Treatment of Relapsed B/T-cell Mixed Phenotype Acute Leukemia With Blinatumomab.

Here, we describe the treatment of a patient with relapsed/refractory B/T mixed phenotype acute leukemia (MPAL) using blinatumomab monotherapy, the first bispecific T cell engager (BiTE) approved by the FDA for relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). A 64-year-old man with a history of stage 3 chronic kidney disease and type 2 diabetes mellitus was discovered to have B/T MPAL on bone marrow biopsy during hospitalization for dyspnea due to pulmonary embolism. The patient achieved brief remission with blinatumomab treatment before succumbing to neutropenic sepsis. The lack of sufficient data to guide therapy in MPAL remains a challenge, highlighting the potential of new targeted approaches such as blinatumomab to improve outcomes in relapsed/refractory MPAL.

Efficacy of LAMP assay for Mycobacterial spp. detection to prevent treatment delays and onset of drug resistance: a systematic review and meta-analysis.

Background: Tuberculosis (TB) remains a deadly disease affecting one-third population globally. Long turnaround time and poor sensitivity of the conventional diagnostics are the major impediments for faster diagnosis of Mycobacterial spp to prevent drug resistance. To overcome these issues, molecular diagnostics have been developed. They offer enhanced sensitivity but require sophisticated infrastructure, skilled manpower and remain expensive. Methods: In that context, loop-mediated isothermal amplification (LAMP) assay, recommended by the WHO in 2016 for TB diagnosis, sounds as a promising alternative that facilitates visual read outs. Therefore, the aim of the present study is to conduct a meta-analysis to assess the diagnostic efficiency of LAMP for the detection of a panel of Mycobacterium spp. following PRISMA guidelines using scientific databases. From 1600 studies reported on the diagnosis of Mycobacterium spp., a selection of 30 articles were identified as eligible to meet the criteria of LAMP based diagnosis. Results: It was found that most of the studies were conducted in high disease burden nations such as India, Thailand, and Japan with sputum as the most common specimen to be used for LAMP assay. Furthermore, IS6110 gene and fluorescence-based detections ranked as the most used target and method respectively. The accuracy and precision rates mostly varied between 79.2% to 99.3% and 73.9% to 100%, respectively. Lastly, a quality assessment based on QUADAS-2 of bias and applicability was conducted. Conclusion: LAMP technology could be considered as a feasible alternative to current diagnostics considering high burden for rapid testing in low resource regions.

Diagnostic Efficacy of LAMP Assay for Human Fungal Pathogens: a Systematic Review and Meta-analysis.

Purpose: Human fungal infections particularly caused by Candida and Aspergillus have emerged as major public health burden. Long turnaround time and poor sensitivity of the conventional diagnostics are the major impediments for faster diagnosis of human fungal pathogens. Recent Findings: To overcome these issues, molecular-based diagnostics have been developed. They offer enhanced sensitivity but require sophisticated infrastructure, skilled manpower, and remained expensive. In that context, loop-mediated isothermal amplification (LAMP) assay represents a promising alternative that facilitates visual read outs. However, to eradicate fungal infections, all forms of fungi must be accurately detected. Thus, a need for alternative testing methodologies is imperative that should be rapid, accurate and facilitate widespread adoption. Therefore, the aim of the present study is to conduct a meta-analysis to assess the diagnostic efficiency of LAMP in the detection of a panel of human fungal pathogens following PRISMA guidelines using scientific databases viz. PubMed, Google Scholar, Science Direct, Scopus, BioRxiv, and MedRxiv. Summary: From various studies reported on the diagnosis of fungi, only 9 articles were identified as eligible to meet the criteria of LAMP based diagnosis. Through this meta-analysis, it was found that most of the studies were conducted in China and Japan with sputum and blood as the most common specimens to be used for LAMP assay. The collected data underlined that ITS gene and fluorescence-based detections ranked as the most used target and method. The pooled sensitivity values of meta-analysis ranged between 0.71 and 1.0 and forest plot and SROC (summary receiver operating characteristic) curve revealed a pooled specificity values between 0.13 and 1.0 with the confidence interval of 95%, respectively. The accuracy and precision rates of eligible studies mostly varied between 70 to 100% and 68 to 100%, respectively. A quality assessment based on QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) of bias and applicability was conducted which depicted low risk of bias and applicability concerns. Together, LAMP technology could be considered as a feasible alternative to current diagnostics considering high fungal burden for rapid testing in low resource regions.

