Clinical Spectrum of Celiac Disease among Adult Population: Experience from Largest Tertiary Care Hospital in Karachi, Pakistan.

Introduction: Celiac disease (CD) is a systemic autoimmune enteropathy triggered by dietary gluten in genetically susceptible individuals. Celiac disease affects 0.6-1.0% of the population worldwide. The prevalence of CD in Pakistan is yet unknown due to under diagnosis and lack of awareness. Objective: To determine a vast variety of presenting features in subtypes of CD to overcome the burden of disease. Materials and methods: This was a prospective, comparative, cross-sectional study conducted at Gastroenterology department of Jinnah Postgraduate Medical Center, Karachi from December 2022 till June 2023. This study included all adult patients ≥18 years diagnosed with CD on the basis of clinical presentation, positive IgA and IgG anti-transglutaminase antibodies (value >12 IU/mL detected by ELISA followed by small intestinal biopsy classified as per Marsh criteria. The data obtained were analyzed on the statistical software SPSS version 23. Descriptive statistics were obtained by frequencies and percentages. Results: About 142 patients were enrolled in the study, 103 (91.5%) had classical CD (CCD) whereas 36 (25%) had non-classical (NCCD). About 89 (62.7%) were females and 53 (37.3%) were males. The mean age was found to be 23 ± 6 years. Nutritional deficiencies including anemia, B12, folate, osteopenia and low body mass index (BMI) <18 was found more in CCD group as compared with NCCD group with significant p-values. Titers of anti-TTG between CCD and NCCD were not statistically significant. Hypothyroidism and PCOS were the most common associated conditions observed in adult CD patients. Conclusion: In conclusion, CD in adults and has diverse presentations. Adults with unexplained extra-intestinal symptoms like anemia and bone pain should be investigated for CD. How to cite this article: Butt N, Shahid B, Butt S, et al. Clinical Spectrum of Celiac Disease among Adult Population: Experience from Largest Tertiary Care Hospital in Karachi, Pakistan. Euroasian J Hepato-Gastroenterol 2024;14(1):24-29.

Reliability and Variability of Ki-67 Digital Image Analysis Methods for Clinical Diagnostics in Breast Cancer.

Ki-67 is a nuclear protein associated with proliferation, and a strong potential biomarker in breast cancer, but is not routinely measured in current clinical management owing to a lack of standardization. Digital image analysis (DIA) is a promising technology that could allow high-throughput analysis and standardization. There is a dearth of data on the clinical reliability as well as intra- and interalgorithmic variability of different DIA methods. In this study, we scored and compared a set of breast cancer cases in which manually counted Ki-67 has already been demonstrated to have prognostic value (n = 278) to 5 DIA methods, namely Aperio ePathology (Lieca Biosystems), Definiens Tissue Studio (Definiens AG), Qupath, an unsupervised immunohistochemical color histogram algorithm, and a deep-learning pipeline piNET. The piNET system achieved high agreement (interclass correlation coefficient: 0.850) and correlation (R = 0.85) with the reference score. The Qupath algorithm exhibited a high degree of reproducibility among all rater instances (interclass correlation coefficient: 0.889). Although piNET performed well against absolute manual counts, none of the tested DIA methods classified common Ki-67 cutoffs with high agreement or reached the clinically relevant Cohen's κ of at least 0.8. The highest agreement achieved was a Cohen's κ statistic of 0.73 for cutoffs 20% and 25% by the piNET system. The main contributors to interalgorithmic variation and poor cutoff characterization included heterogeneous tumor biology, varying algorithm implementation, and setting assignments. It appears that image segmentation is the primary explanation for semiautomated intra-algorithmic variation, which involves significant manual intervention to correct. Automated pipelines, such as piNET, may be crucial in developing robust and reproducible unbiased DIA approaches to accurately quantify Ki-67 for clinical diagnosis in the future.

Accuracy of genotype MTBDRplus line probe assay in patients with tuberculous pleural effusion: comparison with clinical and culture based diagnosis.

