Evaluation of Number Density of Tumor-Associated Macrophages by Immunohistochemistry and Semiquantitative Scoring in Invasive Breast Cancer: An Indian Study.

Context: Tumor microenvironment is emerging as a critical factor for progression of breast cancer. Tumor-associated macrophages (TAMs) play an important role in promoting tumor growth. Aim: This study was aimed at correlation of number density (ND) of TAMs with invasive ductal carcinoma (IDC) grading utilizing an image morphometric technique. We also sought to compare the TAMs and ND in the tumoral area and stromal region. We also explored the relationship between the clinical and pathological prognostic parameters. Subjects and Methods: The study included 75 cases of IDC that had undergone modified radical mastectomy. The Institutional Ethics Committee approved the study. Samples were classified as Grade 1, 2, and 3. Cases were graded as per the modified Bloom and Richardson criterion. Mean with standard deviation was calculated for each group. We utilized CD68 and CD163 immunostained sections for determining the ND of TAMs. TAMs were evaluated using computerized digital photomicrograph system with image analyzing software. ND was defined as the number of TAMs in total number of TAMs in five high-power fields/total area of five fields. ND was calculated separately in tumor and tumor stroma (TS). Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2/neu (HER2/neu) were scored in accordance with recommendations. Ki-67 was scored as per the recommended guidelines. Statistical Analysis Used: Data were tabulated in Microsoft Excel. SPSS version 20.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. To determine the relationship between macrophage density and clinicopathologic parameters, we used the independent t-test. To determine the differences in the parameters, analysis of variance (ANOVA) was utilized. Results: Age of the patients ranged from 34 to 58 years (mean: 55.5). One-way ANOVA between various grades of tumor indicating significant differences in terms of CD68 and CD163 densities in tumor and stroma (P < 0.0001). i.e., significant increased density of CD68 and CD163 was observed in Grade 3 tumor as compared to other two groups. A greater histological grade, ER, PR negative status, and a high Ki-67 index were all associated with TAM ND. There was no relation to HER2/neu status. Result of unpaired t-test indicates increased density in stroma as compared to tumor among various grades of IDC. Conclusions: We analyzed images with a software using photographs of the stained slides. This helped in quantitative analysis of TAMs on the CD68 and CD163 stained sections. This approach standardizes and reproducibly counts TAMs per unit area. We found significant difference between the number densities of TAMs in grades of invasive breast carcinoma. There were statistically significant differences in numerical densities of TAMs with ER, PR negativity, and Ki-67. There was no correlation with HER2/neu. Densities of CD68 and CD163 densities are more prevalent in TS as compared to intratumoral region.

Retrospective Evaluation of Platelet-Leukocyte Indices and Cardiac Surgical Outcomes in Acyanotic Heart Disease Patients with Pulmonary Hypertension (REPLICA-PH)

Abstract Introduction: Acyanotic congenital heart disease (ACHD) patients with pulmonary hypertension (PH) are prone to postoperative complications, and characterization of the risk profile continues to fail in identifying inflammatory predilection. Our objective is to investigate the role of platelet-leukocyte indices (neutrophil-lymphocyte ratio [NLR], platelet-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII] [neutrophil × platelet/lymphocyte]) in predicting poor outcomes following cardiac surgery in ACHD cohort with preoperative PH. Methods: This single-center, retrospective risk-predictive study included ACHD patients undergoing surgical correction at our tertiary cardiac center between January 2015 and December 2019. Standard institutional perioperative management protocol was followed, and poor postoperative outcome was defined as ≥ 1 of: low cardiac output syndrome, new-onset renal failure, prolonged mechanical ventilation (MV > 24 hours), stroke, sepsis, and/or death. Results: One hundred eighty patients out of 1,040 (17.3%) presented poor outcome. On univariate analysis, preoperative factors including right ventricular systolic pressure (RVSP) (PH-severity marker), congestive heart failure, albumin, NLR, PLR, SII, and aortic cross-clamping (ACC) and cardiopulmonary bypass (CPB) times predicted poor outcome. However, on multivariate analysis, RVSP, NLR, SII, and ACC and CPB times emerged as independent predictors. An NLR, SII prognostic cutoff of 3.33 and 860.6×103/mm3 was derived (sensitivity: 77.8%, 78.9%; specificity: 91.7%, 82.2%; area under the curve: 0.871, 0.833). NLR and SII values significantly correlated with postoperative MV duration, mean vasoactive-inotropic scores, and length of intensive care unit and hospital stay (P<0.001). Conclusion: Novel parsimonious, reproducible plateletleukocyte indices present the potential of stratifying the risk in congenital cardiac surgical patients with pre-existing PH.

