Bi-allelic loss of function variants in GOLGA2 are associated with a complex neurological phenotype: Report of a second family.

GOGLA2/GM130 is a Golgin protein involved in vesicle tethering, cell proliferation and autophagy. Recessive loss of function mutation in GOLGA2 has been previously reported in a single family with muscular dystrophy and microcephaly. Here we describe a second consanguineous family with the bi-allelic loss of function mutations in GOLGA2. The patient exhibits microcephaly, seizures, and myopathy similar to the previously reported patient with GOLGA2 mutation. This report supports the critical developmental requirement of GOLGA2 and emphasizes a similar and severe clinical presentation with loss of function mutations in affected patients.

Validation and Implementation of a Somatic only Tumor Exome for Routine Clinical Application.

Next generation sequencing based genomic testing is standard of care for tumor workflows. However, its application across different institutions continues to be challenging given the diversity of needs and resource availability amongst different institutions globally. Moreover, the use of a variety of different panels including those from a few individual genes to those involving hundreds of genes results in a relatively skewed distribution of care for patients. It is imperative to obtain a higher level of standardization without having to be restricted to specific kits or require repeated validations which are generally expensive. We show the validation and clinical implementation of the DH-CancerSeq assay, a tumor only whole exome based sequencing assay with integrated informatics while providing similar input requirements, sensitivity and specificity to a previously validated targeted gene panel while also maintaining similar turnaround times for patient care.

Chondrolipoma of the Breast: A Myofibroblastoma Variant or a Distinct Lesion?

The entity commonly referred to as chondrolipoma is a rare and enigmatic breast lesion with unclear histogenesis and a complete lack of molecular characterization. It is uncertain whether it represents a hamartoma, choristoma, or a distinct neoplasm, including possibly a variant of mammary-type myofibroblastoma. We report two additional chondrolipomatous lesions of the breast. The lesions had varying histologic and immunohistochemical features similar to myofibroblastoma, including the loss of retinoblastoma (Rb) protein expression in one lesion. Molecular analysis by chromosomal microarray analysis performed on a second lesion did not demonstrate a loss of 13q14 or 16q typical of myofibroblastoma. Our findings further support the concept that at least a subset of breast lesions that historically have been classified as chondrolipoma are related to myofibroblastoma. However, the lack of myofibroblastoma-specific molecular alterations in one lesion suggests chondrolipomas may also have varying origins.

Chimeric Antigen Receptor T-Cells in Indolent Lymphoma, Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia.

The advent of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of several hematological malignancies. Although the initial benefit was mainly observed in aggressive leukemias and lymphomas, recent data have resulted in the approval of multiple CAR-T therapies in indolent lymphomas, with ongoing research showing great promise for further improvements and therapeutic optimizations. In this article, we review the published data and approved therapies for CAR-T cell therapy for indolent lymphomas focusing on mantle cell lymphoma and follicular lymphoma while describing the work in chronic lymphocytic leukemia and future strategies.

Full metal jacket stenting of the superficial femoral artery: a retrospective review.

BACKGROUND: The technique of long segment stenting of the superficial femoral artery (SFA) has been associated with poorer short- and long-term results. The full metal jacket (FMJ) stenting is typically described as long segment continuous stenting of a vessel segment. Initially, this technique was described in percutaneous coronary interventions. However, until recently, FMJ of the SFA has not been studied. We examined our experience with FMJ of the SFA to evaluate the outcomes and the safety of this technique. METHODS: Retrospective data were gathered for peripheral angioplasties and stenting for the period between January 2005 and December 2008. The cases involving FMJ stenting of the SFA were identified by angiographic findings and the operative dictations providing the stent data. Selective FMJ stenting of the SFA was performed for the residual stenosis after balloon angioplasty of the SFA because of either dissection or significant recoil. The cases with concomitant iliac artery angioplasty and/or stenting were excluded from the data set for analysis. The variables for the evaluation were primary patency rate, mortality rate, and limb salvage rate, which were stratified on the basis of the risk factors. RESULTS: A total of 63 cases involving FMJ stenting of the SFA were identified from the database of 707 patients who had peripheral endovascular interventions between January 2005 and December 2008. Average age of the patients was 70 years (range: 52-104 years, SD: 10.1 years). There were no transatlantic inter-society consensus (TASC) A lesions, 11% (7/63) of the lesions were TASC B, 68% (43/63) were TASC C, and 21% (13/63) were TASC D. The median primary patency rate was 9 months (95% CI: 5.06-12.94). The mortality rate was 4% at 6-month follow-up. The limb salvage rate was 85.7%. In all, 65% (41/63) of the patients were claudicants, whereas 23% (15/63) had intervention for some form of tissue loss (ischemic ulcer, gangrene). Associated infrapopliteal intervention was performed in 15.9% of the patients. Average creatinine level was 1.67 (range: 0.7-10.9, SD: 2.03) and 49% (31/63) of the patients had diabetes. The average 6-month patency rate was 55% (SD: 0.5). Multivariate logistic regression analysis showed that diabetes (OR: 0.33, p = 0.044, 95% CI: 0.11-0.97) and a creatinine level of ≥1.6 (OR: 0.16, p = 0.038, 95% CI: 0.03-0.9) were the independent risk factors for loss of patency in <6 months. CONCLUSION: Our experience suggests promising results for the technique of FMJ of the SFA and also that further examination of the technique is warranted.

