Tumor cell phagocytosis (cannibalism) in lung cancer: possible biomarker for tumor immune escape and prognosis.

BACKGROUND: Tumor cell phagocytosis (cannibalism) is rarely seen in lung carcinomas. Little is known about its underlying cellular pathogenesis and associated significance as tumor immune escape mechanism. METHODOLOGY: The cases of lung cancer diagnosed at department of Pathology, VPCI over 13-year period, 2007-2020 (n = 350) were retrospectively reviewed. The cases displaying cannibalism were correlated with their tumor morphology, coexisting inflammation, patient age at presentation, sex, stage/grade, and smoking status. RESULTS: Cannibalism was identified in 10/350 (2.86%) cases of lung cancer. 9/10 (90%) were males and 1/10 (10%) was female. These patients ranged from 48-71 years of age and presented with history of chest pain, anorexia and weight loss. History of smoking was seen in 9/10 (90%) cases while 10% were non-smokers. Mass lesions were seen on CT scan and CT-guided fine needle aspiration cytology (FNAC) was performed. Cytopathology revealed squamous cell carcinoma (5/10, 50%), adenocarcinoma-3/10 (30%), adenosquamous carcinoma (1/10, 10%), and non small cell lung carcinoma (1/10, 10%). No association with small cell carcinoma was seen in our study. Background inflammation and infiltration of acute on chronic inflammatory infiltrate were seen in 6/10 or 60% cases. CONCLUSION: Lung cancers rarely show cannibalism, a tumor immune escape mechanism, even in advanced stage. This phenomenon correlates with squamous cell and adenocarcinoma morphology, tumor associated inflammatory infiltrate, and smoking status. It may be considered as a possible biomarker for tumor immune escape and poor prognosis.

Primary pulmonary lymphoepithelial-like carcinoma : A rare childhood malignancy.

Lymphoepithelial-like carcinoma (LELC) usually presents as a head and neck tumor with a close resemblance to nasopharyngeal carcinoma. We present an extremely rare case of Primary Pulmonary lymphoepithelioma in a 14-year-old female patient. The patient presented with a right-sided lung mass, which on biopsy revealed to be a lymphoepithelioma. There was no evidence of any mass elsewhere in the body, including the nasopharynx, as evidenced by PET CT. The IHC was positive for both cytokeratin and lymphoid cell markers. Hence, we conclude that lymphoepitheliomas can present as a primary lung mass in a young nonsmoking female, of which only two case reports are available from the Indian subcontinent till date.

Subtyping of advanced lung cancer based on PD-L1 expression, tumor histopathology and mutation burden (EGFR and KRAS): a study from North India.

Immune checkpoint inhibitor (PD-L1) therapy of advanced non-small-cell lung cancer (NSCLC) has variable outcomes. Tumor subtypes based on PD-L1 expression, histopathology, mutation burden is required for patient stratification and formulation of treatment guidelines. Lung cancers (n=57) diagnosed at Pathology department, VPCI (2018-2021) were retrospectively analyzed. PD-L1(SP263) expressed by tumor cells [low (<1%), medium (1-49%), high (≥50%)] was correlated with histopathology, microenvironment, EGFR, KRAS expression. Patients were categorized into high and low risk based on their: i) gender: males (n=47, 30-89 years), females (n=10, 45-80 years); ii) smoking history: males 26/47 (45.61%), females 1/10 (10%); iii) tumor subtyping: squamous cell carcinoma 15/57 (26.32%), adenocarcinoma 6/57 (17.54%), NSCLC-undifferentiated 24/57 (42.10%), adenosquamous carcinoma 5/57 (8.77 %), carcinosarcoma 4/57 (7.02%), small cell carcinoma 1/57 (1.75%); iv) inflammatory tumor microenvironment/TILs 44/57 (77.1%); iv) PD-L1 positivity-31/57 (54.3%); v) concomitant EGFR/KRAS positivity. PD-L1positive cases showed squamous/undifferentiated histopathology, concomitant EGFR+ (9/20, 45%) and KRAS+ (8/15, 53.3%), smoking+ (21/31,67.74%).PD-L1 negative cases (26/57, 45.6%), were EGFR+ (2/14, 14.28%) and KRAS+ (6/19, 31.5%). The high-risk lung cancer subtypes show squamous/undifferentiated histopathology, inflammatory microenvironment, male preponderance, smoking history, higher concomitant PD-L1, KRAS and EGFR positivity. Lung cancer subtyping can predict clinical response/resistance of patients prior to initiation of PD-L1 inhibitor therapies and can be used to guide therapy.

