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Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), and 266 multiple myeloma (MM) patients. Ratio-PA of 0.77 ± 0.12, 1.94 ± 0.52, and 11.2 ± 0.7 (p &lt, 0.0001) were observed in MGUS, SMM, and MM patients. Ten-year overall survival (10y-OS) rates for patients with low/high Ratio-PA were 93.5%/77.3% p &lt, 0.0001) for MGUS, 82.5%/64.7% (p &lt, 0.05) for SMM, and 62.3%/47.0% (p &lt, 0.05) for MM. For patients with low, intermediate, and high risk, 10y-OS for low/high Ratio-PA were 95.5%/72.9% (p &lt, 0.0001), 74.2%/50.4% (p &lt, 0.0001), and 35.3%/20.0% (p = 0.836), respectively. Ratio-PA was an independent prognostic factor for OS (HR = 2.119, p &lt, 0.0001, Harrell-C-statistic = 0.7440 ± 0.0194) when co-analyzed with sex, age, and standard risk. In patients with Ratio-PAhigh, only first-line therapy with VRd/VTd, but not PAD/VCD, coupled with ASCT was associated with high 10y-OS (82.7%). Tumor cell Ratio-PA estimated at diagnosis offers a prognostic biomarker that complements standard risk stratification and helps to guide the clinical management of pre-malignant and symptomatic PCNs. Every effort should be made to provide first-line therapies including VTd or VRd associated with ASCT to patients with Ratio-PAhigh at higher risk of progression and death.

Hepatic involvement with space-occupying lesions seen in patients with multiple myeloma (MM) is a rare phenomenon. We present two cases of extramedullary multiple myeloma (EMM), with different presentations to highlight the diversity of clinical presentation. Clinically relevant hepatic involvement of myeloma is uncommon and can pose management problems. Hepatic involvement of EMM is indicative of a poor prognosis. Early recognition can help stage and prognosticate the disease.

In large-scale antenna array (LSAA) wireless communication systems employing analog beamforming architectures, the placement or selection of a subset of antennas can significantly reduce the power consumption and hardware complexity. In this work, we propose a joint design of analog beamforming with antenna selection (AS) or antenna placement (AP) for an analog beamforming system. We approach this problem from a beampattern matching perspective and formulate a sparse unit-modulus least-squares (SULS) problem, which is a nonconvex problem due to the unit-modulus and the sparsity constraints. To that end, we propose an efficient and scalable algorithm based on the majorization-minimization (MM) framework for solving the SULS problem. We show that the sequence of iterates generated by the algorithm converges to a stationary point of the problem. Numerical results demonstrate that the proposed joint design of analog beamforming with AS outperforms conventional array architectures with fixed inter-antenna element spacing.

The aim of the present study was to investigate the association of long non-coding RNA T cell factor 7 (lncRNA TCF7) with disease risk, prognosis and its cellular function in multiple myeloma (MM). A total of 132 de novo symptomatic patients with MM and 50 controls were enrolled. Plasma cells from patients with MM and controls were separated from bone marrow samples to detect lncRNA TCF7 expression using reverse transcription-quantitative PCR. In addition, treatment responses, event-free survival (EFS) and overall survival (OS) were measured. The effects of lncRNA TCF7 on proliferation, apoptosis and microRNA-200c (miR-200c) expression were assessed by gain- and loss-of-function experiments in RPMI-8226 and U-266 cells. The results demonstrated that lncRNA TCF7 expression was upregulated in patients with MM compared with controls, and the receiver operating characteristic curve revealed that lncRNA TCF7 could distinguish patients with MM from controls with an area under the curve of 0.793 (95% CI, 0.725–0.861). In patients with MM, high lncRNA TCF7 expression was associated with higher β2-microglobulin, more advanced International Staging System stage and increased t (14; 16) mutations. Furthermore, it was demonstrated that lncRNA TCF7 was downregulated in patients with complete response (CR) compared with patients without CR. Furthermore, high lncRNA TCF7 expression predicted worse EFS and OS. lncRNA TCF7 also promoted cell proliferation, whereas it reduced cell apoptosis and miR-200c expression in RPMI-8226 and U-266 cells. In conclusion, the present results suggested that lncRNA TCF7 may be used as a potential biomarker and as a treatment target for MM.