Intracardiac echocardiography from coronary sinus.

Intracardiac echocardiography (ICE) has become an essential tool and is an integral part of percutaneous interventional and electrophysiology (EP) procedures. Intracardiac echocardiography offers real-time, high-quality, near-field evaluation of cardiac anatomy. Standard ICE imaging includes placing the catheter in the right atrium (RA), right ventricle (RV), or left atrium (LA, via the transeptal approach). Coronary sinus echocardiography (CSE) is another alternative, where the ICE catheter is positioned in the coronary sinus (CS). This approach offers better catheter stability and allows operators to visualize cardiac structure with particularly excellent views of the LA, LAA, left ventricle (LV), and mitral annulus. Additionally, CSE is an attractive alternative in cases with unfavorable interatrial septum or fossa ovalis anatomical features that could lead to difficulty advancing ICE catheter in left atrium. In this article focusing on CSE, we provide illustration-based guidance to help operators identify critical cardiac structures from CSE.

Early Local Therapy for the Primary Site in De Novo Stage IV Breast Cancer: Results of a Randomized Clinical Trial (EA2108).

PURPOSE: Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results. METHODS: Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments. RESULTS: Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms. CONCLUSION: Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life.

Covid19-IBO: A Covid-19 Impact on Indian Banking Ontology Along with an Efficient Schema Matching Approach.

The exponential spread of Covid-19 is not only a serious concern for public health but has also severely affected the global economy. India is not an exception. The banking sector must plan innovatively in a wide range of scenarios focusing upon Covid-19 specific requirements. It becomes essential to examine the impact of Covid-19 on the performance of the Indian banking sector and take focused initiatives at both the tactical and the strategic levels. This paper offers the Covid-19 Impact on Banking Ontology (Covid19-IBO) that provides semantic information about the impact of Covid-19 on the banking sector of India. The developed ontology has been verified and validated and has been made available on the Linked Open Data cloud. It can be utilized to annotate the related data to provide meaningful insights. The Covid-19 ontologies already available have some overlapping information that causes redundancy. Unified integration of these ontologies is required to operate upon them unambiguously. It becomes reasonable to develop a matching approach to link all these ontologies semantically. We, therefore, also provide a schema matching approach with reasonable results to map the Covid-19 ontologies.

Nipah Virus Disease: Recent Perspective and One Health Approach.

Background: Nipah virus (NiV) first emerged in 1998 in Malaysia, causing an outbreak of respiratory illness and encephalitis in pigs. Pig-to-human transmission of NiV associated with severe febrile encephalitis was described, and it was thought to occur through close contact with infected animals. The first outbreak was reported in India in Siliguri, West Bengal in 2001 followed by Nadia, West Bengal and adjoining areas of Bangladesh in 2007, where an intermediate animal host was not identified, suggesting bat-to-human and human-to-human transmissions. Although it is extremely difficult to document the spillover event and ascertain crossing of trans-natural boundaries by bats and bringing new viruses in an unexposed population, efforts for source identification are important to understand the epidemiology of disease. As the disease transcends beyond one species and has shown to infect humans, it therefore requires the 'One Health approach' in which multiple sectors coordinate and work together to achieve better public health outcomes. Objective: We summarize the re-emergence and response of the Nipah virus outbreaks (NiVD) in Kerala, India, about 1800 kms away, a decade later in 2018 and 2019. The paper recapitulates involvement of various stakeholders from the Ministry of Health and Family Welfare, Directorate of Health Research, Indian Council of Agricultural Research, State Health Department, State Animal Husbandry, District Administration, and multidisciplinary response mechanism during the NiVD outbreaks of 2018 and 2019. Methods: Information was collected from the Press Information Bureau (PIB), media/weekly alerts from the Integrated Disease Surveillance Programme (IDSP), news articles from print and electronic media, newsletters, advisories from the National Centre for Disease Control (NCDC), Disease Outbreak News (DON), World Health Organization (WHO), and published papers from various stakeholders. Findings & Conclusion: The evidence of NiV in humans and bats, with samples collected from the outbreak sites, was laboratory confirmed. The multidisciplinary response mechanisms during the 2018 outbreak helped in further understanding the importance of the One Health approach for systemic and streamlined response utilizing existing surveillance systems. This was of utmost help in the subsequent outbreak of the disease that occurred during 2019, wherein there was no documented spread of disease from the index case and no mortality was observed. This success reiterates the need for institutionalizing the involvement and cooperation of various departments and organizations during public health emergencies, especially of Zoonotic diseases, using the One Health approach.

