Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma.

Although Janus kinase (JAK) inhibitors have demonstrated efficacy for treating autoimmune disorders and myeloproliferative neoplasms, their efficacy in treating other types of cancer has not been clearly demonstrated. We evaluated oral ruxolitinib (15 mg twice daily) with oral methylprednisolone (40 mg every other day) for multiple myeloma (MM) patients with progressive disease who had received a proteasome inhibitor, lenalidomide, glucocorticosteroids and three or more prior regimens. All of the planned 29 patients had been enrolled with follow-up until 28 April 2022. Median lines of prior therapy were 6 (range 3-12). Cytogenetics and fluorescent in situ hybridization were evaluable in 28 patients; 9 (32%) and 17 (70%) patients showed high-risk cytogenetics and/or 1q+, respectively. The overall response rate was 31%. The median duration of response was 13.1 (range 2.8-22.0) months. Median progression-free survival rate was 3.4 (range 0.5-24.6) months, Overall, the treatment was well tolerated. The combination of ruxolitinib and methylprednisolone demonstrated significant clinical activity among previously heavily-treated MM patients, and responses were achieved among patients who had high-risk cytogenetics. This is the first clinical study to show activity of JAK inhibitors in combination with steroids for MM patients and expands the potential use of these drugs to those with cancers other than myeloproliferative neoplasms.

The JAK1/2 inhibitor ruxolitinib downregulates the immune checkpoint protein B7H3 in multiple myeloma.

We hypothesized that ruxolitinib may inhibit the immune checkpoint protein, B7H3; and, thus, investigated its effects on this immune inhibitor using multiple myeloma (MM) cell lines, bone marrow (BM) mononuclear cells from MM patients and human MM LAGλ -1A xenografts. Ruxolitinib reduced B7H3 gene and protein expression and increased IL-2 and CD8 gene expression. These results suggest that ruxolitinib inhibition of B7H3 may restore exhausted T-cell activity in the MM BM tumor microenvironment.

Factors Affecting Participation in Telerehabilitation Using Transcranial Direct Current Stimulation for Patients with Poststroke Paralysis in South Korea.

Background: The coronavirus disease 2019 pandemic has expanded noncontact health care systems worldwide. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technology that enables treatment monitoring under remote supervision. We investigated the factors affecting patients' decision to participate in telerehabilitation (TR) using tDCS for motor function recovery after suffering a stroke. Materials and Methods: Four medical institutions surveyed 156 patients with poststroke paralysis. The participants were asked whether they would participate in TR therapy using tDCS in the future. We performed logistic regression analysis to examine the factors-demographic data, stroke characteristics, arm function, gait, and cognitive function-that influenced participants' decisions. Results: Of the participants, 66% (103/156) reported that they would participate in TR using tDCS in the future. Participants' monthly salary was a single significant independent factor influencing their decision to participate. Those earning greater than 5 million KRW (4,000 USD) were more likely to engage in TR via tDCS than those earning less than 1 million KRW (800 USD). The most common barriers to participation in telemedicine included the preference for face-to-face treatment and unfamiliarity. The expected medical expenses of TR using tDCS were 46,154 KRW (37 USD) per session. Conclusions: Most participants with poststroke paralysis responded positively to TR using tDCS for hand function recovery. For telemedicine to work effectively in a situation wherein face-to-face rehabilitation is impossible, prior discussion at the governmental level is essential for determining medical finances.

A phase 1 study of ruxolitinib, steroids and lenalidomide for relapsed/refractory multiple myeloma patients.

Ruxolitinib with lenalidomide and dexamethasone shows anti-myeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma (MM) cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. A phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory (RR)MM who had been treated with lenalidomide, steroids and a proteasome inhibitor and showed progressive disease at study entry. A traditional 3 + 3 dose escalation design was used to enroll subjects in four cohorts. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28 day cycle and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Forty-nine patients were enrolled. The median age was 64 years and they had received a median of six prior treatments including lenalidomide and steroids to which 94% were refractory. No dose limiting toxicities occurred. The CBR and ORR were 49% and 36%, respectively. All responding patients were refractory to lenalidomide. Grade 3 or 4 adverse events (AEs) included anemia (17%), decreased lymphocyte count (15%), and hypophosphatemia (10%). Most common serious AEs included sepsis (9.8%) and pneumonia (7.8%). This Phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating MM. NCT03110822.

Effectiveness and Long-Acting of the Hyaluronic Acid Injected into the Nasolabial Fold Measured Through Magnetic Resonance Imaging.

