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.

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.

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.

Impact of tissue-based genomic profiling on clinical decision making in the management of patients with metastatic breast cancer at academic centers.

BACKGROUND: Genomic profiling can identify targetable mutations; however, the impact of tissue-based genomic profiling on clinical decision making for patients with metastatic breast cancer has not been well characterized. METHODS: Patients with stage IV breast cancer who had undergone genomic profiling between 7/2013 and 3/2015 were identified at three academic cancer centers. Genomic analysis was determined to have impacted clinical decision if (A) a patient was enrolled onto a genotype-matched clinical trial or (B) prescribed off-label an FDA-approved therapy targeting an identified mutation. The frequency of mutated genes was determined. RESULTS: A total of 117 patients with stage IV breast cancer were identified. Median age was 46 (25-75). Fifty-three patients (45%) had ER-positive/HER2-negative disease, 50 (43%) had ER-negative/HER2-negative disease, and 14 (12%) had ER-any/HER2-positive disease. Median number of previous therapies received prior to genomic profiling was 2 (range 0-15), and median follow-up after testing was obtained after 5.8 months (range 0-24.4 months). Commercial reports indicated that 85 (73%) patients had at least one mutation targetable by an FDA-approved medication, and 112 (96%) patients had at least one clinical trial available; however, clinical management was only affected in 11 patients (9%). The most frequent mutations observed were those in TP53, FGF, PI3KCA, MYC, ZNF, FGFR, CCND, ARID1A, GATA3, and MAP; frequencies of these mutations varied by clinical subtype. CONCLUSIONS: Tumor genomic profiling affected clinical management in a minority of patients with metastatic breast cancer, thus these data do not support the routine use of genomic profiling outside of a clinical trial.

Severe Pediatric Acute Respiratory Distress Syndrome Due to Scrub Typhus: Successful Ventilation with Airway Pressure Release Ventilation Mode after Becoming Refractory to Protective Ventilation.

Scrub typhus can affect lungs from mild illness like pneumonitis to a severe illness like acute respiratory distress syndrome (ARDS). Such patients may be very challenging to treat when their hypoxemia becomes severe and refractory to treatment. Main treatment is supportive in terms of mechanical ventilation. In adult ARDS, low tidal volume (TV) ventilation has been recommended, but there is no consensus on most effective ventilation mode in children. We present a case of a 12-year-old girl who developed severe ARDS (PO2/FiO2 ratio - 58), refractory to low TV ventilation. There was a rapid improvement in oxygenation on the application of airway pressure release ventilation (APRV) mode within ½ h. She was successfully ventilated and weaned off the ventilator over 5 days. This case highlights the utility of APRV mode of ventilation as a rescue therapy for severe refractory ARDS in children.

Management of Metastatic HER2-Positive Breast Cancer: Where Are We and Where Do We Go From Here?

Human epidermal growth factor receptor 2 (HER2)/neu-positive breast cancer has changed from being an aggressive disease with a poor prognosis to a disease that is highly treatable, with prolonged survival possible even in patients with metastatic disease. A better understanding of HER2 biology has led to the development of powerful targeted therapies, and four drugs are already approved by the US Food and Drug Administration for treatment in the metastatic setting (trastuzumab, pertuzumab, lapatinib, and trastuzumab emtansine). Optimizing how these drugs are delivered and in what sequence is an important part of modern management of HER2-positive breast cancer. However, while the prognosis has improved, metastatic disease is still not curable; newer, better drugs are needed. This review will summarize the current standard of care; key issues that arise when treating patients with HER2-positive disease; and developments in novel therapeutics, including small-molecule inhibitors, nanoparticles, immunotherapy, and agents targeting resistance pathways.

Invasive pulmonary mycosis due to Chaetomium globosum with false-positive galactomannan test: a case report and literature review.

In this case, the authors report Chaetomium globosum as a cause of invasive pulmonary infection in a patient with Wegener's granulomatosis. Fungal hyphae (KOH and Calcofluor) were seen on direct microscopy of lung biopsy sample and bronchoalveolar lavage (BAL) sample. C. globosum isolated on culture clinched the diagnosis of invasive pulmonary infection by Chaetomium spp. A positive galactomannan of serum and BAL was repeatedly seen and was utilised for follow-up and as prognostic marker in patient management. The patient was successfully treated with liposomal amphotericin B followed by voriconazole. All the Chaetomium infections reported till date since 1980 are reviewed. Chaetomium spp. with its unique ecology has a hidden clinical potential to cause invasive mould infections.

Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579).

The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m(2) day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (P = 0.0024) and HR deficiency status (P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (P = 0.020), nuclear CDK4 (P = 0.0030), and nuclear Smad3 (P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population.

The Role of Ovarian Suppression in Premenopausal Women With Hormone Receptor-Positive Early-Stage Breast Cancer.

The optimal adjuvant endocrine therapy in premenopausal women with early-stage breast cancer is yet to be elucidated. Studies have demonstrated that women who experience cessation of ovarian function after chemotherapy (chemotherapy-induced amenorrhea) may experience improved survival. These findings, however, have not been replicated when pharmacologic or surgical interventions have been used to stop ovarian function (eg, gonadotropin-releasing hormone agonists, oophorectomy, or ovarian irradiation) in combination with an endocrine agent such as tamoxifen or an aromatase inhibitor. Recent large phase III clinical trials, including the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG-12), Suppression of Ovarian Function Trial (SOFT), and Tamoxifen and Exemestane Trial (TEXT), did not demonstrate an improvement in disease-free survival with ovarian suppression in the overall population. However, subgroup analyses suggest that women at high risk for recurrence, including very young women or those who have received chemotherapy, may benefit from the addition of ovarian suppression. Still, toxicity and adverse effects on patient-reported outcomes were more frequent in patients who received ovarian suppression; these included more menopausal and sexual dysfunction symptoms, diabetes, hypertension, and osteoporosis. This review will summarize the experience with ovarian suppression in the adjuvant setting for the treatment of premenopausal early-stage breast cancer and offer recommendations for clinical management.

The application of Oncotype DX in early-stage lymph-node-positive disease.

The recurrence score derived from the 21-gene Oncotype DX assay is both prognostic and predictive of adjuvant chemotherapy benefit in node-negative, estrogen-receptor-positive breast cancer patients treated with tamoxifen. This has led to a remarkable shift in the treatment paradigm, with a sizeable number of patients being able to avoid adjuvant chemotherapy. The recurrence score was then analyzed in a large retrospective study with node-positive, estrogen-receptor-positive patients, in which it demonstrated both prognostic and predictive abilities. This review introduces the clinical trials that validated the Oncotype DX assay in the node-negative population, highlights the studies evaluating the utility of the assay in node-positive patients, examines the impact of the assay results on treatment decisions, and discusses the health outcomes and health care expenditures associated with this assay.

A Cross Attention Approach to Diagnostic Explainability Using Clinical Practice Guidelines for Depression.

The lack of explainability in using relevant clinical knowledge hinders the adoption of artificial intelligence-powered analysis of unstructured clinical dialogue. A wealth of relevant, untapped Mental Health (MH) data is available in online communities, providing the opportunity to address the explainability problem with substantial potential impact as a screening tool for both online and offline applications. Inspired by how clinicians rely on their expertise when interacting with patients, we leverage relevant clinical knowledge to classify and explain depression-related data, reducing manual review time and engendering trust. We developed a method to enhance attention in contemporary transformer models and generate explanations for classifications that are understandable by mental health practitioners (MHPs) by incorporating external clinical knowledge. We propose a domain-general architecture called ProcesS knowledgeinfused cross ATtention (PSAT) that incorporates clinical practice guidelines (CPG) when computing attention. We transform a CPG resource focused on depression, such as the Patient Health Questionnaire (e.g. PHQ-9) and related questions, into a machine-readable ontology using SNOMED-CT. With this resource, PSAT enhances the ability of models like GPT-3.5 to generate application-relevant explanations. Evaluation of four expert-curated datasets related to depression demonstrates PSAT's applicationrelevant explanations. PSAT surpasses the performance of twelve baseline models and can provide explanations where other baselines fall short.

New clonal strain of Candida auris, Delhi, India.

A new clonal strain of Candida auris is an emerging etiologic agent of fungemia in Delhi, India. In 12 patients in 2 hospitals, it was resistant to fluconazole and genotypically distinct from isolates from South Korea and Japan, as revealed by M13 and amplified fragment length polymorphism typing.

Frequency of fungal isolation and antifungal susceptibility pattern of the fungal isolates from nasal polyps of chronic rhinosinusitis patients at a tertiary care centre in north India.