Highlights • Plasma ALP could be used as a discriminating marker in presence of bone lesions in solid tumor or MM. • Multiple Myeloma, ALP values were mainly in the range of normality than those observed in patients with solid cancers and bone lesions. • Lower or normal values, should suggest further investigations such as urinary and serum electrophoresis., Introduction Bone involvement in Multiple Myeloma results from increased osteoclast formation and activity that occurs in proximity to myeloma cells. The role of Alkaline Phosphatse (ALP) in this process and the diagnostic significance of plasma levels in patients with MM are unclear. Aim To compare plasma ALP levels in patients with MM and solid cancers and metastatic lesions to the bone. Results In this observational retrospective study we enrolled 901 patients were enrolled: 440 patients (49%) with Multiple Myeloma, 461 (51%) with solid cancers. All 901 patients had bone lesions. Among patients with Multiple Myeloma, ALP values were mainly in the range of normality than those observed in patients with solid cancers and bone lesions. This difference is independent of stage, number and type of bone lesions. Conclusion This study suggests that plasma ALP has a different clinical significance in MM than in other neoplasms and could be used as a discriminating marker in presence of bone lesions. In particular, lower or normal values, should suggest further investigations such as urinary and serum electrophoresis, associated with bone marrow aspirate in case of the presence of a monoclonal component, in order to confirm or exclude a MM diagnosis.

International audience; Serum markers and bone marrow examination are commonly used for monitoring therapy response in multiple myeloma (MM), but this fails to identify minimal residual disease (MRD), which frequently persists after therapy even in complete response patients, and extra-medullary disease escape. Positron emission tomography with computed tomography using 18F-deoxyglucose (FDG-PET/CT) is the reference imaging technique for therapeutic assessment and MRD detection in MM. To date, all large prospective cohort studies of transplant-eligible newly diagnosed MM patients have shown a strong and independent pejorative prognostic impact of not obtaining complete metabolic response by FDG-PET/CT after therapy, especially before maintenance. The FDG-PET/CT and MRD (evaluated by flow cytometry or next-generation sequencing at 10−5 and 10−6 levels, respectively) results are complementary for MRD detection outside and inside the bone marrow. For patients with at least a complete response, to reach double negativity (FDG-PET/CT and MRD) is a predictive surrogate for patient outcome. Homogenization of FDG-PET/CT interpretation after therapy, especially clarification of complete metabolic response definition, is currently underway. FDG-PET/CT does not allow MRD to be evaluated when it is negative at initial workup of symptomatic MM. New PET tracers such as CXCR4 ligands have shown high diagnostic value and could replace FDG in this setting. New sensitive functional magnetic resonance imaging (MRI) techniques such as diffusion-weighted MRI appear to be complementary to FDG-PET/CT for imaging MRD detection. The goal of this review is to examine the feasibility of functional imaging, especially FDG-PET/CT, for therapeutic assessment and MRD detection in MM.

In recent years, following the rapid innovation guidelines of most space agencies, there have been major advances in satellite transmitter technologies. Released in 2012, the CCSDS 131.2-B-1 is one of the most recent downlink standards, with lacking in-depth research, but strongly endorsed by the European Space Agency (ESA). It seems then important to evaluate the performance of different frequency error detectors (FED) on its specific frame structure. This paper firstly deals with the analysis of the most common FEDs, while in the second part it proposes a lightweight architecture to estimate and compensate the carrier error using different algorithms on the same FPGA implementation. Specifically, the Delay & Multiply, Kay, Fitz, Luise & Reggiannini, Mengali & Morelli, and O'Shea et al. estimators are evaluated for both the estimation range and the accuracy. Following the general trade-offs, the design and implementation of the multi-algorithm estimator are detailed for a single feedback loop receiver. The system implements the Mengali & Morelli algorithm in the initial acquisition phase to exploit its wide estimation range, while it implements the Fitz algorithm for the tracking phase to take advantage of the lower RMS frequency error. The implementation follows a serial pipelined architecture, which can provide a new estimate for both algorithms in 5205 clock cycles using 942 LUT, 918 FF, 2.5 BRAM, and 7 DSP on a Xilinx Virtex 7 FPGA. Together with the frequency error detector specifications, the entire acquisition and tracking loop is reported, which shows an output RMS frequency error of about 1.05 kHz at 8.5 Mbaud and 50 kHz/s Doppler rate, that can be easily compensated by a common pilot-assisted phase estimator.