BACKGROUND: MRI analyzed quantitatively the HA injected into the NLF subcutaneous fat to correlate the gel diffusion and degradation with the morphological changes of the NLF appearance for twelve months. Measurements of the gel diffusion and degradation were taken by MRI as parameters to assess the clinical efficacy and long-acting of the HA in NLF rejuvenation. METHOD: HA was applied into the superficial compartment of the subcutaneous fat of twenty NLFs. Each NLF received three injection points, from the nasal ala toward the oral commissure, 1.0-1.5 cm distant from each other, according to the NLF length. A bolus injection technique without retrograde backflow applied per injection point 0.15-0.20 ml of HA for moderate. NLF and 0.20-0.25 ml for severe NLF. Patients were evaluated through MRI and clinically twenty-four hours, one month and twelve months after the HA application. RESULTS: MRI, in T2-weighted, displayed the gel as a dense, spindle-shaped nodule as pattern of the gel diffusion, measuring its largest longitudinal and transverse axes. Twenty-four hours after HA application the longitudinal axis measured 1.79 cm, after one month 2.33 cm and at month twelve 0.91 cm. The transverse axis measured 0.92 cm at 24 hours, 1.13 cm after one month and 0.47 cm at month twelve. CONCLUSION: Despite reduction in size and denseness of the spindle-shaped nodule, the small amount of gel presenting into the subcutaneous fat after twelve months of the application evidenced the HA efficacy and long-acting in NLF rejuvenation. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors - www.springer.com/00266 .

Quality Versus Quantity: The Potential Impact of Public Reporting of Hospital Safety for Complex Cancer Surgery.

OBJECTIVE: To estimate the potential mortality reduction if patients chose the safest hospitals for complex cancer surgery. BACKGROUND: Mortality after complex oncologic surgery is highly variable across hospitals, and directing patients away from unsafe hospitals could potentially improve survivorship. Hospital quality measures are becoming increasingly accessible at a time when patients are more engaged in choosing providers. It is currently unclear what information to share with patients to maximally capitalize on patient-centered realignment. METHODS: The National Cancer Database was queried for adults undergoing 5 complex cancer surgeries (pulmonary lobectomy, pneumonectomy, esophagectomy, gastrectomy, and colectomy) for a primary cancer between 2008 and 2012. Risk-standardized mortality rate (RSMR) methodology, currently used by Medicare-based hospital rating systems, was used to classify hospitals as "safest" and "least safe" by procedure. Patients were modeled moving from "least safe" to "safest" hospitals and the potential number of lives saved through patient realignment determined. As surgical volume has historically been used to distinguish safe hospitals, comparisons were made to models moving patients from low-volume to high-volume hospitals. RESULTS: A total of 292,040 patients were analyzed. In an optimally modeled scenario, realignment using RSMR would result in a greater number of lives saved (3592 vs 2161, P < 0.01) and require only 15 patients to change hospitals to save a life, compared to 78 patients using volume models (P < 0.01). CONCLUSIONS: Public reporting of hospital safety, specifically based on RSMR instead of volume, has the potential to lead to meaningful reductions in surgical mortality after complex cancer surgery, even in the setting of a modest patient realignment.

Measuring Exposure to Incarceration Using the Electronic Health Record.

BACKGROUND: Electronic health records (EHRs) are a rich source of health information; however social determinants of health, including incarceration, and how they impact health and health care disparities can be hard to extract. OBJECTIVE: The main objective of this study was to compare sensitivity and specificity of patient self-report with various methods of identifying incarceration exposure using the EHR. RESEARCH DESIGN: Validation study using multiple data sources and types. SUBJECTS: Participants of the Veterans Aging Cohort Study (VACS), a national observational cohort based on data from the Veterans Health Administration (VHA) EHR that includes all human immunodeficiency virus-infected patients in care (47,805) and uninfected patients (99,060) matched on region, age, race/ethnicity, and sex. MEASURES AND DATA SOURCES: Self-reported incarceration history compared with: (1) linked VHA EHR data to administrative data from a state Department of Correction (DOC), (2) linked VHA EHR data to administrative data on incarceration from Centers for Medicare and Medicaid Services (CMS), (3) VHA EHR-specific identifier codes indicative of receipt of VHA incarceration reentry services, and (4) natural language processing (NLP) in unstructured text in VHA EHR. RESULTS: Linking the EHR to DOC data: sensitivity 2.5%, specificity 100%; linking the EHR to CMS data: sensitivity 7.9%, specificity 99.3%; VHA EHR-specific identifier for receipt of reentry services: sensitivity 7.3%, specificity 98.9%; and NLP, sensitivity 63.5%, specificity 95.9%. CONCLUSIONS: NLP tools hold promise as a feasible and valid method to identify individuals with exposure to incarceration in EHR. Future work should expand this approach using a larger body of documents and refinement of the methods, which may further improve operating characteristics of this method.