Cystic Nephroma and its Varied Management Scenarios: A Report of two Cases.

Cystic nephroma is a rare benign cystic neoplasm of the kidney. The preoperative diagnosis with its malignant counterparts cystic partially differentiated nephroblastoma or cystic Wilms' tumor is not easy but is important when one is considering for nephron-sparing surgery.

Cloud-Based Zero Trust Access Control Policy: An Approach to Support Work-From-Home Driven by COVID-19 Pandemic.

The ubiquitous cloud computing services provide a new paradigm to the work-from-home environment adopted by the enterprise in the unprecedented crisis of the COVID-19 outbreak. However, the change in work culture would also increase the chances of the cybersecurity attack, MAC spoofing attack, and DDoS/DoS attack due to the divergent incoming traffic from the untrusted network for accessing the enterprise's resources. Networks are usually unable to detect spoofing if the intruder already forges the host's MAC address. However, the techniques used in the existing researches mistakenly classify the malicious host as the legitimate one. This paper proposes a novel access control policy based on a zero-trust network by explicitly restricting the incoming network traffic to substantiate MAC spoofing attacks in the software-defined network (SDN) paradigm of cloud computing. The multiplicative increase and additive decrease algorithm helps to detect the advanced MAC spoofing attack before penetrating the SDN-based cloud resources. Based on the proposed approach, a dynamic threshold is assigned to the incoming port number. The self-learning feature of the threshold stamping helps to rectify a legitimate user's traffic before classifying it to the attacker. Finally, the mathematical and experimental results exhibit high accuracy and detection rate than the existing methodologies. The novelty of this approach strengthens the security of the SDN paradigm of cloud resources by redefining conventional access control policy.

A Deep Learning Method to Forecast COVID-19 Outbreak.

A new pandemic attack happened over the world in the last month of the year 2019 which disrupt the lifestyle of everyone around the globe. All the related research communities are trying to identify the behaviour of pandemic so that they can know when it ends but every time it makes them surprise by giving new values of different parameters. In this paper, support vector regression (SVR) and deep neural network method have been used to develop the prediction models. SVR employs the principle of a support vector machine that uses a function to estimate mapping from an input domain to real numbers on the basis of a training model and leads to a more accurate solution. The long short-term memory networks usually called LSTM, are a special kind of RNN, capable of learning long-term dependencies. And also is quite useful when the neural network needs to switch between remembering recent things, and things from a long time ago and it provides an accurate prediction to COVID-19. Therefore, in this study, SVR and LSTM techniques have been used to simulate the behaviour of this pandemic. Simulation results show that LSTM provides more realistic results in the Indian Scenario.

Are anterior urethral valve and anterior urethral diverticulum two separate entities: A radiological and endoscopic review.