The effect of COVID-19 on patients with multiple myeloma (MM), the second most common hematological malignancy, is of particularly great concern due to immunosuppression associated with the disease, and at this time remains incompletely understood. The aim of the current study was the analysis of the characteristics of COVID-19 infection and serological response in MM patients in Armenia for the period of 2020-2021. Methods We performed a retrospective study (epidemiological, clinical, and laboratory characteristics) on a cohort of 125 patients with MM, 42 in which developed COVID-19 between March 1, 2020, and May 30, 2021. Results Of the 42 (33.6%) patients diagnosed with COVID-19, 19 (45.2%) were hospitalized and 23 (66.4%) were managed at home. The median age was 60 years; 40.5% of patients were male. Hypertension (39%), hyperlipidemia (42%), obesity (33%), diabetes mellitus (18%), chronic kidney disease (14%), and lung disease (18%) were the most common comorbidities. In the total cohort, 8 patients (19%) died. The most common initial symptoms were fever (63%), cough (50%), dyspnea (43%), and hypoxemia (28%). Clinical status was considered as mild in 24 (57%), severe in 10 (24%), or critical in 8 (19%), with lung infiltrates reported on imaging in 12 (29%) and multiple organ failure in 4 (10%). Older age, male sex, cardiovascular risk, and patients with noncomplete remission were significantly (p

Context: Single-agent belamaf demonstrated deep and durable responses in the DREAMM-2 ( NCT03525678 ) primary analysis (1) and long-term follow-up (2,3). Keratopathy (microcyst-like epithelial changes [MECs] observed on eye examination with/without symptoms) were managed through dose delays and reductions. Objective: To provide an update on the impact of dose delays on responses in patients receiving single-agent belamaf 2.5-mg/kg in DREAMM-2 (13-month follow-up). Methods: In the DREAMM-2 study (single-agent belamaf 2.5 mg/kg [n=97] or 3.4 mg/kg [n=99] Q3W), dose modifications were permitted to manage adverse events (AEs), including keratopathy (MECs), an eye examination finding that may/may not be associated with symptoms. Objective response (IMWG criteria 2016) was assessed by an independent review committee Q3W, regardless of treatment delays. Here, we report a post-hoc analysis on the impact of dose delays >63 days on clinical response in the 2.5-mg/kg arm (the selected dose for future clinical development based on risk–benefit assessment). Results: In patients receiving single-agent belamaf (2.5 mg/kg), dose delays (54%) and reductions (35%) due to AEs were common (2,3). Keratopathy (MECs) was the most frequent reason for dose delays (47%) and reductions (25%), leading to only 1 patient (1%) discontinuing treatment (2,3). Of 31 patients with ≥partial response, 16 had prolonged treatment interruptions (>63 days). Of these 16 patients, 14 (88%) continued experiencing a clinical benefit during the first prolonged delay: 6 (38%) deepened their response during delay (1 SD to MR; 2 PR to VGPR; 2 MR to VGPR; 1 VGPR to CR); 6 (38%) maintained the same response category as that of the last evaluable assessment during delay/first evaluable assessment after delay; 2 (13%) had increasing paraproteins during the delay but did not meet progression criteria. Two (13%) developed disease progression (1 patient 6 weeks into delay; 1 patient 3 weeks after delay). Conclusions: Despite dose delays lasting for several cycles to manage AEs, most responses were sustained throughout the delay, thus maintaining clinical benefit for the majority of patients. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. References: [1] Lonial Lancet Oncol 2020. [2] Lonial ASCO 2020, EP436. [3] Lonial EHA 2020, EP970.

PURPOSE: To assess clinical performance of single restorations supported by 6-mm long implants in the posterior mandible after 5 years in function.MATERIALS AND METHODS: Twenty-one consecutive patients with the absence of premolars or molars in the posterior mandible and an estimated bone volume of at least 6 mm in width and an estimated height of 8 mm between the top of the ridge and alveolar nerve were included. Each patient received one or more 6-mm implants. Custom-made titanium abutments with cemented zirconia-based porcelain crowns were placed after a 3-month osseointegration period. Data of clinical examinations and radiographs were assessed at placement of the restoration and 12 and 60 months thereafter. The patients answered a questionnaire to score the satisfaction before treatment and after 12 and 60 months with the restoration in function.RESULTS: Implant survival was 100%. Five-years' mean marginal bone loss was 0.14 mm (SD: 0.4). Indices scores for plaque, calculus, gingiva, and bleeding were low as well as mean pocket-probing depth. Patients' satisfaction was high.CONCLUSION: Five-year follow-up data of this limited case series study revealed that 6-mm dental implants inserted in the resorbed posterior mandible provide a solid basis for single tooth restoration.

Mucosal melanoma (MM) is a highly lethal variant of melanoma that carries a poor prognosis. Extremely low incidence and survival rates have led to few clinical trials, and a lack of protocols and guidelines. The present study performed a survival meta-analysis for the quantitative synthesis of available evidence to search for key patterns that would help clinicians tailor optimal therapeutic strategies in MM. PubMed, EMBASE, Cochrane, MEDLINE, Google Scholar and other databases were searched. Hazard ratios, in disease-specific and overall survival, were calculated for each of the survival-determining variables. MM was 2.25 times more lethal than cutaneous melanoma (CM). The most significant threats to survival were advanced Tumor-Node-Metastasis stage, sino-nasal location, and old age. Chemotherapy was the most effective form of adjuvant therapy. Disease-specific survival, the primary measure of the effect sizes, can fluctuate depending on the accuracy of the reported cause of mortality. In conclusion, MM is a peculiar type of melanoma, with clinical and molecular profile vastly different from the much-familiar CM. In the wake of the era of precision oncology, further studies on driver mutations and oncogenic pathways would likely lead to improved patient survival.