Progressive pulmonary fibrosis: an expert group consensus statement.

This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term "progressive pulmonary fibrosis" (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management.

Immunopathogenesis and therapeutic potential of macrophage influx in diffuse parenchymal lung diseases.

INTRODUCTION: The diffuse parenchymal lung diseases (DPLD)/interstitial lung diseases (ILD) are progressive lung disorders with usually unclear etiology, poor long-term survival and no effective treatment. Their pathogenesis is characterized by alveolar epithelial cell injury, inflammation, epithelial-mesenchymal transition, and parenchymal fibrosis. Macrophages play diverse roles in their development, both in the acute phase and in tissue repair. AREAS COVERED: In this review, we summarize the current state of knowledge regarding the role of macrophages and their phenotypes in the immunopathogenesis of DPLDs; CVD-ILD, UIP, NSIP, DIP, RB-ILD, AIP, HP, Sarcoidosis, etc. Our goal is to update the understanding of the immune mechanisms underlying the initiation and progression of fibrosis in DPLDs. This will help in identification of biomarkers and in developing novel therapeutic strategies for DPLDs. A thorough literature search of the published studies in PubMed (from 1975 to 2020) was done. EXPERT OPINION: The macrophage associated inflammatory markers needs to be explored for their potential as biomarkers of disease activity and progression. Pharmacological targeting of macrophage activation may reduce the risk of macrophage activation syndrome (MAS) and help improving the survival and prognosis of these patients.

Beneficial effects of N-acetylcysteine on protease-antiprotease balance in attenuating bleomycin-induced pulmonary fibrosis in rats.

OBJECTIVES: The role of N-acetylcysteine (NAC) as an anti-oxidant in attenuating bleomycin-induced pulmonary fibrosis has been reported. However, its effect on parenchymal remodeling via regulating the protease-antiprotease balance is not fully defined. Therefore, the present study was designed to explore the possible role of matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and transforming growth factor-ß1 (TGF-ß1) pathway and their modulation by NAC in attenuating bleomycin-induced pulmonary fibrosis in rats. MATERIALS AND METHODS: Bleomycin sulphate (7 units/kg) was instilled inside the trachea to induce pulmonary fibrosis. The time course of TGF-ß1, MMP-9, TIMP-1,3 mRNA and protein expression, TGF-ß1 and hydroxyproline levels were evaluated on days 7, 14, and 28. NAC (0.3 mmol/kg and 3 mmol/kg) was administered in bleomycin-instilled animals. RESULTS: NAC treatment significantly attenuated bleomycin-induced histopathological changes by decreasing interstitial inflammation and reducing the deposition of extracellular matrix proteins such as collagen. Moreover, it increased the mRNA and protein expression of MMP-9 and decreased the expression of TIMP-1,3 in alveolar epithelial cells (AECs), interstitial macrophages and inflammatory cells. Indeed, there was decrease in the MMP-9/TIMP ratio in bleomycin-instilled rats, which increased with NAC treatment. Moreover, NAC attenuated bleomycin-induced increased expression of TGF-ß1 and total lung collagen levels. CONCLUSION: NAC attenuates bleomycin-induced pulmonary fibrosis by normalizing the protease-antiprotease balance and favoring the degradation of collegen to reduce fibrosis.

Caveolin-1 as a critical component in the pathogenesis of lung fibrosis of different etiology: Evidences and mechanisms.

Caveolin is a structural protein of flask-shaped invaginations of the plasma membrane termed as caveolae and is widely expressed on the endothelial cells, smooth muscle cells and fibroblasts in the different parts of the body including the lung tissues. The expression of caveolin-1 in the lung tissues is important to prevent the fibrogenic actions of TGF-ß1 in lung fibrosis of different etiology including idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease and allergen-induced airway remodeling. Caveolin-1-mediated internalization and degradation of TGF-ß1 receptors may possibly account for the decreased actions of TGF-ß1. Studies have shown that the deficiency of caveolin-1 is very important in inducing lung fibrosis and its upregulation is reported to prevent lung fibrosis. The biological actions of caveolin-1 involve signaling pathways including JNK signaling, IL-4, STAT-3, miR199a-5p, CXCR4+ and CXCL12. The present review discusses the key role of caveolin and associated signaling pathways in the pathogenesis of lung fibrosis of different etiology.

