Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. RESULTS: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CONCLUSION: CAR-T demonstrates clinical efficacy for patients with RT.

Novel chimeric antigen receptor targets and constructs for acute lymphoblastic leukemia: Moving beyond CD19.

Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults with a poor prognosis with relapsed or refractory (R/R) B-cell lineage ALL (B-ALL). Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown excellent response rates in RR B-ALL, but most patients relapse due to poor persistence of CAR T-cell therapy or other tumor-associated escape mechanisms. In addition, anti-CD19 CAR T-cell therapy causes several serious side effects such as cytokine release syndrome and neurotoxicity. In this review, we will discuss novel CAR targets, CAR constructs, and various strategies to boost CARs for the treatment of RR B-ALL. In addition, we discuss a few novel strategies developed to reduce the side effects of CAR.

Venous Thromboembolism Risk Assessment in Hospitalized Cancer Patients: A Single Center Study.

This study aimed to identify predictors of venous thromboembolism (VTE) in hospitalized cancer patients and develop a predictive model using demographic, clinical, and laboratory data. Our analysis showed that patient groups categorized under a very high risk, and high risk, patients with low hemoglobin levels and renal disease were at a significantly increased risk of developing VTE. We developed a VTE risk-assessment model (RAM) with moderate discriminatory performance, high specificity, and negative predictive value, indicating its potential utility in identifying patients without VTE risk. However, the model's positive predictive value and sensitivity were low due to the low prevalence of VTE within the analyzed population. Future studies are needed to analyze additional predictive factors, and to validate the effectiveness of our VTE RAM to safely rule out VTE, compare it with other VTE RAMs in hospitalized cancer patients, and address any limitations of our study.

Maintenence rituximab following induction in autoimmune cytopenias.

About 50% of immune thrombocytopenia (ITP) patients respond to rituximab induction, but most relapse. The effectiveness of rituximab maintenance remains untested. This study included autoimmune cytopenia patients who had previously responded to rituximab induction but subsequently relapsed. After re-induction, patients received rituximab maintenance regimen consisting of a single 375 mg/m2 dose administered at 4 month intervals, with a maximum of 6 doses. Primary endpoints were duration of response and safety. Sixteen patients: ITP (9), autoimmune haemolytic anaemia (2), and Evans syndrome (5) received rituximab maintenance. 15/16 achieved complete response (CR); 8/15 CR + 1 partial reponse remain in remission. Median response: 43 months; estimated 5-year relapse-free >50%. Three developed hypogammaglobulinemia. Rituximab maintenance led to prolonged remissions in patients with autoimmune cytopenias who had previously responded to rituximab induction.

Start codon targeted (SCoT) polymorphism marker in plant genome analysis: current status and prospects.

MAIN CONCLUSION: The present review illustrates a comprehensive overview of the start codon targeted (SCoT) polymorphism marker and their utilization in various applications related to genetic and genomic studies. Start codon targeted (SCoT) polymorphism marker, a targeted fingerprinting marker technique, has gained considerable importance in plant genetics, genomics, and molecular breeding due to its many desirable features. SCoT marker targets the region flanking the start codon, a highly conserved region in plant genes. Therefore, it can distinguish genetic variations in a specific gene that link to a specific trait. It is a simple, novel, cost-effective, highly polymorphic, and reproducible molecular marker for which there is no need for prior sequence information. In the recent past, SCoT markers have been employed in many commercially important and underutilized plant species for a variety of applications, including genetic diversity analysis, interspecific/generic genetic relationships, cultivar/hybrid/species identification, sex determination, construction of linkage map, association mapping/analysis, differential gene expression, and genetic fidelity analysis of tissue culture-raised plants. The main aim of this review is to provide up-to-date information on SCoT markers and their application in many commercially important and underutilized plant species, mainly progress made in the last 8-10 years.

Bioinspired NiO Nanospheres: Exploring In Vitro Toxicity Using Bm-17 and L. rohita Liver Cells, DNA Degradation, Docking, and Proposed Vacuolization Mechanism.