AMD3100 (plerixafor, Mozobil®) was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the CXCR4 receptor. Through interference with the interaction of CXCR4 with its natural ligand, SDF-1 (also named CXCL12), it also mobilized the CD34+stem cells from the bone marrow into the peripheral blood stream. In December 2008, AMD3100 was formally approved by the US FDA for autologous transplantation in patients with Non-Hodgkin's Lymphoma or multiple myeloma. It may be beneficially used in various other malignant diseases as well as hereditary immunological disorders such as WHIM syndrome, and physiopathological processes such as hepatopulmonary syndrome. ispartof: Antivir Chem Chemother vol:27 pages:2040206619829382- ispartof: location:England status: published

Multiple myeloma (MM) remains an incurable plasma cells malignancy because of its complex genetic heterogeneity and high relapse rate post immunotherapy. The encouraging results of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) immunotherapy clinical trials have shed light on curing MM in recent years. However, many therapeutic side effects limit the promotion and clinical use of this novel effective approach such as cytokine release syndrome, antigen escape, and neurotoxicity. We should make every effort to do further study about this immunotherapy to make it safer and effective. This review focusing on this topic clarifies the following contents: present status of MM treatment, effectiveness of CAR-T cells, features of BCMA, preclinical and clinical trials of BCMA CAR-T cells therapy, and existing problems and strategies. Hoping to provide a reference for the subsequent correlative clinical and research.

Cutaneous malignant melanoma (MM) is the most malignant type of all skin neoplasms. There is wide variability in the characteristics of MM between patients of different races. The aim of the present study was to investigate the clinicopathological characteristics of patients with MM in central China and to assess the value of specific hematological and biochemical indices for predicting metastasis. The data of 167 patients with MM from the First Affiliated Hospital of Zhengzhou University (Henan, China) were retrospectively analyzed and compared with the data of patients with MM available from cBioPortal for Cancer Genomics. Following analysis of the clinicopathological characteristics of the 167 patients, the median overall survival time was 50 months, and the median disease-free survival time was 35 months. Albumin/D-dimer prognosis score (ADPS), lactate dehydrogenase, sex, T stage, tumor-node-metastasis stage, Breslow thickness, Clark level, histological type, growth phase, ulceration and metastasis were all significantly associated with prognosis. An ADPS of

This paper presents an ambient magnetic field map-based matching (MM) positioning algorithm for smartphones in an indoor environment. To improve the low distinguishability of a magnetic field fingerprint at a single point, a magnetic field sequence (MFS) combined with the measured trajectory contour coming from pedestrian dead-reckoning (PDR) is used for MM. Based on the fast approximation of magnetic field gradient, a Gauss-Newton iterative (GNI) method is used to find a rigid transformation that optimally aligns the measured MFS with a reference MFS coming from the magnetic field map. Then, the position of the reference MFS is used to control the position drift error of the inertial navigation system (INS) based PDR by an extended Kalman filter (EKF) and to further improve the accuracy of the trajectory contour. Finally, we conduct several experiments to evaluate the navigation performance of the proposed MM algorithm. The test results show that the position estimation error of the MM algorithm is 0.64 m (RMS) in an office building environment, 1.87 m (RMS) in a typical lobby environment, and 2.34 m (RMS) in a shopping mall environment.