BACKGROUND: Anterior urethral valve (AUV) and anterior urethral diverticulum (AUD) are two rare causes of anterior urethral obstruction with variable presentation and anatomy. Their existence as the same or different entity is still debatable, and management has not yet been standardized. OBJECTIVE: This study is a retrospective review of cases diagnosed with anterior urethral obstruction and correlation of radiological and endoscopic anatomy of AUV and AUD. STUDY DESIGN: A retrospective review of cases diagnosed with AUV and AUD, between May 2013 and February 2020 is presented. The presentation, laboratory, radiological and endoscopic anatomy along with the management required was reviewed. A special emphasis has been given on the correlation of radiological and endoscopic anatomy and an attempt has been made to standardize the management. RESULTS: A total of 8 patients with age ranging from 2 months to 9 years were reviewed. Poor urinary stream and recurrent UTI was the commonest presentation. The anatomy of the anterior urethra on VCUG (voiding cystourethrogram) and Urethrocystoscopy was correlated. Two sets of patients were identified. In the first set, five cases on endoscopy had findings of the classical valve-like fold in the anterior urethra with immediate proximal dilation of the urethra giving the appearance of a 'pseudodiverticula' without any definite opening. In three of these cases, endoscopic findings correlated well with radiological findings of 'pseudodiverticula' in which dilated proximal urethra formed an obtuse angle with the ventral floor of the urethra. The other set of four patients had a 'true diverticula' on endoscopy with a well-defined mouth and prominent distal lip, correlating well with radiological findings of a 'true diverticula' forming an acute angle with the ventral floor of the urethra. One case on endoscopy had both an anterior urethral valve with a proximal 'pseudodiverticula and a large wide-mouthed bulbar 'true diverticula'. All the patients with classical valves were successfully treated using a resectoscope while two patients with 'true diverticula' were successfully managed by incising the distal lip. One of the patients previously managed for the posterior urethral valve (PUV) had both classical valves in the anterior urethra with proximal 'pseudodiverticula' and a bulbar 'true diverticula'. The AUV was ablated with a resectoscope while 'true diverticula' required diverticulectomy. All the patients after follow up of 3 months-8 years, were asymptomatic except the one with 'true diverticulum' who remained symptomatic after TUR (Trans-urethral resection) and required vesicostomy. DISCUSSION: AUV and AUD both can cause obstructive uropathy. The proximal dilatation related to AUV cannot be labeled as a 'true diverticula', which lacks a classical orifice. The distal obstructing lip of 'true diverticula' should not be confused with a classical mucosal valve-like fold seen in AUV. While AUV and small AUD can be treated with endoscopic ablation, large diverticula as a result of wide spongiosal defects require surgical excision. A good understanding of their radiological and endoscopic anatomy is required to differentiate them and decide for appropriate management. CONCLUSION: Based on our experience, AUV and AUD should be differentiated and should be considered as two separate entities.

Phase II study of pembrolizumab and capecitabine for triple negative and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer.

BACKGROUND: Response rates to single agent immune checkpoint blockade in unselected pretreated HER2-negative metastatic breast cancer (MBC) are low. However, they may be augmented when combined with chemotherapy. METHODS: We conducted a single-arm, phase II study of patients with triple negative (TN) or hormone receptor-positive endocrine-refractory (HR+) MBC who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg intravenously day 1 and capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 of a 21-day cycle. The primary end point was median progression-free survival (mPFS) compared with historic controls and secondary end points were overall response rate (ORR), safety and tolerability. The study had 80% power to detect a 2-month improvement in mPFS with the addition of pembrolizumab over historic controls treated with capecitabine alone. RESULTS: Thirty patients, 16 TN and 14 HR+ MBC, were enrolled from 2017 to 2018. Patients had a median age of 51 years and received a median of 1 (range 0-6) prior lines of therapy for MBC. Of 29 evaluable patients, the mPFS was 4.0 (95% CI 2.0 to 6.4) months and was not significantly longer than historic controls of 3 months. The median overall survival was 15.4 (95% CI 8.2 to 20.3) months. The ORR was 14% (n=4), stable disease (SD) was 41% (n=12) and clinical benefit rate (CBR=partial response+SD>6 months) was 28% (n=8). The ORR and CBR were not significantly different between disease subtypes (ORR 13% and 14%, CBR 25% and 29% for TN and HR+, respectively). The 1-year PFS rate was 20.7% and three patients have ongoing responses. The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%) and diarrhea (3%), as well as grade 5 hepatic failure in a patient with liver metastases. CONCLUSIONS: Compared with historical controls, pembrolizumab with capecitabine did not improve PFS in this biomarker unselected, pretreated cohort. However, some patients had prolonged disease control. TRIAL REGISTRATION NUMBER: NCT03044730.

A Rare Association of Posterior Urethral Valve with Anterior Urethral Valve, Large Anterior Urethral Diverticula, and Glanular Hypospadias.

Background: Multiple urethral anomalies are rare with its own challenges in diagnosis and management. The double urethral obstructions are often missed as proximal obstruction can mask the early diagnosis of distal obstruction. We present a rare case of concomitant posterior urethral valve (PUV) and anterior urethral valve (AUV) with a large anterior urethral diverticula (AUD) and hypospadias. Case Presentation: An 11-month-old male child after fulguration of PUVs continued to have urinary symptoms. He was subsequently found to have distal urethral obstruction because of AUV and large anterior urethral bulbar diverticula. He also had associated glanular hypospadias. He was managed with endoscopic ablation of AUV and diverticulectomy. Conclusion: Concomitant PUV, AUV, AUD, and hypospadias is a rare occurrence. The diagnosis and management can be challenging in such cases with multiple anomalies. To avoid a misdiagnosis, a high index of suspicion, proper assessment of urethrogram, and detailed cystourethroscopy is required.