Background: Pleural tuberculosis (TB) diagnosis is challenging due to paucibacillary disease. Diagnostic accuracy of GenoType MTBDRplus Line Probe Assay (MTBDRplus) has been evaluated in this study for pleural TB diagnosis.Objective: To evaluate diagnostic accuracy of MTBDRplus for pleural TB diagnosis compared to clinical and microbiological diagnosis.Methods: This prospective study was conducted at the Aga Khan University, Pakistan. Pleural fluid from 203 suspected pleural TB patients was collected and tested for smear, culture and MTBDRplus. Diagnostic accuracy of MTBDRplus was determined using clinical diagnosis and culture as the gold standard.Results: Out of 203 TB suspect patients, MTBDRplus, culture and smear were positive in 14 (6. 9%), 27 (13.3%) and 4 (1.9%) cases, respectively. A total of 106/203 patients (27 culture positive and 79 culture negative) successfully completed TB treatment. Considering clinical diagnosis as gold standard, sensitivity of MTBDRplus was 13.2%; 95% CI (7.4-21.2%) and specificity was 100%; 95% CI (96.1-100%). The sensitivity and specificity of MTBDRplus in culture positive samples were 44.4%; 95% CI (25.5-64.7%) and 98.9%; 95% CI (95.9-99.9%), respectively. Excluding indeterminate results, MTBDRplus accurately detected isoniazid sensitivity in 5/6 and rifampicin sensitivity in 6/6 cases.Conclusion: MTBDRplus had a low sensitivity of 13.2% in clinically diagnosed and 44% in culture-confirmed pleural TB patients and therefore could not be included in most diagnostic algorithms. Due to a higher sensitivity than smear, MTBDRplus may have a role in tuberculous pleural effusion diagnosis if it is positive pending culture results and pleural biopsy.

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma.

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.

Accuracy of Specimen Radiography in Assessing Complete Local Excision with Breast-Conservation Surgery

Objective: The aim of this study was to evaluate the accuracy of "X- ray examination of surgically resected specimen'' in assessing complete local excision (CLE). Materials and Methods: In this retrospective cross sectional study, data were collected for all female breast cancer cases who underwent breast-conserving surgery after needle localization of mammographically visible disease. Males, patients with mammographically invisible disease and cases with benign or inconclusive histopathology, those undergoing modified radical mastectomy and individuals with dense breast parenchyma were excluded. We evaluated radiography of resected specimens to assess margin spiculation, distance of mass/microcalcification from the excised margin, presence of a mass, and presence of any adjacent microcalcification, Other features including mass size, nuclear grade and patient's age were also recorded and all were analyzed for any association with CLE. Results: Absence of adjacent microcalcification and the presence of a mass on radiographs showed significant associations with CLE, but no links were evident with other features. Specimen radiography was found to be a sufficient tool to predict CLE with a positive predictive value of 83.3%, a sensitivity of 80.7% and a specificity of 81%. Conclusion: Specimen radiography is an important and sensitive tool to predict CLE.

Evaluation of Common Risk Factors for Breast Carcinoma in Females: a Hospital Based Study in Karachi, Pakistan.

BACKGROUND: Breast malignancies are one of the leading causes of deaths in females worldwide. There are a number of risk factors associated with breast cancer but in Karachi Pakistan there are insufficient data available. MATERIALS AND METHODS: A case control study was conducted on females in age group between 30-80 years. This study was accomplished by retrospective data collection in Aga Khan University Hospital Karachi, Pakistan. A total of 108 females with primary malignancy of breast were included along with 108 matched controls. Relationship of various factors with disease was studied using logistic regression to calculate odds ratios with 95 % confidence intervals. RESULTS: A total of 14 variables were analyzed and based on and 7 were found to be risk factors: old age, family history of breast cancer, family history of other carcinomas, personal history of breast carcinoma, early age of menarche, older age of mother at first delivery and lower number of children. Five factors, parity, breast feeding, history of oral contraceptive pills intake, past history of oophorectomy and hysterectomy showed protective associations. One variable, use of hormonal replacement therapy, showed a controversial link and one other, marital status, was not significant in this study. CONCLUSIONS: It is concluded that most of the well-known risk factors for breast cancer are also associated with the disease in the female population of Karachi, Pakistan. High risk patients should be the focus with the help of this study so that screening can be more effective for early diagnosis before clinically evident breast malignancy.