Context: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has resulted in over 100,000 deaths in the United States. Our institution has treated over 2,000 COVID-19 patients during the pandemic in New York City. Objective: We explored the population of myeloma patients who developed COVID-19 to identify risk factors tied to poor outcomes. Design: We performed a retrospective study of a cohort of 58 patients with a plasma cell disorder (54 MM, 4 smoldering MM) who developed COVID-19 between March 1, 2020 and April 30, 2020. We report epidemiological, clinical, and laboratory characteristics, including persistence of viral detection by polymerase chain reaction (PCR) and anti-SARS-CoV-2 antibody testing, treatments initiated, and outcomes. Setting: A large tertiary care cancer center in New York at the epicenter of the COVID-19 pandemic in the USA. Patients: Patient charts were analyzed retrospectively. Patients had MM or SMM and COVID-19. Results: Of the 58 patients diagnosed with COVID-19, 36 were hospitalized and 22 were managed at home. The median age was 67 years; 52% of patients were male, and 63% were non-white. Hypertension (64%), hyperlipidemia (62%), obesity (37%), diabetes mellitus (28%), chronic kidney disease (CKD, 24%), and lung disease (21%) were the most common comorbidities. In the total cohort, 14 patients (24%) died. Older age (>70 years), male sex, and cardiovascular risk were significantly (p < 0.05) associated with hospitalization. Among hospitalized patients, laboratory findings demonstrated elevation of traditional inflammatory markers (CRP, ferritin, D-dimer) and a significant (p < 0.05) association between elevated inflammatory markers, severe hypogammaglobulinemia, non-white race, and mortality. Ninety-six percent (22/23) of patients developed antibodies to SARS-CoV-2 at a median of 32 days after initial diagnosis. Median time to PCR negativity was 43 (range 19–68) days from initial positive PCR. Conclusions: Drug exposure and MM disease status at the time of contracting COVID-19 had no bearing on patient outcome. Mounting a severe inflammatory response to SARS-CoV-2 and severe hypogammaglobulinemia were associated with higher mortality. These findings pave a path to the identification of vulnerable patients who need early intervention to improve outcomes of myeloma patients in future outbreaks of COVID-19. The majority of myeloma patients mounted a specific antibody response to SARS-CoV-2.

The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.

This paper investigates the influence of the spectral irradiance variation and the spectral response (SR) on the production of energy by photovoltaic cells. To determine the impact of SR and spectral irradiance on m-Si and perovskite cells, experimental tests were conducted outdoors, used optical filters to select different zones of the spectrum. For the computational simulations of the different photovoltaic modules, when subjected to a certain spectral irradiance, a model with spectral factor (SF) was implemented. The SF model accurately simulated the experiments performed for the high-pass filters. The highest relative errors for certain irradiation bands occurred due to the input variables used in the model, which did not fully describe the reality of the experiments performed. The effect of the SR and the spectral irradiance for each of them were observed through the simulations for the m-Si, a-Si, CdTe, and copper indium selenide (CIS) modules. The CIS technology presented a better overall result in the near infrared zone, producing about half of the energy produced by the CdTe technology in the visible zone. The SF, spectral incompatibility factor (MM), and spectral effective responsivity (SEF) parameters were verified to be important for studying the photovoltaic energy production.

The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages. The APRIL/BCMA signal cascades promote the survival and drug resistance of MM cells and further modulate immunosuppressive BM milieu. Impressively, anti-BCMA immunotherapeutic reagents, including chimeric antigen receptor (CAR), antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) have all shown high response rates in their first clinical trials in relapse and refractory patients with very limited treatment options. These results rapidly inspired numerous development of next-generation anti-BCMA biotherapeutics, i.e., bispecific molecule, bispecific or trispecific antibodies, a novel form of CAR T/NK cells and T Cell Antigen Coupler (TAC) receptors, antibody-coupled T cell receptor (ACTR) as well as a cancer vaccine. We here highlight seminal preclinical and clinical studies on novel BCMA-based immunotherapies as effective monotherapy and discuss their potential in combination with current anti-MM and novel checkpoint drugs in earlier disease stages to further achieve durable responses in patients.

We present a new version of the simulation software COBRAMM, a program package interfacing widely known commercial and academic software for molecular modeling. It allows a problem-driven tailoring of computational chemistry simulations with effortless ground and excited-state electronic structure computations. Calculations can be executed within a pure QM or combined quantum mechanical/molecular mechanical (QM/MM) framework, bridging from the atomistic to the nanoscale. The user can perform all necessary steps to simulate ground state and photoreactions in vacuum, complex biopolymer, or solvent environments. Starting from ground-state optimization, reaction path computations, initial conditions sampling, spectroscopy simulation, and photodynamics with deactivation events, COBRAMM is designed to assist in characterization and analysis of complex molecular materials and their properties. Interpretation of recorded spectra range from steady-state to time-resolved measurements. Various tools help the user to set up the system of interest and analyze the results.

