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July-September 2020
Volume 16 | Issue 4
Page Nos. 703-956

Online since Monday, September 14, 2020

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REVIEW ARTICLES  

Telepathology: An update on applications, latest advances, and current status in Indian scenario p. 703
Ajeesha Feroz, TP Mohammed Feroz, TS Bastian, M Selvamani
DOI:10.4103/jcrt.JCRT_477_17  PMID:32930106
Pathologists have been using their tool of trade, “the microscope,” since the early 17th century, but now diagnostic pathology or tissue-based diagnosis is characterized by its high specificity and sensitivity. Technological telecommunication advances have revolutionized the face of medicine, and in pursuit of better health-care delivery, telepathology has emerged. Telepathology is the practice of diagnostic pathology performed at a distance, with images viewed on a video monitor rather than directly through the (light) microscope. This article aims to provide an overview of the field, including specific applications, practice, benefits, limitations, regulatory issues, latest advances, and a perspective on the current status of telepathology in Indian scenario based on literature review.
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Tanapoxvirus: From discovery towards oncolytic immunovirotherapy Highly accessed article p. 708
Yogesh R Suryawanshi, Tiantian Zhang, Farzad Razi, Karim Essani
DOI:10.4103/jcrt.JCRT_157_18  PMID:32930107
Insufficiency of standard cancer therapeutic agents and a high degree of toxicity associated with chemotherapy and radiotherapy have created a dearth of therapeutic options for metastatic cancers. Oncolytic viruses (OVs) are an emerging therapeutic option for the treatment of various human cancers. Several OVs, including poxviruses, are currently in preclinical and clinical studies and have shown to be effective in treating metastatic cancer types. Tanapoxvirus (TANV), a member of the Poxviridae family, is being developed as an OV for different human cancers due to its desirable safety and efficacy features. TANV causes a mild self-limiting febrile disease in humans, does not spread human to human, and its large genome makes it a relatively safer OV for use in humans. TANV is relatively well characterized at both molecular and clinical levels. Some of the TANV-encoded proteins that are a part of the virus' immune evasion strategy are also characterized. TANV replicates considerably slower than vaccinia virus. TANV has been shown to replicate in different human cancer cells in vitro and regresses human tumors in a nude mouse model. TANV is currently being developed as a therapeutic option for several human cancers including breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, retinoblastoma, and melanoma. This review provides a comprehensive summary from the discovery to the development of TANV as an OV candidate for a wide array of human cancers.
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ORIGINAL ARTICLES Top

Bone marrow aspirations in Ewing sarcomas: Are they still necessary? A single-center retrospective analysis and review of the literature p. 713
Bernadette Breitegger, Lukas A Holzer, Christine Beham-Schmid, Christian Urban, Bernadette Liegl-Atzwanger, Andreas Leithner
DOI:10.4103/jcrt.JCRT_941_16  PMID:32930108
Background and Objectives: Currently, one of the most useful prognostic indicators in Ewing sarcomas (ES) is the presence of metastatic disease at diagnosis. According to various clinical guidelines, the assessment of bone marrow (BM) metastases, using light microscopy examination of bone marrow aspirates and biopsies (BMAB) is mandatory. However, the prognostic value of BM positivity is discussed controversially. Therefore, the primary aim of this study was to retrospectively review BM samples from patients with ES. Materials and Methods: This retrospective single centre study included 31 patients that were newly diagnosed with ES between 2000 and 2014. Twenty-seven patients had skeletal ES and in 4 patients the tumour was localized in the soft tissue only. Metastases at diagnosis were present in 5 out of 31 patients. BM samples were morphologically and immunohistochemically searched and screened for the presence or absence of BM metastases. Furthermore, in 15 of the 31 patients BM samples were still available and were reanalysed, using nested-polymerase chain reaction. Results: All BM samples of our 31 ES patients, including the 5 metastatic patients, were, morphologically and immunohistochemically tested negative for tumour cell appearance. The nested-PCR results were also negative in all of our 15 retested patients, including two patients with metastatic disease. Conclusions: Based on our results and on the contradictory results reported in the literature we recommend a re-evaluation of the necessity and the prognostic value of BMAB in the initial staging process of newly diagnosed ES patients.