Spontaneous recanalization of an occluded internal carotid artery.

Recanalization after extracranial internal carotid artery (ICA) occlusion is a rare phenomenon and the natural history of the disease is largely unknown. There have been few cases reported in the published data, including early recanalization after a cerebrovascular accident (CVA). We report a case of a 74-year-old man who presented with a CVA and a history of multiple CVAs in the past, the last episode being a year ago. Multiple imaging modalities, including duplex scans, computerized tomographic angiograms, and fluoroscopy-guided angiogram of bilateral carotid arteries, showed occlusion of the left ICA in the past. The duplex scan performed 8 months later demonstrated late spontaneous recanalization of the occluded left ICA. The patient underwent successful carotid endarterectomy. The pathophysiology, natural history, and possible surveillance strategy are discussed in this case report.

Single-day HER2neu amplification assessment using chip-based digital PCR in formalin-fixed paraffin-embedded breast carcinoma tissue.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) amplification is present in almost 15%-20% of breast cancer tumors, making it an important parameter for testing. The present study was designed to evaluate a chip-based digital PCR (dPCR) system for assessing HER2 amplification from formalin-fixed paraffin-embedded breast carcinoma tissue and to compare this system with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). MATERIALS AND METHODS: A total of 84 breast carcinoma tissue samples were analyzed by IHC, FISH, and chip-based dPCR in a blinded manner. RESULTS: All nine IHC-positive and 35 IHC-negative samples had equivalent results with dPCR, taking an amplification ratio threshold of 1.8 as a positive result. Of the 40 IHC equivocal samples, 10 were assessed as positive, 27 as negative, and three as equivocal by dPCR. CONCLUSION: These results demonstrate that chip-based dPCR is suitable for HER2 amplification detection in formalin-fixed paraffin-embedded samples in a clinical setting, providing the advantages of superior turnaround time, cost-effectiveness, and increased precision with absolute quantification compared with conventional tests such as FISH and IHC. This methodology was especially beneficial in tissue samples with low DNA concentration.

Mutation analysis of BRCA1/2 mutations with special reference to polymorphic SNPs in Indian breast cancer patients.

BACKGROUND: Germline mutations BRCA1 and BRCA2 contribute almost equally in the causation of breast cancer (BC). The type of mutations in the Indian population that cause this condition is largely unknown. PURPOSE: In this cohort, 79 randomized BC patients were screened for various types of BRCA1 and BRCA2 mutations including frameshift, nonsense, missense, in-frame and splice site types. MATERIALS AND METHODS: The purified extracted DNA of each referral patient was subjected to Sanger gene sequencing using Codon Code Analyzer and Mutation Surveyor and next-generation sequencing (NGS) methods with Ion torrent software, after appropriate care. RESULTS: The data revealed that 35 cases were positive for BRCA1 or BRCA2 (35/79: 44.3%). BRCA2 mutations were higher (52.4%) than BRCA1 mutations (47.6%). Five novel mutations detected in this study were p.pro163 frameshift, p.asn997 frameshift, p.ser148 frameshift and two splice site single-nucleotide polymorphisms (SNPs). Additionally, four nonsense and one in-frame deletion were identified, which all seemed to be pathogenic. Polymorphic SNPs contributed the highest percentage of mutations (72/82: 87.8%) and contributed to pathogenic, likely pathogenic, likely benign, benign and variant of unknown significance (VUS). Young age groups (20-60 years) had a high frequency of germline mutations (62/82;75.6%) in the Indian population. CONCLUSION: This study suggested that polymorphic SNPs contributed a high percentage of mutations along with five novel types. Younger age groups are prone to having BC with a higher mutational rate. Furthermore, the SNPs detected in exons 10, 11 and 16 of BRCA1 and BRCA2 were higher than those in other exons 2, 3 and 9 polymorphic sites in two germline genes. These may be contributory for BC although missense types are known to be susceptible for cancer depending on the type of amino acid replaced in the protein and associated with pathologic events. Accordingly, appropriate counseling and treatment may be suggested.

