Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. PATIENTS AND METHODS: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. RESULTS: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). CONCLUSIONS: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

Virtual Resonant Emission and Oscillatory Long-Range Tails in van der Waals Interactions of Excited States: QED Treatment and Applications.

We report on a quantum electrodynamic (QED) investigation of the interaction between a ground state atom with another atom in an excited state. General expressions, applicable to any atom, are indicated for the long-range tails that are due to virtual resonant emission and absorption into and from vacuum modes whose frequency equals the transition frequency to available lower-lying atomic states. For identical atoms, one of which is in an excited state, we also discuss the mixing term that depends on the symmetry of the two-atom wave function (these evolve into either the gerade or the ungerade state for close approach), and we include all nonresonant states in our rigorous QED treatment. In order to illustrate the findings, we analyze the fine-structure resolved van der Waals interaction for nD-1S hydrogen interactions with n=8, 10, 12 and find surprisingly large numerical coefficients.

Spectrum of coronary angiographic findings in patients with ST Elevation Myocardial Infarction (STEMI) undergoing primary PCI in a tertiary care center of Nepal.

BACKGROUND: Even in developing countries like Nepal, prevalence of ST-elevation myocardial infarction has been shown to be increased with rise in prevalence of conventional risk factors like diabetes, Hypertension, smoking, dyslipidemia and obesity. Our aim is to retrospectively analyze for various risk factors and angiographic patterns of coronary artery disease in patients with ST-elevation myocardial infarction undergoing Primary Percutaneous Intervention. RESULTS: During the period of 1 year (January 2019 to December 2019), 816 patients presented to our ER with acute STEMI, among them 437 (53.6%) patients underwent primary PCI strategy and among them 22 (5.3%) patients were died. Thirty-six (4.4%) patients received thrombolysis, among them 5 (13.9%) patients were died while remaining 343 (42.0%) patients were managed conservatively and among them 20 (5.8%) were died. The mean age of patient who underwent primary PCI was 58.5±12.7 years range from 25 years to 99 years. Among them 55-75 years old 217 (49.6%) were highest in number followed by<55 years old 180 (41.2%). Males 318 (72.8%) were predominant. Among those who underwent primary PCI, hypertension 214 (49%) was the most common risk factor, followed by smoking 198 (45.3%), diabetes mellitus 123 (28.1%), dyslipidemia 53 (12.1%) and family history of premature coronary artery disease 18 (4.1%). Among those patients, 292 patients (66.8%) had single vessel disease, 99 patients (22.7%) had double vessel disease, 41 patients (9.3%) had triple vessel disease and 5 patients (1.1%) had non-significant coronary artery stenosis. Left anterior descending (53.3%) was the most frequently found culprit artery, followed by right coronary artery, left circumflex, ramus intermedius and left main artery. CONCLUSION: Fifty percent of patients presented with acute ST-elevation myocardial infarction and underwent primary PCI were between 55-75 years of age. Hypertension and smoking were the most common risk factors present in those patients. Single vessel disease was most prevalent with left anterior descending found to be the most commonly involved coronary artery followed by right coronary artery and left circumflex.

Investigation of geo-spatial hotspots for the occurrence of tuberculosis in Almora district, India, using GIS and spatial scan statistic.

BACKGROUND: The World Health Organization has declared tuberculosis a global emergency in 1993. It has been estimated that one third of the world population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. The emergence of TB/HIV co-infection poses an additional challenge for the control of tuberculosis throughout the world. The World Health Organization is supporting many developing countries to eradicate tuberculosis. It is an agony that one fifth of the tuberculosis patients worldwide are in India. The eradication of tuberculosis is the greatest public health challenge for this developing country. The aim of the present population based study on Mycobacterium tuberculosis is to test a large set of tuberculosis cases for the presence of statistically significant geographical clusters. A spatial scan statistic is used to identify purely spatial and space-time clusters of tuberculosis. RESULTS: Significant (p < 0.05 for primary clusters and p < 0.1 for secondary clusters) high rate spatial and space-time clusters were identified in three areas of the district. CONCLUSION: There is sufficient evidence about the existence of statistically significant tuberculosis clusters in Almora district of Uttaranchal, India. The spatial scan statistics methodology used in this study has a potential use in surveillance of tuberculosis for detecting the true clusters of the disease.

Prevalence of Conventional Risk Factors in ST Segment Elevation Myocardial Infarction Patients in Shahid Gangalal National Heart Centre, Nepal.

INTRODUCTION: Smoking, diabetes mellitus, hypertension, and dyslipidemia are labelled as conventional risk factors for coronary artery disease. Prevalence of these risk factors varies across populations. This study aimed to assess the prevalence of these conventional risk factors in patients, who were discharged from our hospital, with the diagnosis of ST elevation myocardial infarction. METHODS: Medical records of 495 ST elevation myocardial infarction patients discharged from our centre in between January 2012 to December 2012 were retrospectively reviewed to evaluate the prevalence of conventional risk factors. RESULTS: Clear dominance (75%) of male patients was seen. Inferior wall myocardial infarction (29.9%) was the most common diagnosis followed by anterior wall myocardial infarction (25.1%). Hypertension (65%), smoking (57.8%) and dyslipidemia (45.5%) were the most common risk factors. Diabetes (31.1%) was the least common. Prevalence of hypertension, dyslipidemia was similar among male and female. Smoking was statistically common in male (76.8%vs 49.5%),though diabetes was common in female (36.5%vs.29.3%) not statistically significant. CONCLUSIONS: Conventional risk factors are common among ST elevation myocardial infarction patients. Early detection and treatment of these risk factors play a vital role for the prevention of coronary artery disease. Much more focus should be stressed on preventive programs throughout the country.

Volatile and non-volatile compounds in irradiated semi-rigid crystalline poly(ethylene terephthalate) polymers.

In this study two different semi-rigid crystalline and oriented polyethylene terephthalate materials were used and were irradiated at 25-kGy dose at room temperature by using a caesium137 radiator. Volatile and non-volatile compounds present in the irradiated materials were identified and quantified. The qualitative results obtained from HS/GC/TCD/FID analysis at room temperature showed volatiles could not be identified. The HS/GC/MSD analysis performed at 106 degrees C showed that the irradiation generated 668-742 micrograms/kg formic acid, 868-922 micrograms/kg acetic acid, 17-32 micrograms/kg 1,3-dioxolane, and 47-71 micrograms/kg 2-methyl-1, 3-dioxolane based on PET weight. The results obtained from the thermal desorption and GC/MSD performed at 200 degrees C showed that 10-12 mg/kg acetaldehyde, 479-975 micrograms/kg 1,3-dioxolane, and 6.6-11.2 mg/kg methyl-1, 3-dioxolane were detected after irradiation. The concentrations of the two dioxolanes found from thermal desorption were much higher than those observed in the HS, although formic and acetic acids were not detected. It is possible that the formic and acetic acids produced by irradiation underwent further reactions with ethylene glycol during thermal desorption to form the dioxolanes. The soluble solid extracted from various PET specimens before and after irradiation were in a range of 0.67-0.78%. PET cyclic trimer is the major component and is present at 0.41-0.50%, accounting for more than 50% of the percent total solid in PET. Statistically, irradiation did not increase the soluble solid and cyclic trimer. The overall results suggest that 25-kGy irradiation had a significant effect on increasing the volatile but not the non-volatile compounds detected in the PET specimens.