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An updated meta-analysis of the relationship between glutathione S-transferase T1 null/presence gene polymorphism and the risk of lung cancer p. 718
Tao Liu, Wen-Zhou Liu, Yu Sun, Xiao-Han Bi, Hua-Fu Zhou
DOI:10.4103/0973-1482.189237  PMID:32930109
Aim of Study: There were many reports published on the relationship between glutathione S-transferase T1 (GSTT1) null/presence gene polymorphism and the risk of lung cancer in these years. In previous, we conducted a meta-analysis to evaluate the relationship between GSTT1 null/presence gene polymorphism and the risk of lung cancer. This study was conducted to update it. Materials and Methods: The association studies were identified from PubMed and Cochrane Library on March 1, 2016. Results: Sixty-three reports were recruited into this meta-analysis for the association of null genotype of GSTT1 with lung cancer susceptibility, consisting of 21,220 patients with lung cancer and 21,496 controls. There was a marked association between GSTT1 null genotype and lung cancer risk in overall populations and in Asians (overall populations: Odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.07–1.28, P = 0.006; Asians: OR = 1.41, 95% CI: 1.23–1.62, P < 0.00001). However, GSTT1 null genotype was not associated with the risk of lung cancer in Caucasians, Brazilian population, and Africans. Conclusion: GSTT1 null genotype is associated with the lung cancer risk in overall populations and in Asians.
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Evaluation of the organs at risk doses for lung tumors in gated and conventional radiotherapy p. 726
Sara Shahzadeh, Somayeh Gholami, Seyed Mahmood Reza Aghamiri, Hojjat Mahani, Mansoure Nabavi
DOI:10.4103/jcrt.JCRT_735_18  PMID:32930110
Purpose: The purpose of this study was to evaluate the organs at risk (OARs) doses for lung tumors in gated radiotherapy (RT) compared to conventional RT using the four-dimensional extended cardiac-torso (4D-XCAT) digital phantom in a simulation study. Materials and Methods: 4D-XCAT digital phantom was used to create 32 digital phantom datasets of different tumor diameters of 3 and 4 cm, and motion ranges (MRs) of 2, 2.5, 3, and 3.5 cm and each tumor was placed in four different lung locations (right lower lobe, right upper lobe, left lower lobe, and left upper lobe). XCAT raw binary images were converted to the digital imaging and communication in medicine format using an in-house MATLAB-based program and were imported to treatment planning system (TPS). For each dataset, gated and conventional treatment plans were prepared using Planning Computerized RadioTherapy-three dimensional (PCRT-3D) TPS with superposition computational algorithm. Dose differences between gated and conventional plans were evaluated and compared (as a function of 3D motion and tumor volume and its location) with respect to the dose-volume histograms of different organs-at-risk. Results: There are statistically significant differences in dosimetric parameters among gated and conventional RT, especially for the tumors near the diaphragm (P < 0.05). The maximum reduction in the mean dose of the lung, heart, and liver were 6.11 Gy, 1.51 Gy, and 10.49 Gy, respectively, using gated RT. Conclusions: Dosimetric comparison between gated and conventional RT showed that gated RT provides relevant dosimetric improvements to lung normal tissue and the other OARs, especially for the tumors near the diaphragm. In addition, dosimetric differences between gated and conventional RT did generally increase with increasing tumor motion and decreasing tumor volume.
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Prognostic values of various hematological variables as markers of systemic inflammation in metastatic lung cancer p. 731
Duygu Bayir, Selcuk Seber, Tarkan Yetisyigit
DOI:10.4103/jcrt.JCRT_397_17  PMID:32930111
Background: Chronic state of inflammation is an important factor in advanced cancer which is used by tumor cells for maintaining survival and growth. Hematological parameters such as neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), and lymphocyte/monocyte ratio (LMR) are reliable indicators of systemic inflammation. We aimed to elucidate the effect of hematological parameters and clinical features of patients on the prognosis of advanced-stage non-small cell lung cancer (NSCLC). Methods: We included 102 Stage IV NSCLC patients who presented to the oncology clinic between 2010 and 2016. Pretreatment clinical parameters and NLR, TLR, and LMR were retrieved from the medical records. The cutoff values, calculated with receiver operating curve analysis, for NLR, LMR, and TLR were 2.5, 3, and 183, respectively. All patients were divided into two groups according to cutoff values and analyzed accordingly. Results: Median overall survival and progression-free survival were 10 and 6 months, respectively. In univariate analysis, high NLR, high TLR, and low LMR were found to be significantly associated with survival. Among clinical parameters having eastern cooperative oncology group performance score 0–1, older age (≥70 years) single metastatic disease was prognostic. In multivariate Cox regression analysis, only the number of metastatic lesions and LMR were found to be independent predictors for survival. Conclusion: Among hematological parameters, only LMR was found to be an independent predictor of survival in patients with advanced-stage NSCLC.