The present work demonstrated a novel Cleome simplicifolia-mediated green fabrication of nickel oxide nanoparticles (NiO NPs) to explore in vitro toxicity in Bm-17 and Labeo rohita liver cells. As-fabricated bioinspired NiO NPs were characterized by several analytical techniques. X-ray diffraction (XRD) revealed a crystalline face-centered-cubic structure. Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible diffuse reflectance spectroscopy (UV-DRS), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS) confirmed NiO formation. The chemical composition was confirmed by energy-dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy. Brunauer-Emmett-Teller (BET) revealed the mesoporous nature. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed the formation of 97 nm diameter nanospheres formed due to the congregation of 10 nm size particles. Atomic force microscopy (AFM) revealed the nearly isotropic behavior of NiO NPs. Further, a molecular docking study was performed to explore their toxicity by binding with genetic molecules, and it was found that the docking energy was about -9.65284 kcal/mol. On evaluating the in vitro toxicity of NiO NPs for Bm-17 cells, the study showed that when cells were treated with a high concentration of NPs, cells were affected severely by toxicity, while at a lower concentration, cells were affected slightly. Further, on using 50 µg/mL, quick deaths of cells were observed due to the formation of more vacuoles in the cells. The DNA degradation study revealed that NiO NPs are significantly responsible for DNA degradation. For further confirmation, trypan blue assay was observed for cell viability, and morphological assessment was performed using inverted tissue culture microscopy. Further, the cytotoxicity of NiO NPs in L. rohita liver cells was studied. No toxicity was observed at 1 mg/L of NiO NPs; however, when the concentration was 30 and 90 mg/L, dark and shrank hepatic parenchyma was observed. Hence, the main cause of cell lysis is the increased vacuolization in the cells. Thus, the present study suggests that the cytotoxicity induced by NiO NPs could be used in anticancer drugs.

Fecal Microbiota Transplantation and Medical Therapy for Clostridium difficile Infection : Meta-analysis of Randomized Controlled Trials.

GOALS: The aim was to assess the effectiveness of fecal microbiota transplantation (FMT) against medical therapy (MT). BACKGROUND: FMT has shown good outcomes in the treatment of Clostridium difficile infection (CDI). We aimed to conduct a systematic review and meta-analysis to compare the effectiveness of FMT versus MT for CDI. STUDY: We performed a comprehensive search to identify randomized controlled trials comparing FMT against MT in patients with CDI. Outcomes of interest were clinical cure as determined by the resolution of diarrhea and/or negative C. difficile testing. Primary CDI is defined as the first episode of CDI confirmed endoscopically or by laboratory analysis. Recurrent C. difficile infection (RCDI) is defined as laboratory or endoscopically confirmed episode of CDI after at least 1 course of approved antibiotic regimen. RESULTS: A total of 7 studies with 238 patients were included in meta-analysis. Compared with MT, FMT did not have a statistically significant difference for clinical cure of combined primary and RCDI after first session [risk ratio (RR): 1.52, 95% confidence interval (CI): 0.90, 2.58; P =0.12; I2 =77%] and multiple sessions of FMT (RR: 1.68; CI: 0.96, 2.94; P =0.07; I2 =82%). On subgroup analysis, FMT has statistically higher rate of response than MT (RR: 2.41; CI: 1.20, 4.83; I2 =78%) for RCDI. However, for primary CDI there is no statistically significant difference between FMT and MT (RR: 1.00; CI: 0.72, 1.39; I2 =0%). CONCLUSION: As per our analysis, FMT should not be utilized for every patient with CDI. It is more effective in RCDI, but the results were not significant in patients with primary CDI.

Pattern and burden of opioid-related hospitalizations in the USA from 2016 to 2018.

AIMS: The current opioid crisis in the USA is a formidable challenge for the healthcare system, and the general population. Our objective is to characterize the burden of opioid-related disorders in an inpatient setting in the USA for the years 2016, 2017 and 2018 using the National Inpatient Sample (NIS). METHODS: A cross-sectional analysis of the NIS was performed to identify and analyse hospitalizations with an opioid-related diagnosis in 2016, 2017 and 2018. Descriptive statistics and regression models were utilized to define the demographics of the population of interest and measure the outcomes. RESULTS: We identified 962 900 discharges with opioid-related diagnosis in 2016, 982 710 in 2017 and 942 110 in 2018. The majority were age <60 years, were found in residents of low-income zip codes and covered by Medicaid. The adjusted mean total hospitalization cost trended up from $12 828 (95% confidence interval [CI] 12 547-13 108) in 2016, to $13164.9 (95% CI 12 872.47-13 457.34) in 2017 and then to $13 626.65 (95% CI 13 325.95-13 927.34) in 2018. The adjusted mortality was highest in 2016; 2.26% (95% CI 2.16-2.35) and it trended down to 1.97% (95% CI 1.88-2.05) in 2017, and to 1.89% (95% CI 1.81-1.98) in 2018. CONCLUSIONS: Opioid-related disorders cause a significant number of hospitalizations in the USA. A large proportion of these patients are age <60 years, have lower household income, and are covered by Medicaid. Programmes directed towards this specific group can help reduce the overall burden of hospitalizations.