Dual role of D-amino acid oxidase in experimental pain models.

D-amino acid oxidase (DAAO) is an astroglial enzyme abundantly present in the pain sensing regions including brain and spinal cord. There have been studies indicating an upregulation and increased activity of DAAO in different pain models. Furthermore, the upregulation of DAAO also results in the development of morphine tolerance as well as morphine-induced hyperalgesia. Accordingly, the knockdown of DAAO gene or pharmacological inhibition of DAAO reduces pain, reverses tolerance to morphine and hyperalgesia. The pain inducing actions of DAAO are related to augmented production of (hydrogen peroxide) H2O2, pro-inflammatory cytokines and activation of (Transient receptor protein Ankyrin-1) TRPA1 channels. On the other hand, exogenously administrated DAAO has also been shown to attenuate the pain in different pain models. The pain attenuating actions of DAAO enzyme has been linked to extensive metabolism of D-serine, which may not be able to activate NMDA receptor and trigger pain. The current review highlights the pain attenuating and pain inducing role of DAAO in experimental studies.

Expanding spectrum of anticancer drug, imatinib, in the disorders affecting brain and spinal cord.

Imatinib is a tyrosine kinase inhibitor and is used as a first line drug in the treatment of Philadelphia-chromosome-positive chronic myeloid leukaemia and gastrointestinal stromal tumors. Being tyrosine kinase inhibitor, imatinib modulates the activities of Abelson gene (c-Abl), Abelson related gene (ARG), platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT3), lymphocyte-specific protein (Lck), mitogen activated protein kinase (MAPK), amyloid precursor protein intracellular domain (AICD), α-synuclein and the stem-cell factor receptor (c-kit). Studies have shown the role of imatinib in modulating the pathophysiological state of a number of disorders affecting brain and spinal cord such as Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and spinal cord injury. The present review discusses the role of imatinib in the above described disorders and the possible mechanisms involved in these diseases.

Mechanisms involved in adenosine pharmacological preconditioning-induced cardioprotection.

Adenosine is a naturally occurring breakdown product of adenosine triphosphate and plays an important role in different physiological and pathological conditions. Adenosine also serves as an important trigger in ischemic and remote preconditioning and its release may impart cardioprotection. Exogenous administration of adenosine in the form of adenosine preconditioning may also protect heart from ischemia-reperfusion injury. Endogenous release of adenosine during ischemic/remote preconditioning or exogenous adenosine during pharmacological preconditioning activates adenosine receptors to activate plethora of mechanisms, which either independently or in association with one another may confer cardioprotection during ischemia-reperfusion injury. These mechanisms include activation of KATP channels, an increase in the levels of antioxidant enzymes, functional interaction with opioid receptors; increase in nitric oxide production; decrease in inflammation; activation of transient receptor potential vanilloid (TRPV) channels; activation of kinases such as protein kinase B (Akt), protein kinase C, tyrosine kinase, mitogen activated protein (MAP) kinases such as ERK 1/2, p38 MAP kinases and MAP kinase kinase (MEK 1) MMP. The present review discusses the role and mechanisms involved in adenosine preconditioning-induced cardioprotection.

Role of insulin like growth factor axis in the bleomycin induced lung injury in rats.