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The prognostic role of thyroid transcription factor-1 in lung adenocarcinoma p. 737
Esin Oktay, Utku Oflazoglu, Yelda Varol, Ozgur Tanriverdi, Necla Mermur, Hayri Ustun Arda, Lutfiye Demir, Ozge Keskin, Tural Ahmadli, Isil Somali, Ilhan Oztop, Nezih Meydan
DOI:10.4103/jcrt.JCRT_1404_16  PMID:32930112
Aims: In this study, we investigated the expression of thyroid transcription factor-1 (TTF-1) in lung adenocarcinoma patients' samples and analyzed the association of TTF-1 with clinicopathological parameters, prognosis, and treatment options in patients with lung adenocarcinoma. Subjects and Methods: This retrospective study enrolled 200 patients who were histologically confirmed lung adenocarcinoma with Stage I-IV disease, between 2008 and 2015 years. The cytological archive of these hospitals' Pathology Department was searched. The available slides and the clinical information were reviewed and correlated. All analyses were conducted by SPSS version 15.0 statistical software. Results: Sixty-five (32.5%) of the patients showed TTF-1 negativity and 135 (67.5%) of them showed TTF-1 positivity. The median survival for TTF-1 positive and negative patients was 19.6 and 12.2 months, respectively. We did not find any statistical significance in-between the parameters in terms of the survival data. In TTF-1-negative group, the survival time of epidermal growth factor receptor mutation positive (P = 0.049), cytokeratin 7 (CK7) positive (P = 0.009) patients and those who had received curative radiotherapy (P = 0.028) was significantly better as compared to TTF-1-positive group. We also analyzed the relation between TTF-1 and survival outcome or chemotherapy selection in Stage IV disease. We could not identify any correlation between TTF-1 and survival outcome or treatment selection. Conclusions: This study suggests that TTF-1 is not a favorable prognostic factor in lung adenocarcinoma patients. The prognostic role of CK7 and relationship between TFF-1 expression in lung adenocarcinoma and predictive role of TTF-1 expression for the selection of first-line treatment in Stage IV lung adenocarcinoma should be validated in prospective and randomized studies.
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The effect of kanglaite injection in combination with gefitinib versus gefitinib alone in patients with nonsmall cell lung cancer: A meta-analysis p. 745
He Hailang, Zhu Jiping, Cao Ailing, Zhou Xianmei
DOI:10.4103/jcrt.JCRT_1213_16  PMID:32930113
Objective: The objective of the study was to evaluate the clinical efficacy of kanglaite (KLT) injection combined with gefitinib versus gefitinib alone in the treatment of nonsmall cell lung cancer (NSCLC). Methods: The randomized controlled trials involving NSCLC treatment with KLT injection combined with gefitinib versus gefitinib alone were searched on seven medical databases up to October 2016. Two reviewers independently assessed the methodological quality of the included studies. The RevMan 5.3 software was employed for data analysis. Results: Seven randomized trials involving 554 patients met our criteria. Compared with gefitinib alone, KLT injection combined with gefitinib showed significant effects in increasing objective response rate (relative risk [RR] =1.38; 95% confidence interval [CI], 1.09–1.75), improving the performance status (RR = 1.80; 95% CI: 1.34–2.42), raising the percentages of CD4+ cells (weighted mean difference [WMD] = 4.45; 95% CI: 2.61–6.28), natural killer cells (WMD = 4.43; 95% CI: 3.85–5.01), and ratio of CD4+/CD8+ (WMD = 0.08; 95% CI: 0.02–0.14), whereas the difference was not significant in gefitinib toxicity including rash (RR 0.90; 95% CI: 0.58–1.40, P = 0.65), diarrhea (RR 1.04; 95% CI: 0.66–1.64, P = 0.88), and liver injury (RR 1.00; 95% CI: 0.58–1.73, P = 1.00), CD3+ cells (WMD = 1.16; 95% CI: -2.64–4.97) and CD8+ cells (WMD = 6.78; 95% CI: -1.68–15.23). Conclusion: Co-use of KLT injection and gefitinib may benefit the patients with NSCLC through enhancing the therapeutic effectiveness compared with gefitinib alone. To confirm these results, further rigorously designed trials are warranted.