Background High-dose therapy with autologous stem cell transplantation (HDT-ASCT) and maintenance treatment with novel agents are the best options for patients with newly diagnosed multiple myeloma, increasing the rate of complete response (CR) and prolonging progression-free survival (PFS) and overall survival (OS). Indeed, the achievement of a CR is a predictor of long-term survival among transplant-eligible patients. However, it is unclear whether patients reaching a CR after induction treatment could receive less intense consolidation or avoid maintenance therapy. Patients and Methods We analyzed CR patients treated in 2 phase III trials, GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441, to compare HDT-ASCT with an R-Alk (lenalidomide, alkylator) regimen as consolidation, and lenalidomide (R) maintenance with no maintenance. The primary endpoints were PFS, second PFS (PFS2), and OS from consolidation and maintenance (_m). Results Overall, the data from 166 patients in CR were analyzed, 95 in the HDT-ASCT group and 71 in the R-Alk group. The CR patients who received HDT-ASCT had a better PFS (hazard ratio [HR], 0.55; P = .01), PFS2 (HR, 0.46; P = .02), and OS (HR, 0.42; P = .03) compared with patients randomized to R-Alk. The survival benefit with HDT-ASCT was confirmed among all the subgroups, according to age, International Staging System (ISS stage, cytogenetic profile, and receipt of maintenance therapy. CR patients who received lenalidomide maintenance had a better PFS_m (4 years: 54% vs. 19%; HR, 0.43; P = .02) compared with those who received no maintenance. However, no difference was observed in terms of PFS2_m (4 years: 72% vs. 58%; HR, 0.83; P = .67) and OS_m (4 years: 79% vs. 72%; HR, 0.82; P = .73) with maintenance therapy. Conclusion Even in CR patients, outcomes were improved by an intensified approach with HDT-ASCT consolidation and lenalidomide-based maintenance therapy.

Objective This study aims to compare composite maternal and neonatal morbidities (MM, NM) among pregnant women with diabetes mellitus whose body mass index (BMI) at delivery was Methods This is a retrospective cohort study. MM was defined as: chorioamnionitis, wound infection, eclampsia, diabetic ketoacidosis, hypoglycemia admission, third/fourth degree laceration, and/or death. NM was defined as umbilical arterial pH Results MM was noted in 8, 13, and 24% of groups 1, 2, and 3, respectively, and significantly more common in group 2 versus 1 (adjusted odds ratio [aOR]: 1.66) and group 3 versus 1 (aOR: 3.06). NM was noted in 7, 8, and 15% of each BMI group, respectively, and differed significantly between group 3 vs. 2 (aOR: 1.77). Conclusions The increased rate of morbidities between the BMI groups is useful to inform diabetic women and highlights the need for further investigation of diabetes and obesity as comorbidities in pregnancy.

In recent years, using smartphones for indoor positioning has become increasingly popular with consumers. This paper presents an integrated localization technique for inertial and magnetic field sensors to challenge indoor positioning without Wi-Fi signals. For dead-reckoning (DR), attitude angle estimation, step length calculation, and step counting estimation are introduced. Dynamic time warping (DTW) usually calculates the distance between the measured magnetic field and magnetic fingerprint in the database. For DR/Magnetic matching (MM), we creatively propose 3-dimensional dynamic time warping (3DDTW) to calculate the distance. Unlike traditional DTW, 3DDTW extends the original one-dimensional signal to a two-dimensional signal. Finally, the weighted least squares further improves indoor positioning accuracy. In the three different experimental scenarios&mdash, teaching building, study room, office building&mdash, DR/MM hybrid positioning accuracy is about 3.34 m.

Multiple myeloma (MM) is a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow. With the advent of novel targeted agents, the median survival rate has increased to 5 -7 years. However, majority of patients with myeloma suffer relapse or develop chemoresistance to existing therapeutic agents. Thus, there is a need to develop novel alternative therapies for the treatment of MM. Thus in the present study, we investigated whether thymoquinone (TQ), a bioactive constituent of black seed oil, could suppress the proliferation and induce chemosensitization in human myeloma cells and xenograft mouse model. Our results show that TQ inhibited the proliferation of MM cells irrespective of their sensitivity to doxorubicin, melphalan or bortezomib. Interestingly, TQ treatment also resulted in a significant inhibition in the proliferation of CD138+ cells isolated from MM patient samples in a concentration dependent manner. TQ also potentiated the apoptotic effects of bortezomib in various MM cell lines through the activation of caspase-3, resulting in the cleavage of PARP. TQ treatment also inhibited chemotaxis and invasion induced by CXCL12 in MM cells. Furthermore, in a xenograft mouse model, TQ potentiated the antitumor effects of bortezomib (p < 0.05, vehicle versus bortezomib + TQ; p < 0.05, bortezomib versus bortezomib + TQ), and this correlated with modulation of various markers for survival and angiogenesis, such as Ki-67, vascular endothelial growth factor (VEGF), Bcl-2 and p65 expression. Overall, our results demonstrate that TQ can enhance the anticancer activity of bortezomib in vitro and in vivo and may have a substantial potential in the treatment of MM.