Mechanism of nanotoxicity in Chlorella vulgaris exposed to zinc and iron oxide.

Usage of nanoparticle in various products has increased tremendously in the recent past. Toxicity of these nanoparticles can have a huge impact on aquatic ecosystem. Algae are the ideal organism of the aquatic ecosystem to understand the toxicity impact of nanoparticles. The present study focuses on the toxicity evaluation of zinc oxide (ZnO) and iron oxide (Fe2O3) nanoparticles towards freshwater microalgae, Chlorella vulgaris. The dose dependent growth retardation in Chlorella vulgaris is observed under ZnO and Fe2O3 nanoparticles and nanoform attributed more toxicity than their bulk counterparts. The IC50 values of ZnO and Fe2O3 nanoparticles was reported at 0.258 mg L-1 and 12.99 mg L-1 whereas, for the bulk-form, it was 1.255 mgL-1 and 17.88 mg L-1, respectively. The significant decline in chlorophyll content and increase in proline content, activity of superoxide dismutase and catalase, indicated the stressful physiological state of microalgae. An increased lactate dehydrogenase level in treated samples suggested membrane disintegration by ZnO and Fe2O3 nanoparticles. Compound microscopy, scanning electron microscopy and transmission electron microscopy confirm cell entrapment, deposition of nanoparticles on the cell surface and disintegration of algal cell wall. Higher toxicity of nanoform in comparison to bulk chemistry is a point of concern.

Iatrogenic Severe Splenic Injury after Colonoscopy.

Colonoscopy is a low-risk procedure performed for screening and diagnostic purposes. About 15 million colonoscopies were carried out in the United States in 2012 with this number projected to increase. Injury to the spleen as a complication of colonoscopy is still a rather rare occurrence. We report a case of significant splenic injury, American Association of Surgery for Trauma (AAST) grade III with hemoperitoneum, in a patient following diagnostic colonoscopy, managed conservatively without the need for invasive or salvage surgical procedure.

An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants.

Non-vitamin K antagonist oral anticoagulants (NOACs) include thrombin inhibitor dabigatran and coagulation factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. NOACs have several benefits over warfarin, including faster time to the achieve effect, rapid onset of action, fewer documented food and drug interactions, lack of need for routine INR monitoring, and improved patient satisfaction. Local hemostatic measures, supportive care, and withholding the next NOAC dose are usually sufficient to achieve hemostasis among patients presenting with minor bleeding. The administration of reversal agents should be considered in patients on NOAC's with major bleeding manifestations (life-threatening bleeding, or major uncontrolled bleeding), or those who require rapid anticoagulant reversal for an emergent surgical procedure. The Food and Drug Administration (FDA) has approved two reversal agents for NOACs: idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban. The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) have released an updated guideline for the management of patients with atrial fibrillation that provides indications for the use of these reversal agents. In addition, the final results of the ANNEXA-4 study that evaluated the efficacy and safety of andexanet alfa were recently published. Several agents are in different phases of clinical trials, and among them, ciraparantag has shown promising results. However, their higher cost and limited availability remains a concern. Here, we provide a brief review of the available reversal agents for NOACs (nonspecific and specific), recent updates on reversal strategies, lab parameters (including point-of-care tests), NOAC resumption, and agents in development.

Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End-Stage Renal Disease: A Systematic Review and Meta-analysis.