Prenatal Screening for Rare Co-Inheritance of HbE and ß-Thalassaemia Traits in Western India.

The mutations in Haemoglobin Beta (HBB) gene, bring about less or no production of Hb ß-chain synthesis in affected cases, leading from minor to major types depending on haematological indices. In compound heterozygotic conditions, two traits are involved, in which one parent has HbE trait and the other has ß-thalassaemia carrier (trait). Here, we report a family of Rajasthan, West India which had a proband (son) having HbE/ ß-thalassaemia a co-inherited compound heterozygosity as revealed by DNA sequencing. It also contained upper levels of HbE with altered Hb and red cell indices showing asymptomatic to symptomatic state requiring blood transfusion periodically. The parents and Chorionic Villus Sampling (CVS) were HbE and ß-thalassaemia traits only. Such case is rare in Western India and we recommend this family for genetic counseling and genetic testing before they want reproductive choices in future for better management in a society.

Mutation analysis of ß-thalassemia in East-Western Indian population: a recent molecular approach.

BACKGROUND: ß-Thalassemia is the most prevalent genetic disorder in India. Its traits and coinheritance vary from mild to severe conditions, resulting in thalassemia minor, intermediate, and major, depending upon many factors. PURPOSE: The objective of this study was to identify the incidence of ß-thalassemia traits, their coinheritance, and mutations, as well as to support the patients already diagnosed with ß-thalassemia in East-Western Indian population for better management. PATIENTS AND METHODS: Seventy-five referral cases for ß-thalassemia were analyzed for various ß-thalassemia traits, heterozygosity, and homozygosity conditions. Blood phenotypic parameters using cell counter and capillary electrophoresis were investigated. Analyses of eight common mutations of thalassemia in India were carried out using polymerase chain reaction-amplification refractory mutation system, end point polymerase chain reaction, and DNA sequencing methods. RESULTS: Of these (75) referral cases from East-Western Indian region, 68 were positive for ß-thalassemia (90.67%). The majority of case types were of ß-thalassemia minor (49, 65.33%), followed by HbE traits (6, 8.0%) and ß-thalassemia major, including heterozygous and homozygous (5, 6.66%; 4, 5.33%) types and then HbE homozygous (2, 2.66%), as well as one each of the HbE/ß-thalassemia and HbD/ß-thalassemia (1, 1.34%) combination. Mutation analysis also revealed that the highest frequency of mutation was c.92+5G>C (41, 60.29%) followed by deletion 619bp (9, 13.23%) and c.79G>A (8, 11.76%) in our study group. Five cases (nos. 24, 27, 33, 58, and 71) exhibited coinheritance between ß0/ß+ (2), ß0/ß D (1), and c.124_127delTTCT/ß+ or ß0(2) affecting the Rajasthani and Gujarati populations in our study of the Western region of India. CONCLUSION: We strongly recommend these Western populations for genetic screening before adopting reproductive technologies and interracial marital relations.

Chronic obstructive pulmonary disease and cardiac comorbidities: A cross-sectional study.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a global health issue with cigarette smoking being an important risk factor. COPD affects pulmonary blood vessels, right ventricle, as well as left ventricle leading to the development of pulmonary hypertension (PH), cor-pulmonale (COR-P), right and left ventricular dysfunction. Echocardiography provides a rapid, noninvasive, portable, and accurate method to evaluate cardiac functions. Early diagnoses and intervention for cardiac comorbidities would reduce mortalities. MATERIALS AND METHODS: A cross-sectional study. Total 50 patients of moderate to severe COPD according to GOLD guidelines were taken from Department of Respiratory Medicine, Smt. B. K. Shah Medical Institute and Research Centre, Vadodara. All patients underwent investigations such as chest X-ray PA view, ECG, and spirometry followed by two-dimensional echocardiography. RESULTS: We investigated 49 males and 1 female patients ranging from 35 to 80 years of age. Twenty-nine individuals were of moderate COPD and twenty-one of severe COPD. Of these cases 29 had left ventricular diastolic dysfunction (LVDD) changes, 24 were diagnosed with PH and 16 had changes of COR-P. The study showed the linear relation between the severity of LVDD, PH, and COR-P with the severity of COPD. CONCLUSION: Our study put emphasis on early cardiac screening of all COPD patients which will be helpful in the assessment of the prognosis and will further assist in identifying the individuals likely to suffer increase morbidity and mortality.

Bronchial venous plexus in left ventricular dysfunction.

Chronic pulmonary venous hypertension causes dilatation and engorgement of bronchial veins because of a close communication between bronchial and pulmonary veins. We report a case of severe left ventricular systolic dysfunction with chronically elevated pulmonary venous pressure leading to characteristic bronchoscopic findings of engorgement of bronchial veins.