BCR-ABL1-like B-Acute Lymphoblastic Leukemia/Lymphoma: A Comprehensive Review.

CONTEXT.­: In the 2016 update of the World Health Organization (WHO) classification of hematopoietic neoplasms, BCR-ABL1-like B-acute lymphoblastic leukemia/lymphoma (B-ALL) is added as a new provisional entity that lacks the BCR-ABL1 translocation but shows a pattern of gene expression very similar to that seen in B-ALL with BCR-ABL1. OBJECTIVE.­: To review the kinase-activating alterations and the diagnostic approach for BCR-ABL1-like B-ALL. DATA SOURCES.­: We provide a comprehensive review of BCR-ABL1-like B-ALL based on recent literature and the 2016 update of the World Health Organization classification of hematopoietic neoplasms. CONCLUSIONS.­: Several types of kinase-activating alterations (fusions or mutations) are identified in BCR-ABL1-like B-ALL. The main categories are alterations in the ABL class family of genes, encompassing ABL1, ABL2, PDGFRB, PDGFRA (rare), and colony-stimulating factor 1 receptor (CSF1R) fusions, or the JAK2 class family of genes, encompassing alterations in JAK2, CRLF2, EPOR, and other genes in this pathway. These alterations determine the sensitivity to tyrosine kinase inhibitors. As a wide variety of genomic alterations are included in this category, the diagnosis of BCR-ABL1-like B-ALL is extremely complex. Stepwise algorithms and comprehensive unbiased testing are the 2 ways to approach the diagnosis of BCR-ABL1-like B-ALL.

Relationship of pathological features and a 21 gene expression assay in younger versus older women with node-negative endocrine receptor-positive breast cancer.

PURPOSE: Determining the need for adjuvant chemotherapy in estrogen receptor (ER)+ disease can be influenced by pathological characteristics and gene expression assays [i.e., Oncotype Dx recurrence scores (RSs)]. The primary objective of this study is to investigate the relationship between the RSs and pathological markers in younger (< 50) versus older (≥ 50) women with early-stage node-negative ER+ breast cancer. METHODS: This was a single academic-center retrospective cohort study. Subjects who underwent Oncotype gene expression testing were retrospectively and sequentially identified. 436 Subjects were identified of which 344 were eligible for analysis (133 younger subjects < 50 years of age, and 211 older subjects ≥ 50 years). Pathological data assessed included the progesterone receptor (PR), histological grade (grade), Ki-67, and P53. A multivariable regression analysis was performed using age, PR, and grade as predictor variables for RS. Adjusted R2 was determined. To investigate the primary objective, subjects were stratified based on age, PR, and grade status in that sequence. Within each tumor subtype as determined by PR and grade statuses, the RSs in the younger versus older age group were compared using Student's t-test and the differences in the 95% confidence interval limits in RS means calculated. Age influence on adjuvant chemotherapy recommendation was also assessed by stratifying subjects based on age (< 50 vs. ≥ 50) and then by RS risk group (≤ 10, 11-25, ≥ 26). Subsequently, the proportions of younger versus older subjects within identical RS risk groups who were explicitly advised by their oncologist to proceed with chemotherapy as documented in their electronic health records were compared using χ2 test. RESULTS: Based on the multivariable regression analysis, the adjusted R2 was 0.229232 and RS was found to be independent of age (p = 0.7169). Between younger and older subjects with tumors with similar PR and grade pathological features, the differences in the RS were insignificant (p > 0.05). Chemotherapy was recommended in younger versus older women, in 0% when the RS was ≤ 10, 39% and 40% when the RS was 11-25 (p = 0.82), and 100% and 98% when the RS was ≥ 26 (p = 0.51), respectively. CONCLUSIONS: The relationship between pathological features and RS is consistent irrespective of age; therefore, models predicting RS may be applicable irrespective of age.

Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy.

PURPOSE: Activation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC. METHODS: Patients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan-Meier method. RESULTS: Seventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months. CONCLUSIONS: The combination of alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results.