Importance: Several studies have examined the role of warfarin in preventing strokes in patients with atrial fibrillation and end-stage renal disease; however, the results remain inconclusive. Objective: To assess recently published studies to examine the outcomes of the use of warfarin among patients with atrial fibrillation and end-stage renal disease. Data Sources: A literature search was performed using the terms warfarin and atrial fibrillation and end-stage renal disease and warfarin and atrial fibrillation and dialysis in the MEDLINE, Embase, and Google Scholar databases from January 1, 2008, to February 28, 2019. Study Selection: The studies included were those with patients with end-stage renal disease and atrial fibrillation who were receiving warfarin and with hazard ratios (HRs) of at least 1 primary outcome. The studies excluded were those with a lack of information on outcomes and unreliable 95% CIs of the results. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed in selecting studies. Collected data were also scrutinized for reliable 95% CIs. Finally, studies were examined for perceived biases, their limitations, and the definitions of the outcomes. Main Outcomes and Measures: The HRs and 95% CIs were calculated for the incidence of ischemic stroke, hemorrhagic stroke, major bleeding, and mortality among patients receiving anticoagulants and those not receiving anticoagulants. Results: Study selection yielded 15 studies with a total of 47 480 patients with atrial fibrillation and end-stage renal disease. Of these patients, 10 445 (22.0%) were taking warfarin. With a mean (SD) follow-up period of 2.6 (1.4) years, warfarin use was associated with no significant change for the risk of ischemic stroke (HR, 0.96; 95% CI, 0.82-1.13), with a significantly higher risk of hemorrhagic stroke (HR, 1.49; 95% CI, 1.03-1.94), with no significant difference in the risk of major bleeding (HR, 1.20; 95% CI, 0.99-1.47), and with no change in overall mortality (HR, 0.95; 95% CI, 0.83-1.09). Conclusions and Relevance: In the studies reviewed, warfarin use appears to have been associated with no change in the incidence of ischemic stroke in patients with atrial fibrillation and end-stage renal disease. However, from the studies reviewed, it does appear to be associated with a significantly higher risk of hemorrhagic stroke, with no significant difference in the risk of major bleeding, and with no change in mortality.

Do USMLE steps, and ITE score predict the American Board of Internal Medicine Certifying Exam results?

BACKGROUND: To evaluate if United States Medical Licensing Examination (USMLE) Step 1, USMLE Step 2 CK, USMLE Step 3, and residency third-year in-service training exam (ITE) scores predict the results of American Board of Internal Medicine Certifying Exam (ABIM-CE). METHODS: We performed a retrospective review of USMLE Step 1, USMLE Step 2 CK, USMLE Step 3, third-year residency ITE scores and ABIM-CE results of IM residents at our residency program from 2004 through 2017. Statistical analysis was perfrormed using Pearson correlation coefficient, and logistic regression to assess the relationship between USMLE Step 1, USMLE Step 2CK, USMLE Step 3, 3rd year ITE scores and ABIM-CE results. We used Multivariate logistic regression to predict pass or fail results in ABIM-CE based on USMLE and third-year ITE test scores controlling for other covariates. RESULTS: Among 114 Internal Medicine MD residents included in the study, 92% (n = 105) passed the ABIM-CE. The OR of passing ABIM-CE was 2.70 (95% CI = 1.38-5.29), 2.31 (95% CI = 1.33-4.01), and 1.63 (95% CI = 0.81-3.29) with a ten-point increase in USMLE Step 1, USMLE Step 2 CK and USMLE Step 3 scores respectively. The OR of ABIM-CE passing chance was 2.96 (95% CI = 0.95-9.20), with a ten-point increase in the average score of the above three exams. A 5 % increase in ITE percentage raised the likelihood of passing ABIM-CE (OR 2.92, 95% CI 1.15-7.38). All residents who failed ABIM-CE had Step 1 scores < 220. Among 31 residents with Step 2 CK score < 220, 20% (n = 6) failed ABIM. Similarly, 9% of residents with USMLE Step 3 score < 220 failed ABIM-CE; all residents who failed had scored < 220. The probability curve predicted that the chance of passing ABIM- CE was around 80% with USMLE scores greater than 200 and increased to almost 100% with USMLE scores of 250 or more. CONCLUSION: USMLE Step 1, USMLE Step 2 CK, and third-year ITE scores can predict the chances of passing ABIM-CE. The third-year ITE score has a higher preditive value compared to USMLE Step 1 and USMLE Step 2 scores. USMLE Step 1 scores more predictive of ABIM-CE results compared to USMLE Step 2CK scores. Thus, residency programs can identify internal medicine residents at risk of failing ABIM-CE and formulate interventions at an early stage during residency training. Measures such as enrolling them in question banks or board review courses can be helpful in improving their chances of passing ABIM-CE.

Splenic sequestration crisis as an index manifestation of heterozygous hemoglobinopathy in an adult.

Sickle ß+-thalassemia rarely manifests with acute splenic sequestration crisis in adults. We report a case of a 20-year-old female who presented with fever and left upper quadrant abdominal pain. Laboratory studies revealed hemolytic anemia. Tests for autoimmune hemolysis and hemolytic diseases were negative except for Hemoglobin (Hb) electrophoresis, which revealed sickle cell trait (Hb AS). Infectious workup was unremarkable. Computed tomography scan of the abdomen showed marked splenomegaly. The patient received blood transfusions and empiric antibiotics with no improvement; thus, splenectomy was performed. Pathology specimen revealed peripheral serpiginous infarcts alternating with surrounding acute inflammation and small capillaries plugged with sickle cell shaped red blood cells consistent with splenic sequestration. DNA test later revealed beta-globin mutations consistent with sickle cell-beta+ thalassemia. Post-splenectomy, there was a gradual improvement in her clinical symptoms with concomitant rise in Hb to 10.6 g/dl at discharge.