Government political structure and violent death rates: A longitudinal analysis of forty-three countries, 1960-2008.

OBJECTIVES: Currently, little is known regarding the effect of regime type on mortality on a global level. The purpose of this study is to examine the effect of regime type on the rates of violent deaths (homicide, suicide, and combined rates). METHODS: Three measures of democracy were used to quantify regime type, the independent variable. Homicide and suicide rates were obtained from the World Health Organization. Multivariate conditional fixed-effects models were run to examine associations between regime characteristics and logged rates of homicide, suicide, and violent deaths. Models were adjusted for unemployment and economic inequality. RESULTS: Nations that scored higher on democracy indices, especially emerging democracies, experienced increased mortality due to violence. Homicide and suicide were divergent, showing a different time course and decreasing statistical power as a combined variable. Unemployment and inequality were associated with higher violence-related mortality. CONCLUSIONS: Homicide and suicide appear to be more prevalent in democracies. Future analyses should examine which aspects of democracies lead to higher rates of violent death and should seek to use independently collected mortality data.

A Manual Bristleless Toothbrush Demonstrates Slight Improvement in Gingival Recession Compared to a Conventional Soft Manual Brush.

PURPOSE: This randomized clinical trial tested whether a novel bristleless toothbrush design is more effective in preventing gingival recession in adults receiving periodontal maintenance than is a soft toothbrush with nylon bristles. MATERIALS AND METHODS: Twenty-three subjects with gingival recession were recruited who received regular periodontal maintenance care at Western University of Health Sciences Dental Center, and who did not exhibit signs of acute dental or systemic disease, occlusal discrepancies or parafunctional habits. These subjects were randomly assigned to to two groups, one using a soft nylon-bristled toothbrush, and the other using the experimental toothbrush that contains a brush head with short, soft, rubbery cones. Both groups received regular periodontal maintenance and periodontal exams by blinded examiners every 3-4 months, measuring probing depth, bleeding on probing, and plaque indices. Gingival recession was assessed clinically and through use of a stent on diagnostic casts obtained at each visit. RESULTS: Average probing depths, plaque levels, and the number of sites with bleeding on probing did not change over at least 9 months. After 9 months, there was a small but statistically significant improvement in gingival recession (0.4 mm, p < 0.01) at sites with gingival recession in the experimental toothbrush group compared to the control group. CONCLUSION: In periodontal maintenance patients, the bristleless toothbrush used in this study was as effective in plaque removal and prevention of gingival inflammation than a conventional toothbrush with soft nylon bristles, while increasing the possibility of gingival tissue rebound over denuded root surfaces.

Extension of Disease Risk Score-Based Confounding Adjustments for Multiple Outcomes of Interest: An Empirical Evaluation.

Use of disease risk score (DRS)-based confounding adjustment when estimating treatment effects on multiple outcomes is not well studied. We designed an empirical cohort study to compare dabigatran initiators and warfarin initiators with respect to risks of ischemic stroke and major bleeding in 12 sequential monitoring periods (90 days each), using data from the Truven Marketscan database (Truven Health Analytics, Ann Arbor, Michigan). We implemented 2 approaches to combine DRS for multiple outcomes: 1) 1:1 matching on prognostic propensity scores (PPS), created using DRS for bleeding and stroke as independent variables in a propensity score (PS) model; and 2) simultaneous 1:1 matching on DRS for bleeding and stroke using Mahalanobis distance (M-distance), and compared their performance with that of traditional PS matching. M-distance matching appeared to produce more stable results in the early marketing period than both PPS and traditional PS matching; hazard ratios from unadjusted analysis, traditional PS matching, PPS matching, and M-distance matching after 4 periods were 0.72 (95% confidence interval (CI): 0.51, 1.03), 0.61 (95% CI: 0.31, 1.09), 0.55 (95% CI: 0.33, 0.91), and 0.78 (95% CI: 0.45, 1.34), respectively, for stroke and 0.65 (95% CI: 0.53, 0.80), 0.78 (95% CI: 0.60, 1.01), 0.75 (95% CI: 0.59, 0.96), and 0.78 (95% CI: 0.64, 0.95), respectively, for bleeding. In later periods, estimates were similar for traditional PS matching and M-distance matching but suggested potential residual confounding with PPS matching. These results suggest that M-distance matching may be a valid approach for extension of DRS-based confounding adjustments for multiple outcomes of interest.

