Lahore Medical and Dental College

Age-related proliferation of indeterminate capacity hematopoietic stem and progenitor cells bearing somatic mutations, mainly in DNMT3A, TET2, and ASXL1, is referred to as clonal hematopoiesis of indeterminate potential (CHIP). In addition to the well-known premalignant effects, CHIP causes systemic effects and predisposes to cardiovascular disease, thromboembolism, and dysfunction of multiple organs. Mutant neutrophils have been increasingly recognized as contributors to this pathology. These cells exhibit aberrant phenotypes and epigenetic alterations associated with pro-inflammatory and pro-thrombotic phenotypes that may favor NET formation. Uncontrolled NETosis may promote endothelial damage, platelet aggregation, and microvascular thrombosis that creates a vicious loop of thromboinflammation. The association of CHIP-related NETosis with venous and arterial thromboses, ischemic stroke, myocardial infarction, and organ-specific damage has been reported, although the main contribution is largely referred from indirect biomarker-based evidence or extrapolation from related conditions. Instead of detecting NET production directly, several studies employ indirect NET markers (such as MPO-DNA, citH3, and cfDNA). Activation of PAD4, generation of reactive oxygen species and inflammatory cytokines are the main modulators implicated in mechanistic studies. Clinically, therapies against NETs using DNase, PAD4, or cytokine blockade have the potential to reduce the risk of thromboinflammation. Although supported by compelling preclinical and observational evidence, there are still challenges because of the use of retrospective studies, murine models, and indirect measure of NET.The current evidence base consists primary of preclinical (murine and in vitro) studies along with observational human data. Future studies are required on prospective trials, mutation-directed biomarkers, and precision medicine modalities to regulate mutant neutrophil functions. Insight into NET-mediated pathogenesis in CHIP does not just clarify the pathways between clonal hematopoiesis and thromboinflammation and dysfunction in the body but also provides opportunities to formulate specific solutions to decrease cardiovascular and systemic illnesses in victims.

BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options, primarily relying on chemotherapy, yet often leading to recurrence due to chemoresistance. Cancer stem cells (CSCs) contribute to tumor heterogeneity, resistance, and poor prognosis, but data in Pakistani populations are scarce. This study hypothesizes that a positive CSC phenotype independently predicts reduced pathological complete response (pCR) and inferior survival outcomes. AIM To investigate CSC markers' association with chemotherapy response and survival in Pakistani TNBC patients. METHODS Retrospective cohort study at Institute of Radiotherapy and Nuclear Medicine, Peshawar, Pakistan, including 256 women with TNBC from January 2015 to December 2022. CSC markers (CD44 high, CD24 low, aldehyde dehydrogenase 1 positive) were assessed via immunohistochemistry on pre-treatment biopsies. Outcomes: pCR to neoadjuvant chemotherapy, overall survival, disease-free survival. Data were analyzed with multivariable logistic regression and Cox proportional hazards models, adjusting for age, tumor grade, and stage. RESULTS The CSC-positive phenotype was identified in 26 patients (10.2%). Compared to negative cases, positive cases had lower pCR rates [5.0% vs 51.8%; adjusted odds ratio = 0.05, 95% confidence interval (CI): 0.01-0.39, P = 0.004]. The positive phenotype was associated with poorer overall survival (adjusted hazard ratio = 4.35, 95%CI: 2.43-7.79, P < 0.001), with a median overall survival of 19 months vs 27 months. No association with disease-free survival was observed (hazard ratio = 0.86, 95%CI: 0.43-1.73, P = 0.675). CONCLUSION CSC markers are associated with reduced chemotherapy response and inferior overall survival in Pakistani TNBC patients. These findings suggest their potential as prognostic biomarkers and highlight the need for future research into targeted strategies, such as proteomic profiling and Proteolysis Targeting Chimeras technology, to overcome chemoresistance in this population.

Cervical cystic hygroma, or lymphatic malformation, is a rare congenital anomaly that can present as a life-threatening airway emergency in neonates. Prompt recognition and timely management are critical for survival. While surgical excision has traditionally been the mainstay of treatment, extensive lesions involving vital neck structures carry significant operative risks in the neonatal period. We report a full-term neonate presenting at birth with a giant cervical cystic hygroma causing airway compression and respiratory distress. Due to high surgical risk, emergency ultrasound-guided intralesional bleomycin sclerotherapy was performed, resulting in a marked reduction in lesion size. At the six-month follow-up, there was no recurrence. This case underscores the role of image-guided intralesional sclerotherapy as a safe, effective, and minimally invasive life-saving alternative for neonates with giant cervical cystic hygroma.

To compare the diagnostic accuracy of the Raja Isteri Pengiran Anak Saleha Appendicitis (RIPASA) and Alvarado scoring systems in patients with suspected acute appendicitis using histopathology as the gold standard. A prospective study was conducted from December 2024 to April 2025 involving 100 patients at Ghurki Trust Teaching Hospital, Lahore. Patients presenting with right iliac fossa pain were assessed using both scoring systems. A score of 7 or higher from the Alvarado scale and 7.5 or higher from RIPASA indicated a positive result. Histopathological examination functioned as the definitive diagnostic method to establish correct diagnoses. The calculation of diagnostic accuracy and predictive values, together with sensitivity and specificity, was performed for both systems. In 100 patients (66% men and 64% under 40 years), histopathology showed appendicitis in 90% of patients. The RIPASA score demonstrated higher sensitivity (90.00%, 95% confidence interval [CI]: 81.85–95.31) compared to the Alvarado score (76.67%, 95% CI: 66.64–84.94), whereas Alvarado showed higher specificity (70.00%, 95% CI: 34.75–93.33) than RIPASA (20.00%, 95% CI: 2.52–55.61). Both scores had high positive predictive values (RIPASA: 91.01%; Alvarado: 95.83%) and low negative predictive values (RIPASA: 18.18%; Alvarado: 25.00%). Overall diagnostic accuracy was 83.00% for RIPASA and 76.00% for Alvarado. The RIPASA scoring system was found to be more sensitive and overall more diagnostic than the Alvarado score, but this difference was not found to be statistically significant. Both scoring systems are still clinically useful, and low scores cannot be used alone to rule out acute appendicitis.