The dilemma in the management of haemodynamically stable pulmonary embolism with right heart thrombus.

Right ventricular thrombus (RVT) can be life-threatening, since it has the potential to embolise and cause saddle pulmonary embolism (PE). We present a patient who initially presented with haemodynamically stable PE with evidence of RVT on echocardiogram. She was placed on heparin drip; however, she later developed cardiac arrest and died due to embolisation of RVT to the pulmonary vasculature. Although management of haemodynamically stable PE in patients with RVT is still a matter of debate, 1 given the outcome we suggest that thrombolysis or emergent embolectomy at the presentation, in this case, may have had a favourable outcome.

Updates in Treatment of Recurrent Clostridium difficile Infection.

Recurrent Clostridium difficile infection (CDI) is a perpetual problem that leads to increased economic burden, higher healthcare cost, and significant morbidity and mortality. Its treatment remains a challenge. While various treatment approaches have been attempted with different levels of success, robust data establishing the superiority of one approach over the others is lacking. In this article, we review the current evidence pertaining to conventional pharmacological treatment as well as fecal microbiota transplantation (FMT) as a novel, rapidly emerging treatment modality for recurrent CDI.

Severe recurrent gastrointestinal bleeding following percutaneous endoscopic gastrostomy tube placement: a rare complication.

Severe bleeding requiring blood transfusions following endoscopic, percutaneous gastrostomy tube placement is a rare complication. We describe a case of severe recurrent haemorrhage with bright red blood from rectum from endoscopic, percutaneous gastrostomy tube placement, which ultimately required removal of the percutaneous endoscopic gastrostomy tube.

Genetic homogeneity revealed in micropropagated Bauhinia racemosa Lam. using gene targeted markers CBDP and SCoT.

Two gene targeted markers i.e. CAAT box-derived polymorphism (CBDP) and start codon targeted (SCoT) polymorphism were applied to analyze the genetic stability of in vitro propagated plants of Bauhinia racemosa Lam. multiplied by enhanced axillary shoot proliferation of mature tree derived nodal explant. Nine randomly selected micropropagated plants of 1 year age were subjected to molecular analysis. The isolated genomic DNA samples were subjected to PCR amplification with a total of 61 primers (25 CBDP and 36 SCoT) out of which 39 primers (21 CBDP and 18 SCoT) produced scorable amplicons. A total of 97 and 88 clear, distinct and reproducible amplicons were produced by CBDP and SCoT primers, respectively. The monomorphic banding pattern obtained through all the tested primers corroborated the true to type nature of in vitro propagated plants of B. racemosa.

Overutilisation of imaging studies for diagnosis of pulmonary embolism: are we following the guidelines?

OBJECTIVE: To evaluate if imaging studies such as CT pulmonary angiography (CTPA) or ventilation-perfusion (V/Q) scan are ordered according to the current guidelines for the diagnosis of pulmonary embolism (PE). METHODS: We performed a retrospective observational cohort study in all adult patients who presented to the Sparrow Hospital Emergency Department from January 2014 to December 2016 and underwent CTPA or V/Q scan. We calculated the Wells' score retrospectively, and d-dimer values were used to determine if the imaging study was justified. RESULTS: A total of 8449 patients underwent CTPA (93%) or V/Q scan (7%), among which 142 (1.7%) patients were diagnosed with PE. The Wells' criteria showed low probabilities for PE in 96 % and intermediate or high probabilities in 4 % of total patients. Modified Wells' criteria demonstrated PE unlikely in 99.6 % and PE likely in 0.4 % of total patients. D-dimer was obtained in only 37 % of patients who were unlikely to have a PE or had a low score on Wells' criteria. Despite a low or unlikely Wells' criteria score and normal d-dimer levels, 260 patients underwent imaging studies, and none were diagnosed with PE. CONCLUSION: More than 99 % of CTPA or V/Q scans were negative in our study. This suggests extraordinary overutilisation of the imaging methods. D-dimer, recommended in patients with low to moderate risk, was ordered in only one-third of patients. Much greater emphasis of current guidelines is needed to avoid inappropriate utilisation of resources without missing diagnosis of PE.

Angioedema of the small bowel caused by lisinopril.

In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years.