Evaluating morphological features for predicting microsatellite instability status in colorectal cancer.

Background: Colorectal cancer (CRC) is one of the commonest cancers worldwide, with incidence rates in India being around 4%. It is a heterogeneous disease with multiple established prognostic factors. Ten to fifteen percent originate from microsatellite instability (MSI) pathway, characterized by defect in mismatch repair (MMR) gene. Identification of MMR defective protein is relevant for diagnosis, prognosis, and prediction. Certain clinical and histological features are known to be associated with defective MMR genes. The objectives of this study are to find the prevalence of MSI in CRC to identify features associated with MSI and assess the value of histopathology in predicting MSI. Methods: We evaluated various clinical and histological parameters for identifying prognostically favorable colon cancers in a tertiary hospital. One hundred fifty colon cancers were evaluated, and MSI status was correlated with clinicopathologic variables. Results: The prevalence of MSI in CRC was found to be 11.3%. The factors associated with MSI were tumor differentiation, stage, tumor site, tumor size, tumor-infiltrating lymphocytes, Crohn's-like lymphoid reaction, and dirty necrosis. We have defined a "P" score for prediction of MSI using the clinicohistological parameters, which could be used to select patients who are to be tested for MSI. Conclusion: Assessment of clinical and histopathological features will help in patient stratification and selection of patients for MSI testing. The evaluation is economical, reproducible, and easy to apply.

Cervical Cancers: Varieties and the Lower Anogenital Squamous Terminology.

Carcinoma of cervix is classified as per the WHO classification into primary tumors which are predominantly epithelial tumors, mesenchymal tumors and tumor like lesions, mixed epithelial stromal tumors, melanocytic, germ cell, and lymphoid tumors. Secondary tumors are uncommon. Squamous cell carcinoma (SCC) in various morphological forms needs to be separated from other epithelial tumors for treatment modality selection. Majority of SCC are human papilloma virus (HPV) positive. The histological pattern, HPV type, and grading do not affect prognosis. Mixed mesenchymal and epithelial tumors are of Mullerian origin. Among sarcomas, Botryoid rhabdomyosarcoma needs to be looked for, as a small biopsy may miss it. Carcinoma cervix is not the only cancer caused by HPV. High-risk HPV is implicated in causation of various other cancers such as anal cancers, oropharyngeal cancers, vulval cancers, vaginal cancers, and penile cancers. Low-risk HPV viruses similarly cause infections of perianal and genital region in males and females. The terminology for these lesions has evolved before understanding of pathogenesis of low- and high-risk HPV. The lower anogenital squamous terminology (LAST), an acronym for LAST, incorporates the low- and high-grade squamous intraepithelial lesion (HSIL) terminology. In invasive cancers, a superficially invasive SCC is a well-defined entity. LAST outlines areas where p16 use is recommended. No benefit of addition of other biomarkers like p63 or ki67 is found in problem-solving in differentiation of HSIL from mimics or low-grade squamous intraepithelial lesion. Routine use of biomarkers is not advocated.

Cervical cytology: Radiation and other therapy effects.