BACKGROUND: Alveolar epithelial cell injury has been proposed as a causative factor for the onset and progression of pulmonary fibrosis. However, the role of type II alveolar epithelial cells (AECs) in the epithelial mesenchymal transition (EMT) is controversial. AIMS: The present study performed in rats instilled with bleomycin investigated a) the expressions of the insulin growth factor (IGF-1) and insulin growth factor binding protein 5 (IGFBP-5) and transforming growth factor (TGF-ß1) in the type II AECs, b) the role of type II AECs in EMT and extracellular matrix (ECM) formation and, c) the effect of pioglitazone on all the above parameters. METHODS: Male Wistar rats were divided into three Groups: Group I (saline control), Group II (Bleomycin, given as a single intratracheal instillation, 7U/kg) and Group III (Bleomycin+Pioglitazone (40mg/kg/day orally, starting 7days post bleomycin instilled as in Group II). From lung tissues, the protein expressions of IGF-1, IGFBP-5, TGF-ß1, surfactant protein C (SP-C, as a marker for type II AECs) and α-smooth muscle actin (α-SMA, as a marker for EMT), were determined on day 7 in Groups I and II and on days 14, 21 and 35 in all the three groups. RESULTS: IGFBP-5 and IGF-1 expressions were reduced significantly and TGF-ß1 expression increased significantly in type II AECs in Group II from day 7 till day 35 as compared to Group I. An increase in SP-C and α-SMA expression and their co-localization were seen in the type II AECs undergoing EMT from day 7 till day 35. A concomitant remodeling and laying down of ECM was observed also. In Group III, with pioglitazone, there was a reversal with significant up-regulation in IGFBP-5 and IGF-1 expressions and down-regulation of TGF-ß1 in the type II AECs along with a significant decrease in the solid area fraction, EMT and ECM in the lung tissue. CONCLUSIONS: IGFBP-5, IGF-1 and TGF-ß1 in the type II AECs play a key role in lung injury caused by bleomycin and pioglitazone attenuates the lung injury/fibrosis by restoring IGFBP-5 and IGF-1 and decreasing TGF-ß1 expressions in the type II AECs.

Role of a pattern-based approach in interpretation of transbronchoscopic lung biopsy and its clinical implications.

BACKGROUND: Transbronchial lung biopsy (TBLB) is commonly performed for confirming the tissue diagnosis of diffuse parenchymal lung diseases (DPLDs). There is an urgent need to establish guidelines for interpretation of TBLB in order to improve its diagnostic utility. METHODS: We retrospectively studied 916 consecutive patients (494 males; mean age 49 years) who underwent TBLB over a 5-year period (July 2005 to July 2010) at Vallabhbhai Patel Chest Institute. RESULTS: In 615 (67.1%) procedures, material obtained during TBLB was adequate for histopathology interpretation. Pathological features evaluated in each case were: alveolar architecture, inflammatory infiltrate, interstitial fibrosis, atypical cells, pigment deposition, honey-comb change and fibroblast foci. The cases were categorised on the basis of histopathology into six patterns: (1) adequate biopsy without a specific diagnostic abnormality (n = 137, 22.3%); (2) acute pneumonitis (n = 29, 4.7%); (3) neoplasia (n = 109, 17.7%); (4) chronic interstitial inflammation with or without fibrosis (n = 138, 22.4%); (5) granulomatous inflammation, (n = 186, 30.2%); and (6) other specific causes (n = 16, 2.6%). Definitive diagnosis could be made after correlation of TBLB histopathology with clinical and radiological features in 55.3% cases. CONCLUSIONS: TBLB appears to be an important diagnostic tool for the diagnosis of DPLDs. The use of a pattern-based approach to TBLB adds to its diagnostic yield and can be helpful in cases where open lung biopsy is not available.

Translational control of TOP2A influences doxorubicin efficacy.

The cellular abundance of topoisomerase IIα (TOP2A) critically maintains DNA topology after replication and determines the efficacy of TOP2 inhibitors in chemotherapy. Here, we report that the RNA-binding protein HuR, commonly overexpressed in cancers, binds to the TOP2A 3'-untranslated region (3'UTR) and increases TOP2A translation. Reducing HuR levels triggered the recruitment of TOP2A transcripts to RNA-induced silencing complex (RISC) components and to cytoplasmic processing bodies. Using a novel MS2-tagged RNA precipitation method, we identified microRNA miR-548c-3p as a mediator of these effects and further uncovered that the interaction of miR-548c-3p with the TOP2A 3'UTR repressed TOP2A translation by antagonizing the action of HuR. Lowering TOP2A by silencing HuR or by overexpressing miR-548c-3p selectively decreased DNA damage after treatment with the chemotherapeutic agent doxorubicin. In sum, HuR enhances TOP2A translation by competing with miR-548c-3p; their combined actions control TOP2A expression levels and determine the effectiveness of doxorubicin.

miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors.

