Developing local guidelines for management of sepsis in adults: sepsis guidelines for Pakistan (SGP)

Background: The purpose of developing ‘Sepsis Guidelines for Pakistan’ (SGP) is to provide clinicians practicing in local hospitals with a framework to aid timely recognition and management of adult patients in sepsis by adopting evidence-based recommendations of Surviving Sepsis Campaign (SSC) tailored to available resources. These recommendations are not meant to replace the SSC Guidelines. Methodology: SGP is an initiative of Pakistan Society of Critical Care Medicine (PSCCM). Four key decision points to be addressed in the guidelines were identified by a thirteen member multidisciplinary committee i.e., grading the hospitals in the country, recognition of sepsis and associated organ dysfunction, essential interventions to manage sepsis, and general measures for provision of a comprehensive care to patients in sepsis according to the level of education and training of healthcare providers and facilities and resources available in different levels of hospitals. The draft was presented at the 3rd Sepsis Symposium held on 13th September, 2014 in Karachi. The final document was approved by a panel of experts from across the country, representatives of relevant societies and Global Sepsis Alliance (GSA). Recommendations: Hospitals are divided into basic, intermediate and tertiary depending on the availability of diagnostic facilities and training of the medical personnel. Modified definitions of sepsis, severe sepsis, and septic shock are used given the lack of facilities to diagnose sepsis according to international definitionsand criteria in Pakistan. Essential interventions include fluid resuscitation, vasopressors to support the circulation, maintaining oxygen saturation ≥ 90% with oxygen, non-invasive ventilation or mechanical ventilation with lung protective strategies, prompt administration of antibiotics as recommended by the Medical Microbiology & Infectious Diseases Society of Pakistan (MMIDSP) and early source control. It is recommended to avoid starvation, keep an upper blood glucose ≤180 mg/dL, use daily pharmacoprophylaxis against venous thromboembolism (VTE), use stress ulcer prophylaxis, target haemoglobin of 7-9 g/dl in the absence of ischaemic heart disease, avoid sodium bicarbonate therapy as long as pH \u3e 7.20, avoid fresh frozen plasma in the absence of bleeding, transfuse platelets if indicated, not use intravenous immunoglobulins and avoid neuromuscular blocking agents (NMBAs) in the absence of ARDS, target specific titration endpoints when continuous or intermittent sedation is required in mechanically ventilated patients and use continuous renal replacement therapy (CRRT) to facilitate management of fluid balance in hemodynamically unstable septic patients in tertiary care centers. In addition a comprehensive, meticulous and multidisciplinary general care is required to improve outcome of sepsis by reinforcing hand hygiene and other infection control measures, adequate monitoring and documentation tailored to the available resources. Goals of care and prognosis should be discussed with patients and families early and either shifting the patient to a hospital with better facilities or limiting or withdrawing therapy in case of poor prognosis should be considered

Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions

Abstract Gastro-esophageal adenocarcinomas (GEA) represent a severe global health burden and despite improvements in the multimodality treatment of these malignancies the prognosis of patients remains poor. HER2 overexpression/amplification has been the first predictive biomarker approved in clinical practice to guide patient selection for targeted treatment with trastuzumab in advanced gastric and gastro-esophageal junction cancers. More recently, immunotherapy has been approved for the treatment of GEA and PD-L1 expression is now a biomarker required for the administration of pembrolizumab in these diseases. Significant progress has been made in recent years in dissecting the genomic makeup of GEA in order to identify distinct molecular subtypes linked to distinct patterns of molecular alterations. GEA have been found to be highly heterogeneous malignances, representing a challenge for biomarkers discovery and targeted treatment development. The current review focuses on an overview of established and novel promising biomarkers in GEA, covering recent molecular classifications from TCGA and ACRG. Main elements of molecular heterogeneity are discussed, as well as emerging mechanisms of primary and secondary resistance to HER2 targeted treatment and recent biomarker-driven trials. Future perspectives on the role of epigenetics, miRNA/lncRNA and liquid biopsy, and patient-derived xenograft models as a new platform for molecular-targeted drug discovery in GEA are presented. Our knowledge on the genomic landscape of GEA continues to evolve, uncovering the high heterogeneity and deep complexity of these tumors. The availability of new technologies and the identification of promising novel biomarker will be critical to optimize targeted treatment development in a setting where therapeutic options are currently lacking. Nevertheless, clinical validation of novel biomarkers and treatment strategies still represents an issue

Effectiveness of topical application of 15℅ salicyclic acid and 0.1℅ diphencyprone combined in an ointment form for treatment of plantar warts

Objective: To determine the Effectiveness of topical application of 15℅ salicyclic acid and 0.1℅ Diphencyprone combined in an ointment form for treatment of plantar warts. Place and Duration: This Descriptive, case series was held in Dermatology outpatient department, Abbasi Shaheed Hospital Karachi. Method: A sample size of 80 patients with plantar warts were included as calculated by exact 95% confidence interval. Results: Total 80 patients of plantar warts were enrolled. 40 (50%) were females and 40 (50%) were males, with mean age of 31 yrs. 65 patients (81.25%) showed positive response to treatment with combined DPCP and salicyclic acid, while remaining 15 (18.75%) had some mild adverse reactions. Conclusion: As Plantar wart is a common problem in all populations therefore more randomized trials should be done on combined chemical treatments for better outcomes