Sinonasal polyposis is considered to be the end-result of a chronic inflammatory process in the sinonasal mucosa. Its underlying mechanisms are still unclear, but the involvement of fungi has been suggested for many years. In the present study, we retrospectively evaluated the clinical and mycological profile of 161 patients with chronic rhinosinusitis (CRS) and nasal polyps who were undergoing surgery at our tertiary care facility during 2002 to 2010. CT scan findings and per-operative presence of allergic mucin were provisionally suggestive of fungal rhinosinusitis (FRS) in all the patients. Total serum IgE and peripheral eosinophilia were noted. Histological examination of polyp tissue showed eosinophilic mucin in 100% of the cases and the incidence of allergic fungal rhinosinusitis (AFRS) was 83.9% in the patient population. KOH and/or culture were positive for fungal hyphae or yeast in 93% (150/161) of the patients. Aspergillus spp. were the most commonly recovered isolates (70%). MICs of all A. flavus and A. fumigatus isolates were within the susceptible zone for itraconazole, voriconazole, and amphoterecin B. In conclusion, allergic fungal rhinosinusitis (FRS) is a common disorder in patients with sinonasal polyposis and due to its recurrent and intractable nature, a high degree of clinical suspicion for the presence of FRS in nasal polyposis should be considered.

Blastomycosis in India: report of an imported case and current status.

We report a case of disseminated blastomycosis in a female resident of Delhi, who acquired the infection during travel to the USA, which was successfully treated with oral itraconazole. In addition, we present a critical literature review, indicating that blastomycosis is endemic in India but its areas of endemicity, prevalence, and the natural habitat of the etiologic agent, remain undetermined. The diagnosis of blastomycosis was made by examination of Gomori's methenamine silver stained sections of tissue obtained from a biopsy of a subcutaneous, abdominal nodular. These studies revealed thick-walled, broad-based budding yeast cells compatible with Blastomyces dermatitidis, and consistent with the isolation of the fungus in cultures inoculated with posterior auricular lymph node aspirate. Microscopically, the isolate had thin, septate hyphae and characteristic spherical to pyriform, smooth-walled microconidia. Its identity was confirmed by conversion to its typical yeast form on pea seed agar at 37°C and by DNA sequencing of ITS and BAD 1 promoter regions.

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.

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.

Incremental increase in VEGFR1⁺ hematopoietic progenitor cells and VEGFR2⁺ endothelial progenitor cells predicts relapse and lack of tumor response in breast cancer patients.

Animal models have demonstrated the critical role of bone marrow-derived VEGFR1(+) hematopoietic progenitor cells (HPCs) and VEGFR2(+) endothelial progenitor cells (EPCs) in metastatic progression. We explored whether these cells could predict relapse and response in breast cancer (BC) patients. One hundred and thirty-two patients with stages 1-4 BC were enrolled on 2 studies. Circulating CD45(+)/CD34(+)/VEGFR1(+) HPCs and CD45(dim)/CD133(+)/VEGFR2(+) EPCs were assessed from peripheral blood mononuclear cells using flow cytometry. Changes in HPCs and EPCs were analyzed in (1) patients without overt disease that relapsed and (2) metastatic patients according to response by RECIST. At study entry, 102 patients were without evidence of disease and 30 patients had metastatic BC. Seven patients without evidence of BC by exam, labs, and imaging developed recurrence while on study. Median HPC/ml (range) increased from 645.8 (23.5-1,914) to 2,899 (1,176-37,336), P = 0.016, followed by an increase in median EPC/ml from 21.3 (4.7-42.5) to 94.7 (28.2-201.3), P = 0.016, prior to clinical relapse. In metastatic patients with progressive disease, median HPC/ml increased from 1,696 (10-16,470) to 5,124 (374-77,605), P = 0.0009, and median EPC/ml increased from 26 (0-560) to 71 (0-615) prior to progression, P = 0.10. In patients with responding disease, median HPC/ml decreased from 6,147 (912-85,070) to 633 (47-18,065), P = 0.05, and EPC/ml decreased from 46 (0-197) to 23 (0-105), P = 0.41, at response. There were no significant changes in these cells over time in patients with stable disease. Circulating bone marrow-derived HPCs and EPCs predict relapse and disease progression in BC patients.