Combined Pulmonary Fibrosis and Emphysema in a Patient With Chronic Occupational Exposure to Trichloroethylene.

Combined pulmonary fibrosis and emphysema (CPFE) is a clinical syndrome of upper-zone-predominant emphysema on high-resolution CT and a peripheral and basal-predominant diffuse pulmonary fibrosis. Multiple occupational and inhalational exposures have been associated with CPFE. We describe a U.S. veteran, who developed CPFE after a prolonged, intense exposure to trichloroethylene as an aircraft maintenance worker. We believe that this may be another example of occupational-associated CPFE.

Pulmonary fibrosis in sarcoidosis.

Sarcoidosis may progress to pulmonary fibrosis in 5% of patients with significantly increased mortality. Histopathology shows fibrosis in a lymphangitic pattern surrounding the granulomas. Th1 to Th2 shift in environment along with angiogenesis is implicated in exuberant fibrosis. Clinical features include dyspnea, cough, and frequently with pulmonary function tests showing a mixed ventilatory defect with severely decreased diffusion capacity of carbon monoxide.  Serologic markers including soluble interleukin 2 receptor, chitotriosidase and kern von den lunges 6, and chemokine ligand 18 are elevated and implicated in progression of disease. CT imaging shows fibrosis along bronchovascular bundles with reticulations, traction bronchiectasis and honeycombing predominantly in the upper and central distribution. Complications include sarcoidosis-associated pulmonary hypertension (SAPH) and chronic pulmonary aspergillosis. Treatment involves glucocorticoids and steroid-sparing agents in the presence of active granulomas. Anti-fibrotic agents such as pirfenidone and nintedanib have been shown to slow down pulmonary function decline in randomized clinical trials involving sarcoidosis-associated pulmonary fibrosis. Transplant workup is indicated in New York Heart Association class III or IV with similar success rates as in other lung transplant patients.

Management of nontuberculous mycobacteria in lung transplant cases: an international Delphi study.

Rationale: Nontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing on Mycobacterium avium complex (MAC), M. abscessus and M. kansasii. Methods: Pulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to -5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or <-4 indicating for or against the given statement. After the last round of questionnaires, a cumulative report was generated. Results: Panellists recommend performing sputum cultures and a chest computed tomography scan for NTM screening in LTx candidates. Panellists recommend against absolute contraindication to LTx even with multiple positive sputum cultures for MAC, M. abscessus or M. kansasii. Panellists recommend MAC patients on antimicrobial treatment and culture negative can be listed for LTx without further delay. Panellists recommend 6 months of culture-negative for M. kansasii, but 12 months of further treatment from the time of culture-negative for M. abscessus before listing for LTx. Conclusion: This NTM LTx study consensus statement provides essential recommendations for NTM management in LTx and can be utilised as an expert opinion while awaiting evidence-based contributions.

Role of IgG against N-protein of SARS-CoV2 in COVID19 clinical outcomes.

The Nucleocapsid Protein (N Protein) of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV2) is located in the viral core. Immunoglobulin G (IgG) targeting N protein is detectable in the serum of infected patients. The effect of high titers of IgG against N-protein on clinical outcomes of SARS-CoV2 disease has not been described. We studied 400 RT-PCR confirmed SARS-CoV2 patients to determine independent factors associated with poor outcomes, including Medical Intensive Care Unit (MICU) admission, prolonged MICU stay and hospital admissions, and in-hospital mortality. We also measured serum IgG against the N protein and correlated its concentrations with clinical outcomes. We found that several factors, including Charlson comorbidity Index (CCI), high levels of IL6, and presentation with dyspnea were associated with poor clinical outcomes. It was shown that higher CCI and higher IL6 levels were independently associated with in-hospital mortality. Anti-N protein IgG was detected in the serum of 55 (55%) patients at the time of admission. A high concentration of antibodies, defined as signal to cut off ratio (S/Co) > 1.5 (75 percentile of all measurements), was found in 25 (25%) patients. The multivariable logistic regression models showed that between being an African American, higher CCI, lymphocyte counts, and S/Co ratio > 1.5, only S/Co ratio were independently associated with MICU admission and longer length of stay in hospital. This study recommends that titers of IgG targeting N-protein of SARS-CoV2 at admission is a prognostic factor for the clinical course of disease and should be measured in all patients with SARS-CoV2 infection.

Lack of tocilizumab effect on mortality in COVID19 patients.