Retinoic acid and CTCF play key roles in inducing the collinear expression of the Hoxa cluster.

During the development of an embryo, the initiation of the collinear expression of Hox genes is essential for the proper formation of the anteroposterior body axis. Retinoic acid (RA), a natural derivative of vitamin A, plays a role in vertebrate development by regulating Hox gene expression. CCCTC-binding factor (CTCF), an insulator protein that controls gene transcription, also regulates the expression of Hox genes by binding to the CTCF-binding sites (CBSs). It has been reported that upon RA signaling, retinoic acid response elements (RAREs) located in the Hox clusters become occupied. Interestingly, RAREs exist in close proximity with CBSs, and therefore when RA is bound, CTCF cannot bind. Without CTCF and its insulator activities, the repressive domain in the chromatin becomes open for gene transcription. Here, we examine the relationship between RA and CTCF during the RA-induced expression of the Hoxa cluster genes, using F9 murine embryonic teratocarcinoma cells as a model system. We treated F9 cells with RA for different time, confirmed the collinear expression of Hoxa genes, and validated CTCF-binding in F9 cells as well as in CTCF-overexpressing F9 cells, in the presence of RA. The present study suggests that RA and CTCF pose antagonistic effects on each other during vertebrate development to attain Hox gene collinearity.

Prenatal exposure to dexamethasone in the mouse induces sex-specific differences in placental gene expression.

Prenatal stress during pregnancy leads to sex-specific effects on fetal development and disease susceptibility over the life span; however, the origin of sex differences has not been identified. The placenta not only plays a key role in fetal growth and development throughout pregnancy, but also affects the fetal programming underlying subsequent adult health and accounts. Therefore, sex-specific adaptation of the placenta may be central to the sex differences in fetal growth and survival. Here, we analyzed the effects of prenatal dexamethasone (Dex) on sex-specific changes in placental gene expression using RNA-Seq. Placental tissues from males and females were separated into two developmentally distinct fetal and maternal parts at E11.5 stage. The majority of genes in female placentas were downregulated by prenatal Dex, whereas those were mostly maintained or rather upregulated in male placentas. RNA-Seq results were validated using independent biological replicates from the same stage and placental tissue samples from E18.5 by realtime PCR assays. Activation of various inflammatory response-related genes, chemokines and their receptors, particularly in male placentas, strongly implies that prenatal Dex exposure causes sex-specific physiological responses that can lead to inflammatory diseases involving vascular pathology.

Dementia is a risk factor for major adverse cardiac and cerebrovascular events in elderly Korean patients initiating hemodialysis: a Korean national population-based study.

BACKGROUND: Dementia is common in end-stage renal disease (ESRD) patients on hemodialysis (HD) and is associated with worse outcomes. This study aimed to investigate the risk of major adverse cardiac and cerebrovascular event (MACCE) in elderly patients with dementia initiating HD. METHODS: Using the database from the Health Insurance Review & Assessment Service, we analyzed 10,171 patients aged 65 years or older who had initiated dialysis from 2005 to 2008. MACCE was defined as a composite outcome of all-cause mortality, nonfatal acute myocardial infarction, target vessel revascularization, and nonfatal ischemic and hemorrhagic stroke. The Kaplan-Meier method and Cox proportional hazards model were used, and further comparisons using propensity-score matching at 1:2 ratio were also performed. RESULTS: A total of 303 elderly patients (3.0%) had dementia at initiating HD. During follow-up, dementia was a significant predictor of MACCE after adjustment for confounding variables. In addition, further analyzed in the propensity-score matched groups, dementia was an independent predictor of both nonfatal ischemic stroke and all-cause mortality. CONCLUSIONS: Dementia is an independent risk factor for mortality and ischemic stroke in elderly ESRD patients initiating HD. Patients with dementia who start dialysis should be closely monitored to reduce the risk of mortality and ischemic stroke.

Crown Lengthening Needs and Outcomes in Adults Attending a Predoctoral Clinic.