Treatment Efficacy of Sofosbuvir and Ribavirin Combination at Two Weeks in Chronic Hepatitis C

Background:To determine the effectiveness of sofosbuvir plus ribavirin in terms of frequency of negative qualitative PCR at 2nd week of treatment in chronic hepatitis C patients with genotype 3. Methods: In this case control study  60 patients with hepatitis C who were planned to receive sofobuvir and ribavarin combination therapy were included . Patients included  were  chronically infected with hepatitis C virus genotype 3 for whom treatment with peg-interferon is not an option and have contraindication for their use like decompensated liver disease, and patients are either non responder or relapsers to previous interferon based therapy. Pregnant or breast-feeding women, patients taking any of the medications which had interactions with sofosbuvir and patients who had not been compliant to sofosbuvir plus ribavirin therapy were excluded. Sofosbuvir was given in dose 400 mg once daily and ribavirin was given in dose of 400 or 600 twice daily(if weight <75kg or >75kg respectively). Patients were followed at 2nd week of treatment and qualitative PCR for HCV RNA was carried out Results:Total sixty patients fulfilling the inclusion criteria were included in this study. Overall efficacy of sofosbuvir and ribavirin combination was 91. 7%. Majority of patients 55(91.7%) attained negative PCR for HCV RNA at2nd week of treatment). Conclusion: Sofosbuvir plus ribavirin is an effective Treatment regimen as far as viral clearance at 2nd week of treatment is considered

CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy.

Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment

B cell and B cell-related pathways for novel cancer treatments.

B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, -21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies

Mammographic microcalcifications and breast cancer tumorigenesis: a radiologic-pathologic analysis

Abstract Background Microcalcifications (MCs) are tiny deposits of calcium in breast soft tissue. Approximately 30% of early invasive breast cancers have fine, granular MCs detectable on mammography; however, their significance in breast tumorigenesis is controversial. This study had two objectives: (1) to find associations between mammographic MCs and tumor pathology, and (2) to compare the diagnostic value of mammograms and breast biopsies in identifying malignant MCs. Methods A retrospective chart review was performed for 937 women treated for breast cancer during 2000–2012 at St. Michael’s Hospital. Demographic information (age and menopausal status), tumor pathology (size, histology, grade, nodal status and lymphovascular invasion), hormonal status (ER and PR), HER-2 over-expression and presence of MCs were collected. Chi-square tests were performed for categorical variables and t-tests were performed for continuous variables. All p-values less than 0.05 were considered statistically significant. Results A total of 937 patient charts were included. About 38.3% of the patients presented with mammographic MCs on routine mammographic screening. Patients were more likely to have MCs if they were HER-2 positive (52.9%; p < 0.001). There was a significant association between MCs and peri-menopausal status with a mean age of 50 (64%; p = 0.012). Patients with invasive ductal carcinomas (40.9%; p = 0.001) were more likely to present with MCs than were patients with other tumor histologies. Patients with a heterogeneous breast density (p = 0.031) and multifocal breast disease (p = 0.044) were more likely to have MCs on mammograms. There was a positive correlation between MCs and tumor grade (p = 0.057), with grade III tumors presenting with the most MCs (41.3%). A total of 52.2% of MCs were missed on mammograms which were visible on pathology (p < 0.001). Conclusion This is the largest study suggesting the appearance of MCs on mammograms is strongly associated with HER-2 over-expression, invasive ductal carcinomas, peri-menopausal status, heterogeneous breast density and multifocal disease

Mammographic microcalcifications and breast cancer tumorigenesis: a radiologic-pathologic analysis

Background: Microcalcifications (MCs) are tiny deposits of calcium in breast soft tissue. Approximately 30% of early invasive breast cancers have fine, granular MCs detectable on mammography; however, their significance in breast tumorigenesis is controversial. This study had two objectives: (1) to find associations between mammographic MCs and tumor pathology, and (2) to compare the diagnostic value of mammograms and breast biopsies in identifying malignant MCs. Methods: A retrospective chart review was performed for 937 women treated for breast cancer during 2000–2012 at St. Michael’s Hospital. Demographic information (age and menopausal status), tumor pathology (size, histology, grade, nodal status and lymphovascular invasion), hormonal status (ER and PR), HER-2 over-expression and presence of MCs were collected. Chi-square tests were performed for categorical variables and t-tests were performed for continuous variables. All p-values less than 0.05 were considered statistically significant. Results: A total of 937 patient charts were included. About 38.3% of the patients presented with mammographic MCs on routine mammographic screening. Patients were more likely to have MCs if they were HER-2 positive (52.9%; p < 0.001). There was a significant association between MCs and peri-menopausal status with a mean age of 50 (64%; p = 0.012). Patients with invasive ductal carcinomas (40.9%; p = 0.001) were more likely to present with MCs than were patients with other tumor histologies. Patients with a heterogeneous breast density (p = 0.031) and multifocal breast disease (p = 0.044) were more likely to have MCs on mammograms. There was a positive correlation between MCs and tumor grade (p = 0.057), with grade III tumors presenting with the most MCs (41.3%). A total of 52.2% of MCs were missed on mammograms which were visible on pathology (p < 0.001). Conclusion: This is the largest study suggesting the appearance of MCs on mammograms is strongly associated with HER-2 over-expression, invasive ductal carcinomas, peri-menopausal status, heterogeneous breast density and multifocal disease