Off-label tocilizumab use in COVID-19 patients reflects concern for cytokine release syndrome. Comparison of matched COVID-19 pneumonia patients found elevated IL-6 levels correlated with mortality that did not change with tocilizumab administration. Correlating mortality with increased IL-6 doesn't imply causality however lack of improvement by tocilizumab requires further clinical trial alterations.

Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters.

OBJECTIVES: Ki67 is the most commonly used marker to evaluate proliferative index in breast cancer, however no cutoff values have been clearly defined for high ki67 index. Cancer management should be according to loco-regional profile; therefore, we aimed to determine ki67 index in 1951 cases of intrinsic breast cancer subtypes and its association with other prognostic parameters in our set up. RESULTS: Triple negative breast cancers showed highest ki67 index (mean 50.9 ± 23.7%) followed by Her2neu (mean 42.6 ± 21.6%) and luminal B cancers (mean 34.9 ± 20.05%). Metaplastic and medullary breast cancers significantly showed higher ki67 index as compared to ductal carcinoma, NOS. No significant association of ki67 index was noted with any of the histologic parameters in different subtypes of breast cancer expect for tumor grade. Although, ki67 index is a valuable biomarker in breast cancer, however no independent prognostic significance of ki67 could be established in our study.

Microsatellite Instability in Endometrial Carcinoma by Immunohistochemistry, Association with Clinical and Histopathologic Parameters.

Objective: We aimed to investigate the frequency of microsatellite instability (MSI) in endometrial carcinoma in our population and its association with clinico-pathologic features. Methods: A total of 126 cases of primary endometrial carcinoma were included in the study that underwent surgical resections. All slides of these cases were reviewed and representative paraffin fixed tissue blocks were selected for MLH1, MSH2, MSH6 and PMS2 IHC staining. IHC expression was categorized into five groups: no loss of expression; loss of expression of all four antibodies; combined loss of MLH1/PMS2; combined loss of MSH2/MSH6; and isolated loss of MLH1. Pathological records of all cases were retrieved from patient files. Result: Abnormal expression of MSI was noted in 56 cases (44.4%) among which 16 cases showed loss of nuclear expression of all markers, 34 cases showed loss of MLH1/PMS2 expression, 4 cases showed loss of MSH2/MSH6 while only 2 cases revealed isolated loss of MLH. Personal and family history suggestive of inherited cancer susceptibility was revealed in 11 cases most of which were associated with MSH2/MSH6 loss. Significant association of MSI expression was found with tumor stage and personal/family history of endometrial/ colon cancer. Conclusion: A high frequency of endometrioid cancers in our study showed abnormal expression of MSI markers, most of which depicted MLH1/PMS2 loss and were not associated with inherited cancer susceptibility. On the other hand, a minority of cases showed loss of all MSI markers or MSH2/MSH6 loss and were significantly associated with family/personal history of cancer. Therefore, we suggest that epigenetic changes in MLH1 locus may be a predominant pathway of tumorigenesis in our population rather than inherited mutation of MSI genes; however more large scale studies with genetic testing are required to validate this observation.

The Importance of Melanocortin Receptors and Their Agonists in Pulmonary Disease.

Melanocortin agonists are ancient neuropeptides that have steroidogenesis and anti-inflammatory properties. They activate melanocortin receptors (MCR), a family of five seven-transmembrane G-protein coupled receptors. MC1R and MC3R are mainly involved in immunomodulatory effects. Adrenocorticotropin hormone (ACTH) and alpha-Melanocortin stimulating hormone (α-MSH) reduce pro-inflammatory cytokines in several pulmonary inflammatory disorders including asthma, sarcoidosis, and the acute respiratory distress syndrome. They have also been shown to reduce fibrogenesis in animal models with pulmonary fibrosis. By understanding the functions of MCR in macrophages, T-helper cell type 1, and T-helper cell type 17, we may uncover the mechanism of action of melanocortin agonists in sarcoidosis. Further translational and clinical research is needed to define the role of ACTH and α-MSH in pulmonary diseases.