High-dose chemotherapy with autologous stem cell transplantation (ASCT) remains the standard of care for patients with multiple myeloma. Outpatient ASCT can be an attractive option given wait times and costs associated with inpatient procedures. We initiated an outpatient transplantation protocol in 2006. Patients were treated at a university hospital outpatient clinic that was open 5 days a week. The present study investigated safety and cost-effectiveness of the outpatient program. Ninety-one patients underwent ASCT between 2006 and 2010. The majority of patients (77%) had Durie-Salmon stage III disease; 38% had 1 or more comorbidities. Seventy-six patients (84%) were hospitalized during the first 100 days, mainly for febrile neutropenia (n = 71). Overall survival at day 100 was 100%. No patient was admitted to an intensive care unit. Risk factors for prolonged hospitalization (longer than 7 days) were disease stage IIB or higher and age >60 years. The cost savings was $19,522 (Canadian dollars) per patient compared with inpatient ASCT, for an annual savings of approximately $740,000. In summary, outpatient ASCT performed in a weekday clinic for patients with multiple myeloma appears to be safe and cost-effective, but is associated with a relatively high hospitalization rate.

To prospectively investigate whether combined interpretation of dynamic and hepatobiliary phase magnetic resonance (MR) images can improve the accuracy of gadobenate dimeglumine-enhanced MR imaging in the detection of hepatocellular carcinoma (HCC) compared with either dynamic MR or multiphasic multidetector computed tomographic (CT) images alone.Institutional review board approval and informed patient consent were obtained. Fifty-two patients (39 men, 13 women; mean age, 68 years; range, 38-81 years) suspected of having HCC underwent gadobenate dimeglumine-enhanced MR imaging and multiphasic 64-section multidetector CT. Images were qualitatively analyzed independently by three observers in three separate reading sessions. The alternating free-response receiver operating characteristic (AFROC) method was used to analyze the results. Differences in sensitivity and positive predictive values were calculated at a statistical significance of P.05.A total of 67 HCCs were detected in 36 patients. The mean area under the AFROC curve (A(z)) was significantly higher for either the combined interpretation of dynamic and hepatobiliary phase MR images (A(z) = 0.95) or dynamic MR images alone (0.91) than for CT images (0.77) (P = .01 for both comparisons). The mean sensitivity of combined interpretation of MR images (0.72) was significantly higher than those of dynamic MR images alone (0.63) and multidetector CT images (0.61) (P = .008 and .001, respectively). The mean positive predictive value was not significantly different among the three imaging sets.The combined interpretation of dynamic and hepatobiliary phase MR images improves diagnostic accuracy of gadobenate dimeglumine-enhanced MR imaging for the detection of HCC compared with either dynamic MR or multiphasic multidetector CT images alone.

The risk of recurrent postmenopausal bleeding in women whose endometrial thickness after a first episode was 4 mm or less could have major implications for management. If the recurrence rate is low, follow-up by transvaginal ultrasonography (TVU) would suffice. In contrast, a high recurrence rate (or the diagnosis of malignancy at follow-up) would call for immediate endometrial sampling. The investigators, from 7 university-affiliated teaching hospitals in The Netherlands, practiced expectant management for consecutive patients not on hormone replacement therapy who presented with a first episode of postmenopausal bleeding and were found to have a thin endometrium. Of 607 women with a first episode of postmenopausal bleeding, 249 had an endometrial thickness of 4 mm or less. During a median follow-up of approximately 3.25 years, 25 of these 249 women (10%) had recurrent bleeding. The median interval before bleeding recurred was 49 weeks. Two patients with recurrent bleeding proved to have endometrial carcinoma and another had malignant melanoma. Recurrent bleeding appeared not to correlate with age, time since menopause, body mass index, hypertension, diabetes, or anticoagulant therapy. Whether or not endometrial sampling was carried out in the office at initial presentation did not influence the findings. There was, however, a significant difference in recurrent bleeding between patients who underwent hysteroscopy and/or dilatation and curettage at initial workup (5/21) and those who did not (20/208). The hazard rate ratio was 2.8, with a 95% confidence interval of 1.05 to 7.5. These findings endorse the use of TVU as an initial measure in women with postmenopausal bleeding. It is, however, vital that patients who are managed expectantly be reevaluated and have endometrial sampling should bleeding recur.

The casein kinase 2 (CK2) protein kinase is a pro-survival kinase and therapeutic target in treatment of various human cancers. CK2 overexpression has been demonstrated in hematological malignancies, including chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and multiple myeloma. CX-4945, also known as Silmitasertib, is an orally administered, highly specific, ATP-competitive inhibitor of CK2. CX-4945 induces cytotoxicity and apoptosis and is currently being evaluated in clinical trials for treatment of many cancer types. In the past two years, the focus on the therapeutic potential of CX-4945 has shifted from solid tumors to hematological malignancies. CX-4945 exerts anti-proliferative effects in hematological tumors by downregulating CK2 expression and suppressing activation of CK2-mediated PI3K/Akt/mTOR signaling pathways. Furthermore, combination of CX-4945 with other inhibitors yielded synergistic effects in cell death induction. These new findings demonstrate that CK2 overexpression contributes to blood cancer cell survival and resistance to chemotherapy. Combinatorial use of CX-4945 is a promising therapeutic tool for treatment of hematological malignancies.