The different treatment options for carcinoma cervix include radiation, chemotherapy, and surgical treatments. Cytological analysis of smears is crucial for patient follow-up to determine response to therapy and to diagnose the persistence or recurrence of malignancy. Anatomical alterations and changes in cell morphology following radiation or chemotherapy make collecting and interpreting cervical cytology samples difficult. These issues can be mitigated by liquid-based cytology. Ionizing radiation is used in radiotherapy (RT) to kill cells. It is important that cytologists are aware of alterations in morphology of the cells. Radiation can cause cytoplasmic and nuclear changes. Cellular enlargement, vacuolation, granularity loss, and other changes linked with cell death are examples of cytoplasmic alterations. Nuclear enlargement and multinucleation are the most frequent nuclear alterations. These changes are determined by the amount of time that has passed since radiation. It should be emphasized that no one characteristic is pathognomonic. Post-irradiation dysplasia is a condition described as abnormal cellular changes in non-neoplastic epithelial cells after RT. Chemotherapy causes comparable alterations as radiation but impacts fewer cells. Busulfan and other chemotherapeutic treatments may produce morphological alterations, which cytologists must be aware of and able to identify. Immunosuppressive treatments, hormonal therapy, and tamoxifen are some of the other drugs that might cause changes in cervical morphology. Surgical methods used in the detection and treatment of cervical cancer may potentially cause alterations as a result of thermal damage and healing. For the treatment of cervical lesions, electrocautery and the loop electrosurgical excisional procedure are available. These procedures employ electric current ablation leading to ischemic changes in the cervical smear. Cytological analysis of smears following treatment with these modalities necessitates a comprehensive history, kind of therapy, and duration of treatment.

Retrospective Evaluation of Platelet-Leukocyte Indices and Cardiac Surgical Outcomes in Acyanotic Heart Disease Patients with Pulmonary Hypertension (REPLICA-PH).

INTRODUCTION: Acyanotic congenital heart disease (ACHD) patients with pulmonary hypertension (PH) are prone to postoperative complications, and characterization of the risk profile continues to fail in identifying inflammatory predilection. Our objective is to investigate the role of platelet-leukocyte indices (neutrophil-lymphocyte ratio [NLR], platelet-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII] [neutrophil × platelet/lymphocyte]) in predicting poor outcomes following cardiac surgery in ACHD cohort with preoperative PH. METHODS: This single-center, retrospective risk-predictive study included ACHD patients undergoing surgical correction at our tertiary cardiac center between January 2015 and December 2019. Standard institutional perioperative management protocol was followed, and poor postoperative outcome was defined as ≥ 1 of: low cardiac output syndrome, new-onset renal failure, prolonged mechanical ventilation (MV > 24 hours), stroke, sepsis, and/or death. RESULTS: One hundred eighty patients out of 1,040 (17.3%) presented poor outcome. On univariate analysis, preoperative factors including right ventricular systolic pressure (RVSP) (PH-severity marker), congestive heart failure, albumin, NLR, PLR, SII, and aortic cross-clamping (ACC) and cardiopulmonary bypass (CPB) times predicted poor outcome. However, on multivariate analysis, RVSP, NLR, SII, and ACC and CPB times emerged as independent predictors. An NLR, SII prognostic cutoff of 3.33 and 860.6×103/mm3 was derived (sensitivity: 77.8%, 78.9%; specificity: 91.7%, 82.2%; area under the curve: 0.871, 0.833). NLR and SII values significantly correlated with postoperative MV duration, mean vasoactive-inotropic scores, and length of intensive care unit and hospital stay (P<0.001). CONCLUSION: Novel parsimonious, reproducible plateletleukocyte indices present the potential of stratifying the risk in congenital cardiac surgical patients with pre-existing PH.

Development of a portfolio framework for implementation of an outcomes-based healthcare professional education curriculum using a modified e-Delphi method.

BACKGROUND: The explicit declaration of Entrustable Professional Activities (EPA) and milestones are an essential component of a competency based medical education curricula. The present study attempts to develop a portfolio framework to document them for adaptation in any healthcare professional education curriculum development. METHODS: A modified e-Delphi method was used after incorporation of a study group of medical education experts (MEDEX-G). Consensus was defined as 75% agreement. Both qualitative and quantitative data was collected and analysed to conduct three rounds of the Delphi. RESULTS: The draft template was prepared by the core faculty of medical education centre. The final template was approved by the experts after 03 iterations of anonymous online voting and presentation of summary results by the moderator. The final template lists out the milestones of each EPA separately with provision for expected expertise and level, suggestive teaching learning activities and assessments, reflections by the students and feedback by facilitator for each EPA. CONCLUSION: The MEDEX-G consensus template is an important development to encourage the adoption of portfolios in a competency based medical education curriculum. It can be freely adopted by various healthcare professional education bodies in various disciplines.