Prognostic Significance of High Androgen Receptor Expression in Prostatic Acinar Adenocarcinoma

Background: Quantitative immunohistochemical expression of Androgen receptor (AR) has not been evaluated as a prognostic biomarker of prostate cancer in our population, therefore in the current study we aimed to evaluate the association of AR expression in prostatic acinar adenocarcinoma with various prognostic parameters like tumor quantification, Gleason score, WHO grade group and perineural invasion. Methods: Total 121 cases of biopsy proven prostatic acinar adenocarcinoma were selected from records of pathology department archives from January 2013 till December 2017. Hematoxylin and eosin stained slides and paraffin blocks were retrieved and new sections were cut where necessary. Slides of all cases were reviewed by two senior histopathologists and pathologic characteristics like Gleason score, WHO grade, tumor quantification, perineural and lymphovascular invasion were evaluated. Androgen receptor immunohistochemistry was applied on all cases. Results: Low AR expression was noted in 53 cases (43.8%) while high AR expression was seen in 68 cases (56.2%). Significant association of AR expression was noted with total Gleason score, WHO grade and percentage of tissue involvement (tumor quantification). Univariate binary logistic regression showed patients with low Gleason scores (scores 6,7 or 8) and low WHO grade (grade 1, 2 or 3) were less likely to express high AR expression in comparison to high Gleason score (score 9) and high WHO grade group (grade 5) respectively. Similarly, cases with low tissue involvement by carcinoma (<50%) were less likely to show high AR expression in comparison to cases with >50% tissue involvement by carcinoma. Conclusion: Significant association of AR expression was noted with total Gleason score, WHO grade and percentage of tissue involvement (tumor quantification) which are among the most important markers of tumor progression; therefore we suggest that AR expression should be performed in patients with prostatic adenocarcinoma for prognostic stratification of the patients.

ERG oncoprotein expression in prostatic acinar adenocarcinoma; clinicopathologic significance.

OBJECTIVES: T/E fusion results in constitutive expression of ERG oncoprotein resulting in enhanced proliferation and invasive potential of prostatic cancer cells. In the present study we aimed to evaluate the ERG overexpression in 78 cases prostate acinar adenocarcinoma and its association with other prognostic parameters. RESULTS: ERG protein expression was noted in 39.7% (31 cases), out of which 3 cases (3.8%) showed low ERG expression, 10 cases (12.8%) showed intermediate expression and 18 cases (23.1%) revealed high ERG expression. Significant association of ERG expression was noted with gleason score (p = 0.009), WHO grade group (p = 0.008) and perineural invasion (p = 0.043). We found a significant proportion of our patients of prostatic acinar adenocarcinoma to over-express ERG protein which can help in devising therapeutic protocols. Significant association of ERG protein expression with gleason score and perineural invasion signifies its prognostic significance in prostatic carcinoma. Moreover, we also suggest that molecular studies should be performed in patients with prostatic carcinoma to look for T/E fusion gene and its correlation with ERG protein expression.

Mycobacterium abscessus-Bronchial Epithelial Cells Cross-Talk Through Type I Interferon Signaling.

Introduction:Mycobacteria are aerobic non-motile organisms with lipid rich, hydrophobic cell walls that render them resistant to antibiotics. While there are over 150 different species of NTM, Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) are two of the most common culprits of pulmonary infection. MAB has been found to be most common in southeastern United States (Florida to Texas) and the third most rapidly growing NTM infection. It is responsible for chronic lung infections. Mycobacterial cell wall components initiate the interaction between bacteria and host. The reaction between bronchial epithelia and components in the envelope of mycobacterial cell wall is poorly understood. Methods: A lung-on-membrane model was developed with normal human bronchial epithelial (NHBE) cells re-differentiated at the air-liquid interface (ALI) and human endothelial cells on a transwell® polyester membrane. Microparticles from MAB cell walls were developed by an inhouse protocol and added to the ALI side of lung model. NHBE cells were harvested at day 3. RNA was isolated and analyzed with RNASeq. NHBE cells were lysed and protein assay was performed with western blot. We tested whether lung INF-alpha expression would increase in mice treated with intratracheal MAB cell wall particles. A paired t-test is used to compare two population means using GraphPad Prism 7 software. Results: RNAseq analysis identified 1759 differentially expressed genes between NHBE cells challenged with and without MAB microparticles with FDR < 0.5. 410 genes had a 2.5-fold change (FC) or greater. NHBE cells exposure to MAB microparticles significantly enriched the IFN I signaling pathway. Protein overexpression of IFN I family (2'-5'-Oligoadenylate Synthetase 1, Interferon-induced GTP-binding protein Mx1, Interferon-stimulated gene 15) was found in bronchial epithelial cells following exposure to MAB cell wall microparticles. IFN-α protein and gene expressions were significantly increased in mice lung challenged with microparticles in comparison with controls. Conclusion: These data strongly support the role of Type I IFN in cross-talk between NHBE cells and MAB. They also suggest that initiating immune response by NHBE cells may play a central role in innate immunity. Furthermore, this study underscores the importance of mycobacterial cell wall in initiating innate immune response.

