patients were 6.2 and 0.7, respectively. The odds ratio for fracture at diagnosis in patients with elevated MOS (>2), and HFS (>4.5) was significant OR (1.48, 95% confidence interval (1.35,1.62)) and OR (1.61, 95% confidence interval (1.42, 1.81)), respectively. In sum, an elevated baseline FRAX score was highly predictive of baseline vertebral fractures in MM patients at presentation. In addition, patients with higher FRAX scores had significantly shorter survival in the low-risk (TT4) group but this survival effect was not seen in the high-risk (TT5) group. These findings suggest that FRAX assessment of baseline fracture risk is beneficial in MM patients to identify an individual patients' risk of vertebral fracture.

Comparison of Postbaccalaureate and Baccalaureate Graduates' Performance in First and Second Years of Dental School.

Postbaccalaureate programs help predental students strengthen their basic science knowledge and improve their study skills before applying or reapplying for dental school admission. A high percentage of postbac students are admitted to and graduate from dental schools, but gaining greater understanding of how well these students perform in key areas of the first two years' curriculum would be useful for the design of those programs. The aim of this study was to evaluate postbac dental students' performance in the D1 and D2 years at one U.S. dental school compared to dental students with a four-year baccalaureate degree only. Performance assessed was the students' dental school grades in basic science courses, in all D1 and D2 didactic courses, and on preclinical simulation lab practical exams. Didactic and practical scores were gathered anonymously for the Classes of 2013-18 at the College of Dental Medicine-Arizona (CDMA) at Midwestern University, where postbac students with master's degrees from the affiliated College of Health Sciences made up 6-19% of each class. The two cohorts chosen for comparison were students with baccalaureate degrees only and students with one-year Master of Arts degrees from the College of Health Sciences. The scores of these postbac dental students and their non-postbac peers were found to be comparable in the basic science courses. However, for all the didactic courses combined, the non-postbac cohort had significantly higher mean scores than the postbac cohort for the fall quarter 2 and winter quarter 2 in 2013-15 and all years combined. The practical scores for the two cohorts were not significantly different for any year. Overall, this study demonstrated that the MA program in the College of Health Sciences prepared the postbac students to compete on an equal level with the non-postbac students in the CDMA D1 and D2 curriculum.

Extensive Remineralization of Large Pelvic Lytic Lesions Following Total Therapy Treatment in Patients With Multiple Myeloma.

Osteolytic bone lesions are a hallmark of multiple myeloma (MM) bone disease. Bone destruction is associated with severely imbalanced bone remodeling, secondary to increased osteoclastogenesis and significant osteoblast suppression. Lytic lesions of the pelvis are relatively common in MM patients and are known to contribute to the increased morbidity because of the high risk of fracture, which frequently demands extensive surgical intervention. After observing unexpected radiological improvement in serial large pelvic CT assessment in a patient treated in a total therapy protocol, the radiographic changes of pelvic osteolytic lesions by PET/CT scanning in patients who received Total Therapy 4 (TT4) treatment for myeloma were retrospectively analyzed. Sixty-two (62) patients with lytic pelvic lesions >1 cm in diameter were identified at baseline PET/CT scanning. Follow-up CT studies showed that 27 of 62 patients (43%) with large baseline pelvic lesions achieved significant reaccumulation of radiodense mineralization at the lytic cortical site. The average size of lytic lesions in which remineralization occurred was 4 cm (range, 1.3 to 10 cm). This study clearly demonstrates that mineral deposition in large pelvic lesions occurs in a significant proportion of MM patients treated with TT4, potentially affecting patient outcomes, quality of life, and future treatment strategies. © 2017 American Society for Bone and Mineral Research.

The varied distribution and impact of RAS codon and other key DNA alterations across the translocation cyclin D subgroups in multiple myeloma.

We examined a set of 805 cases that underwent DNA sequencing using the FoundationOne Heme (F1H) targeted sequencing panel and gene expression profiling. Known and likely variant calls from the mutational data were analyzed for significant associations with gene expression defined translocation cyclin D (TC) molecular subgroups. The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF. In addition, the presence of RAS-RAF mutations was inversely associated with NFκB pathway activation in all subgroups excluding MAF. In the MMSET subgroup, cases with low FGFR3 expression frequently had RAS-RAF mutations. Conditional inference tree analysis determined that mutation and homozygous deletion of TP53, CDKN2C, and RB1 were key prognostic factors associated with adverse outcome in a non-relapse clinical setting. In conclusion, this study highlights the heterogeneity in the distribution and clinical outcomes of RAS codon and other mutations in multiple myeloma dependent upon primary molecular subgroup.

Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma.

Purpose: Fluorine-18 fluorodeoxyglucose positron emission tomography with CT attenuation correction (18F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semiquantitative characterization of metabolic activity (glycolytic phenotype) by calculation of glucose uptake. Total lesion glycolysis (TLG) and metabolic tumor volume (MTV) have the potential to improve the value of this approach and enhance the prognostic value of disease burden measures. This study aims to determine whether TLG and MTV are associated with progression-free survival (PFS) and overall survival (OS), and whether they improve risk assessments such as International Staging System (ISS) stage and GEP70 risk.Experimental Design: 192 patients underwent whole body PET/CT in the Total Therapy 3A (TT3A) trial and were evaluated using three-dimensional region-of-interest analysis with TLG, MTV, and standard measurement parameters derived for all focal lesions with peak SUV above the background red marrow signal.Results: In multivariate analysis, baseline TLG > 620 g and MTV > 210 cm3 remained a significant factor of poor PFS and OS after adjusting for baseline myeloma variables. Combined with the GEP70 risk score, TLG > 205 g identifies a high-risk-behaving subgroup with poor expected survival. In addition, TLG > 205 g accurately divides ISS stage II patients into two subgroups with similar outcomes to ISS stage I and ISS stage III, respectively.Conclusions: TLG and MTV have significant survival implications at baseline and offer a more precise quantitation of the glycolytic phenotype of active disease. These measures can be assessed more readily than before using FDA-approved software and should be standardized and incorporated into clinical trials moving forward. Clin Cancer Res; 23(8); 1981-7. ©2016 AACR.

The impact of preexisting illness and substance use on functional and neuropsychological outcomes following traumatic brain injury.

Traumatic brain injury (TBI) is a significant public health problem in the US. Specific preexisting medical illnesses delay recovery after TBI and increase mortality or risk of repeat TBI. This study examined the impact of preexisting illness and substance use on patient rehabilitation outcomes following TBI. The Functional Independence Measure total score and Disability Rating Scale score measured functional outcomes at discharge from inpatient rehabilitation, while the Trail Making Test A and B and Total Trials 1-5 of the California Verbal Learning Test-II measured neuropsychological outcomes in 128 TBI survivors with moderate or severe TBI. Results showed that the presence of a heart condition or diabetes/high blood sugar was associated with lower functional outcomes by discharge. A history of a heart condition, stroke, or respiratory condition prior to TBI was associated with reduced cognitive flexibility. Those with preexisting diabetes/high blood sugar demonstrated poorer visual attention, visuomotor processing speed, and ability to learn and recall verbal information. Those with pre-TBI cancer also had greater auditory-verbal memory deficits. The findings showed that specific preexisting medical conditions are independently associated with lower functional and cognitive outcomes for patients with TBI. By screening patients for preexisting medical conditions, multidisciplinary TBI rehabilitation teams can identify patients who require more aggressive treatments or greater length of stay.