Enhancing communication skills among residents in India: An interprofessional education approach.

BACKGROUND: Interprofessional education (IPE) provides opportunities to postgraduates to develop communication skills which are vital for interactions with patients, their relatives, colleagues, paramedical and nursing staff. There is a need to develop an innovative IPE based module on communication skills for postgraduates stressing upon the existing lacunae and requirements detected by a validated assessment tool. We assessed the residents' appraisal of communication skills by a validated questionnaire to identify key areas to improve their communication skills and to determine perceptions of all the stakeholders i.e. faculty, nursing staff and paramedical staff. METHODS: A descriptive correlational design using an online self-administered questionnaire on a sample of a total of 200 participants comprising residents, paramedical staff, nursing staff and faculty of tertiary care hospital. Study was approved by the Institutional Ethical Committee. Data was analysed by SPSS Version 22.0 used. (p value < 0.05 significant). RESULTS: The participants included 113 residents, 17 paramedical staff, 33 Nursing staff and 37 faculty members. The present study found a significant difference of scores of means between the residents, faculty, paramedical staff and nursing staff p value < 0.05 except for alter centrism, interaction management and environmental control. The mean scores were also significantly different between the first, second and third year residents. CONCLUSION: This study validates the need to enhance the communication skills of residents. The scores obtained will help us design and refine IPE module for the benefit of the residents.

Systemic Immune-Inflammation Index Predicts Poor Outcome After Elective Off-Pump CABG: A Retrospective, Single-Center Study.

OBJECTIVES: To investigate the role of preoperative hematologic indices (neutrophil-lymphocyte ratio [NLR], platelet-lymphocyte ratio [PLR], systemic immune-inflammation index [SII; neutrophil × platelet/lymphocyte) in predicting short-term outcomes after off-pump coronary artery bypass grafting (OPCABG). DESIGN: A single-center, retrospective, risk-prediction study. SETTING: A tertiary cardiac center. PARTICIPANTS: 1,007 patients undergoing elective OPCABG. INTERVENTIONS: No specific intervention. MEASUREMENTS AND MAIN RESULTS: Two hundred five patients out of 1,007 (20.4%) manifested poor postoperative outcome (defined by ≥1 of: major adverse cardiac and cardiovascular events, duration of mechanical ventilation (DO-MV) >24 hours, new-onset renal failure, sepsis, and death). On univariate analysis, age, diabetes mellitus (DM), European System for Cardiac Operative Risk Evaluation II (EuroSCORE II), left-main disease, recent myocardial infarction, poor left ventricular ejection fraction, hemoglobin, NLR, PLR, and SII significantly predicted poor outcome. However, DM, EuroSCORE II, and SII emerged as independent predictors on multivariate analysis (odds ratio 0.136; 0.035-0.521, 3.377; 95% confidence interval 2.373-4.806, 1.01, 1.003-1.016). The SII cutoff of 878.06 × 103/mm3 predicted poor outcome with 97.6% sensitivity, 91%, specificity, and area under the curve 0.984. There was a significant positive correlation between the SII values and DO-MV and length of intensive care unit stay (R = 0.676; 0.527, p < 0.001). The incidence of complications, such as atrial fibrillation, intra-aortic balloon pump requirement, vasoactive-ionotropic score >20 for >6 hours, and other infections, was also significantly higher in patients with SII ≥878.06 × 103/mm3. CONCLUSIONS: SII constitutes a parsimonious and reproducible parameter demonstrating the potential of delineating the patients vulnerable to poor outcomes after OPCABG given the combined contribution of pro-inflammatory and pro-thrombotic corpuscular lines in computing the novel index.