International audience; Multiple myeloma (MM), a plasma cell malignancy, remains incurable despite the development of new therapies. Curcumin anti-tumor effects were previously characterized in multiple myeloma, however only few MM cell lines were included in these studies. Since myeloma is a heterogeneous disease it is important to address the impact of myeloma molecular heterogeneity in curcumin cell death induction. In the present study, a large panel of human myeloma cell lines (HMCLs) (n = 29), representing the main molecular MM subgroups, was screened for curcumin sensitivity. We observed that curcumin cell death induction was heterogeneous, of note 16 HMCLs were highly sensitive to curcumin (LD50 < 20.5 μM), 6 HMCLs exhibited intermediate LD50 values (20.5 μM ≤ LD50 < 32.2 μM) and only 7 HMCLs were weakly sensitive (35 < LD50 < 56 μM). Cell lines harboring the t(11;14) translocation were less sensitive (median LD50 32.9 μM) than non-t(11;14) (median LD50 17.9 μM), which included poor prognosis t(4;14) and t(14;16) cells. Interestingly, curcumin sensitivity was not dependent on TP53 status. For the first time we showed that primary myeloma cells were also sensitive, even those displaying del(17p), another poor prognosis factor. We also unravel the contribution of anti-apoptotic Bcl-2 family molecules in curcumin response. We found that down-regulation of Mcl-1, an essential MM survival factor, was associated with curcumin-induced cell death and its knockdown sensitized myeloma cells to curcumin, highlighting Mcl-1 as an important target for curcumin-induced apoptosis. Altogether, these results support clinical trials including curcumin in association with standard therapy.

Background\ud \ud The global burden from cancer is rising, especially as low-income countries like Bangladesh observe rapid aging. So far, there are no comprehensive descriptions reporting diagnosed cancer group that include hematological malignancies in Bangladesh.\ud \ud Methods\ud \ud This was a multi-center hospital-based retrospective descriptive study of over 5000 confirmed hematological cancer cases in between January 2008 to December 2012. Morphological typing was carried out using the “French American British” classification system.\ud \ud Results\ud \ud A total of 5013 patients aged between 2 to 90 years had been diagnosed with malignant hematological disorders. A 69.2% were males (n = 3468) and 30.8% females (n = 1545), with a male to female ratio of 2.2:1. The overall median age at diagnosis was 42 years. Acute myeloid leukemia was most frequent (28.3%) with a median age of 35 years, followed by chronic myeloid leukemia with 18.2% (median age 40 years), non-Hodgkin lymphoma (16.9%; median age 48 years), acute lymphoblastic leukemia (14.1%; median age 27 years), multiple myeloma (10.5%; median age 55 years), myelodysplastic syndromes (4.5%; median age 57 years) and Hodgkin’s lymphoma (3.9%; median age 36 years). The least common was chronic lymphocytic leukemia (3.7%; median age 60 years). Below the age of 20 years, acute lymphoblastic leukemia was predominant (37.3%), followed by acute myeloid leukemia (34%). Chronic lymphocytic leukemia and multiple myeloma had mostly occurred among older patients, aged 50-over.\ud \ud Conclusions\ud \ud For the first time, our study presents the pattern and distribution of diagnosed hematological cancers in Bangladesh. It shows differences in population distributions as compared to other settings with possibly a lower presence of non-Hodgkin lymphoma. There might be under-reporting of affected women. Further studies are necessary on the epidemiology, genetics and potential environmental risk factors within this rapidly aging country.

Background Reflectance confocal microscopy (RCM) is an imaging tool that allows the visualization of cellular details without biopsy. To our knowledge, RCM sensitivity and specificity has not been studied in a telemedicine setting. Objective We sought to assess RCM diagnostic accuracy in a support teleconsultation setting. Methods Between June 2010 and September 2011, 340 lesions were imaged using a confocal scanning microscope. The images were evaluated by 2 readers, one on site, and the other at a distance. Results A total of 334 cases were included. For each reader the sensitivity was greater than 90% and specificity for each reader was greater than 60%. Both readers had a combined sensitivity of 98.6% and 44% specificity. Limitations RCM may be limited in the correct classification of epithelial tumors. Conclusions RCM is a tool in the clinical diagnosis of skin lesions, providing a high diagnostic accuracy in teleconsultation use.