Prognostic utility of epidermal growth factor receptor (EGFR) expression in prostatic acinar adenocarcinoma

Background: Epidermal growth factor receptor (EGFR) is potential prognostic biomarker expressed in many human cancers. Prognostic significance of EGFR immunohistochemical expression has not been established in prostatic acinar adenocarcinoma, therefore we aimed to evaluate the frequency of expression of EGFR in prostatic adenocarcinoma and its association with other prognostic parameters. Methods: The study included 123 cases of biopsy proven prostatic acinar adenocarcinoma treated at Liaquat National hospital, Karachi from January 2013 till December 2017. Paraffin blocks of all cases were retrieved; sections were cut and stained with haematoxylin and eosin. Pathologic characteristics including tumor quantification, WHO grade group, gleason score, perineural and lymphovascular invasion were evaluated. EGFR immunohistochemistry (IHC) was performed on all tissue blocks. Results: Mean age of the patients included in the study was 69.05±8.68years. High gleason scores i.e. 8 & 9 were noted in 22% (27 cases) and 22.8% (28 cases) respectively. Similarly, 22.8% (28 cases) showed WHO grade group 5. 52.8% (65 cases) had > 50% tissue involvement by carcinoma and perineural invasion was seen in 37.4% (46 cases). Positive EGFR expression was noted in 18.7% (23 cases), while 81.3% (100 cases) showed negative EGFR expression. Significant association of EGFR expression was noted with gleason score (p-value = < 0.001), WHO grade (p = < 0.001), tumor quantification (p =0.007) and perineural invasion (p = < 0.001). Moreover, significant association of EGFR expression was also seen with disease recurrence and Her2neu over expression. Patients with low gleason scores (score 6 and 7) and lower grade group (1, 2 & 3) were less likely to have positive EGFR expression as compared to patients with high gleason score (score 9) and higher grade group (5). Similarly, patients with perineural invasion were more likely to have positive EGFR expression. Conclusion: We found a relatively low EGFR expression in our patients with prostatic adenocarcinoma; however, its association with poor prognostic parameters like high gleason score, higher grade group, perineural invasion, higher tissue involvement by cancer and disease recurrence signifies its importance as a prognostic parameter in prostatic acinar adenocarcinoma (AU)

Low p27kip1 expression in head and neck squamous cell carcinoma: association with risk factors and adverse outcomes

Background: Squamous cell carcinoma (SCC) of head and neck is highly prevalent in South-asian countries, owing to high consumption of areca nut/gutka and chewing tobacco. p27kip1 is a tumor suppressor gene, thought to be downregulated in oral squamous cell carcinoma. Therefore, in the present study we used immunohistochemical analysis to investigate an association between low p27kip1 expression in SCC of the head and neck and adverse outcomes/risk factors. Methods: Total 105 cases of SCC of head and neck excision specimens were selected from records of pathology department archives that underwent surgeries at Liaquat National hospital, Karachi from January 2008 till December 2013. Clinical and pathologic characteristics of patients were evaluated and p27kip1 immunohistochemistry was applied on tumor blocks. Results: In our study, low expression of p27kip1 in SCC of head and neck was seen in 39(37.1%) cases while 66(62. 9%) of the cases showed high expression for p27kip1. Significant association of p27kip1 expression with pan/gutka usage (p = 0.004), and recurrence (p = 0.001) was noted; however, no significant association of p27kip1 expression with other clinicopathologic features was seen. Multivariate binary logistic regression showed cases with history of pan/gutka usage were more likely to show low p27kip1 expression. Similarly, we also found that recurrence was more likely to develop in patients with low expression of p27kip1 in comparison to cases showing high p27kip1 expression. Conclusion: Loss of p27kip1 expression is a significant event involved in the pathogenesis of SCC head and neck especially that of oral cavity. Significant association of gutka/areca nut with low p27kip1 expression in our study suggests that loss p27kip1 expression is a major event involved in areca nut induced SCC of head and neck in this part of the world; however, more large scale molecular based studies are required to validate this observation. Moreover, significant association of low p27kip1 expression with tumor recurrence suggests its importance as a prognostic biomarker in SCC of head and neck (AU)

Traumatic aortic injury: a case report.

Trauma is the leading cause of death under the age of 35 years worldwide. Traumatic aortic rupture is responsible for 18% of all road accident mortality. Eighty percent of these patients die at the scene of the accident. Of the survivors, 50% die within 24 hours if left untreated. Rapid transport and resuscitation, awareness of the injury, availability of multi-slice computed tomography (MSCT), and timely intervention can significantly improve survival in aortic injury.