Expression of BRCA1 is commonly decreased in sporadic breast tumors, and this correlates with poor prognosis of breast cancer patients. Here we show that BRCA1 transcripts are selectively enriched in the Argonaute/miR-182 complex and miR-182 downregulates BRCA1 expression. Antagonizing miR-182 enhances BRCA1 protein levels and protects them from IR-induced cell death, while overexpressing miR-182 reduces BRCA1 protein, impairs homologous recombination-mediated repair, and render cells hypersensitive to IR. The impaired DNA repair phenotype induced by miR-182 overexpression can be fully rescued by overexpressing miR-182-insensitive BRCA1. Consistent with a BRCA1-deficiency phenotype, miR-182-overexpressing breast tumor cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). Conversely, antagonizing miR-182 enhances BRCA1 levels and induces resistance to PARP1 inhibitor. Finally, a clinical-grade PARP1 inhibitor impacts outgrowth of miR-182-expressing tumors in animal models. Together these results suggest that miR-182-mediated downregulation of BRCA1 impedes DNA repair and may impact breast cancer therapy.

Immunohistochemical staining on fine needle aspiration biopsy-cell block specimens in the differential diagnosis of lung cancers.

BACKGROUND: Fine needle aspiration biopsy [FNAB] is used extensively in the clinical work-up of radiologically detected lung lesions. However, categorisation of lung cancer by computed tomography guided FNAB alone is limited by overlapping morphological features. AIM: To examine further the utility of immunohistochemical panel of antibodies to thyroid transcription factor [TTF-1], synaptophysin, chromogranin A [CgA], cytokeratin-pan, cytokeratin-7 [CK-7], cytokeratin-20 [CK-20], leucocyte common antigen [LCA], and carcinoembryonic antigen [CEA] in cytologic cell block samples in the differential diagnosis of lung cancer. METHODS: Twenty-nine FNABs of newly diagnosed cases of lung cancer were studied. Immunohistochemistry was done on paraffin embedded cell block sections using Dako monoclonal antibodies. RESULTS: Morphological diagnosis of non-small cell carcinoma (NSCLC) was made in 22/29 [76%] and small cell carcinoma in 7/29 (24%) cases. Five of the seven (71.4%) cases of small cell carcinoma were CgA+/TTF-1+, 14.3% [1/7] were CgA+/ synaptophysin+/TTF-1-negative. In one case, LCA positivity lead to the diagnosis of non-Hodgkins lymphoma. The NSCLC was categorised further into well differentiated 11/22 [50%], moderately differentiated 7/22 [31.8%] and poorly differentiated 4/22 [18.2%] cases. Cytokeratin-pan positivity in squamous cell carcinomas [n=15] was seen to be related to cellular differentiation. All the three cases of adenocarcinoma were CK-7+/CK-20 negative. In one case with large cell carcinoma, CgA-positivity lead to recategorisation as large cell neuroendocrine carcinoma. CONCLUSIONS: Our results suggest that the proposed panel of immunohistochemical markers might help further classification of lung carcinomas even in small FNAB material and permit more consistent patient enrollment for trials with targeted treatments.

Cystic schwannoma of eyelid in an Indian male: a rare presentation.

Eyelid schwannoma (neurilemmomas) is an extremely rare, benign neoplasm. A case of Cystic Schwannoma in eyelid of a young adult is reported. A 19-year-old male presented with a firm-nodular painless lesion, 3.5 cms in diameter, located on the left lower eyelid for the last 2 years. The lesion was surgically excised. Histopathological diagnosis of cystic schwannoma was made. Immunohistochemistry revealed strong S-100 positivity indicative of Schwann cell origin. No recurrance was seen after a follow up of 1 year.

Osteolipoma of the eyelid.

A 50-year-old woman presented with a nodular swelling on her right upper eyelid. The tumour was diagnosed as osteolipoma histologically after resection. Osteolipoma is a very rare variant of lipoma and only a few cases affecting the head and neck are reported in literature. To the best of the author's knowledge this is the first reported case of osteolipoma of the eyelid.