In this retrospective study of 5,536 patients admitted over four years at a predoctoral dental clinic for comprehensive care, general dentists identified crown lengthening needs in 584 patients and 760 teeth. Only 51 patients and 68 teeth actually received crown lengthening procedures. For the other cases, patients discontinued treatment or chose extraction or restoration without crown lengthening procedures. Teeth that received crown lengthening procedures were most likely restored and functioning for at least one year.

Urinary Periostin Excretion Predicts Renal Outcome in IgA Nephropathy.

BACKGROUND: Periostin is a matricellular protein and plays a vital role in tissue regeneration, fibrosis and wound healing. However, data about its significance in nephrology are limited. We investigated the correlation between urinary periostin excretion and its clinical significance including renal histologic findings and prognosis in IgA nephropathy (IgAN). METHODS: Of 399 patients from a glomerulonephritis cohort recruited between January 2009 and December 2014, 314 were enrolled. Serum and urine periostin (uPOSTN) were measured using enzyme-linked immunosorbent assay. We divided the patients into 3 groups by uPOSTN/creatinine (uPOSTN/Cr): group 1 (undetectable), group 2 (lower than the median) and group 3 (higher than the median). RESULTS: The uPOSTN level was correlated with pathologic classifications and both initial and final IDMS-MDRD estimated glomerular filtration rates (eGFRs; p < 0.001). Histologically, group 3 patients were correlated with severe interstitial fibrosis/tubular atrophy (p = 0.004), interstitial inflammation (p = 0.007), hyaline arteriolosclerosis (p = 0.001) and glomerular sclerosis (p < 0.001). A higher initial uPOSTN/Cr level was associated with a greater decline in eGFR during follow-up (p = 0.043 when initial eGFR ≥60; p = 0.025 when eGFR <60 ml/min/1.73 m2), and the renal outcomes with end-stage renal disease (ESRD; p = 0.003), ESRD and/or eGFR decrease of >30% (p = 0.033) and ESRD and/or eGFR decrease of >50% (p = 0.046) occurred significantly more in group 3. In multivariate analysis, uPOSTN group 3 (hazards ratio 2.839, 95% CI 1.013-7.957; p = 0.047) was independently associated with ESRD in IgAN patients. CONCLUSION: uPOSTN/Cr value at initial diagnosis correlated with renal fibrosis and predicted the renal outcomes in patients with IgAN. It could be a promising urinary biomarker for renal fibrosis.

The role of quantitative safety evaluation in regulatory decision making of drugs.

Evaluation of safety is a critical component of drug review at the US Food and Drug Administration (FDA). Statisticians are playing an increasingly visible role in quantitative safety evaluation and regulatory decision-making. This article reviews the history and the recent events relating to quantitative drug safety evaluation at the FDA. The article then focuses on five active areas of quantitative drug safety evaluation and the role Division of Biometrics VII (DBVII) plays in these areas, namely meta-analysis for safety evaluation, large safety outcome trials, post-marketing requirements (PMRs), the Sentinel Initiative, and the evaluation of risk from extended/long-acting opioids. This article will focus chiefly on developments related to quantitative drug safety evaluation and not on the many additional developments in drug safety in general.

Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008.

Therapy-related acute myeloid leukemia (tAML) is a rare but highly fatal complication of cytotoxic chemotherapy. Despite major changes in cancer treatment, data describing tAML risks over time are sparse. Among 426068 adults initially treated with chemotherapy for first primary malignancy (9 US population-based cancer registries, 1975-2008), we identified 801 tAML cases, 4.70 times more than expected in the general population (P < .001). Over time, tAML risks increased after chemotherapy for non-Hodgkin lymphoma (n = 158; Poisson regression Ptrend < .001), declined for ovarian cancer (n = 72; Ptrend < .001), myeloma (n = 62; Ptrend = .02), and possibly lung cancer (n = 65; Ptrend = .18), and were significantly heterogeneous for breast cancer (n = 223; Phomogeneity = .005) and Hodgkin lymphoma (n = 58; Phomogeneity = .007). tAML risks varied significantly by age at first cancer and latency and were nonsignificantly heightened with radiotherapy for lung, breast, and ovarian cancers. We identified newly emerging elevated tAML risks in patients treated with chemotherapy since 2000 for esophageal, cervical, prostate, and possibly anal cancers; and since the 1990s for bone/joint and endometrial cancers. Using long-term, population-based data, we observed significant variation in tAML risk with time, consistent with changing treatment practices and differential leukemogenicity of specific therapies. tAML risks should be weighed against the benefits of chemotherapy, particularly for new agents and new indications for standard agents.