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Can consolidative thoracic radiotherapy improve outcomes in extensive-disease small cell lung cancer after chemotherapy with complete/near-complete responders? p. 752
Esra Korkmaz Kirakli, Hasan Yilmaz, Cimen Akcay, Berna Komurcuoglu, Ufuk Yilmaz
DOI:10.4103/jcrt.JCRT_776_17  PMID:32930114
Background: In extensive-disease-small cell lung cancer (ED-SCLC), the median survival is 8–10 months and 2-year survival is <5%. Primary tumor progression occurs in 90% of patients approximately within 1 year. The role of consolidative thoracic radiotherapy (C-TRT) for the postchemotherapy residue with the aim of improving local control (LC) and survival is currently of great interest. The objective of this study is to determine the effectiveness of C-TRT on LC, progression-free survival (PFS), and overall survival (OS) in ED-SCLC. Materials and Methods: Medical records of patients diagnosed as SCLC between January 2010 and December 2015 were evaluated retrospectively. Patients who received C-TRT were identified. Pre- and post-chemotherapy radiological evaluations, radiotherapy schedules, relapse patterns, toxicity incidence, LC, PFS, and OS were analyzed. Results: Among 552 SCLC patients, 26 ED-SCLC patients who underwent C-TRT were analyzed. Median follow-up was 7.5 months (range, 6.5–8.5 months). Nearly 50% of the patients had >4 metastatic lesions. Restaging was performed mostly by positron emission tomography/computed tomography and cranial magnetic resonance imaging. All patients had complete or near-complete response distantly. C-TRT was 10 × 300 cGy (n = 1), 23 × 200 cGy (n = 2), 25 × 200 cGy (n = 7), 30 × 200 cGy (n = 12), and 33 × 200 cGy (n = 4). There was no toxicity ≥ Grade 3. LC rate was 77%; there was no isolated local relapse. PFS was 3 months. Median survival was 13 months. The 1- and 2-year OS rates were 62% and 8%, respectively. Conclusion: In ED-SCLC patients, C-TRT may prevent isolated local recurrence and may improve 1-year survival. This survival improvement might be the reflection of high intrathoracic control achieved in 77% of patients.
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Definitive concurrent chemoradiotherapy outcomes in Stage IIIB nonsmall cell lung cancer patients younger than 45 years: A retrospective analysis of 145 patients p. 757
Erkan Topkan, Ozan Cem Guler, Yurday Ozdemir
DOI:10.4103/jcrt.JCRT_1063_16  PMID:32930115
Purpose: To assess the survival outcomes and prognostic factors of young (≤45 years) Stage IIIB nonsmall cell lung cancer (NSCLC) patients treated with definitive concurrent chemoradiotherapy (C-CRT). Materials and Methods: Medical records of 145 Stage IIIB NSCLC patients (≤45 years) who received 60–66 Gy thoracic radiotherapy and concurrent 1–3 cycles of cisplatin-based doublet chemotherapy were retrospectively evaluated. The primary endpoint was overall survival (OS), while locoregional progression-free survival (LRPFS), progression-free survival (PFS), and evaluation of potential prognostic factors constituted the secondary endpoints. Results: At median 21.6 months (range: 7.3–62.5) of follow-up, the median and 4-year survival estimates were 24.8 months and 24.2% for OS, 15.7 months and 18.9%, for LRPFS and 12.0 months and 11.2% for PFS, respectively. On univariate analyses, among all factors, the smaller tumor size (≤7.0 cm; P = 0.03), lower T-stage (T1–T2; P = 0.02), lower N-stage (N2; P = 0.01), absence of anemia before C-CRT (hemoglobin [Hb] ≥12 g/dL; P < 0.001), and lower/no pretreatment weight loss (WL ≤5%; P < 0.001) were found to be associated significantly with longer median OS durations, which also retained their independent significance on multivariate analyses, except for tumor size category. Conclusions: The encouraging median 24.8 months OS duration observed here in young NSCLC patients accords well with the results of recent landmark locally advanced NSCLC series without age stratification. Other than the well-established T and N stages, extra exhibit of superior OS in patients with initial Hb ≥12 g/dL and ≤5% WL levels suggests a noteworthy prognostic role for these two latter variables in the stratification of such patients.
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Post-progression survival is strongly linked to overall survival in refractory small-cell lung cancer patients who received amrubicin p. 764
Hisao Imai, Kyoichi Kaira, Keita Mori, Nodoka Watase, Takeshi Hisada, Masanobu Yamada, Koichi Minato
DOI:10.4103/jcrt.JCRT_1170_16  PMID:32930116
Background: The benefits of second-line chemotherapy on the overall survival (OS) of small-cell lung cancer (SCLC) patients might be confounded by subsequent therapies. In this study, we aimed to determine the influence of progression-free survival (PFS) and postprogression survival (PPS) on OS after second-line chemotherapy in patients with refractory SCLC treated with amrubicin monotherapy. Materials and Methods: We analyzed the data of 35 patients with refractory SCLC who were treated with amrubicin monotherapy as second-line chemotherapy between July 2005 and December 2015. The correlations of PFS and PPS with OS were statistically analyzed at the individual level using Spearman's rank correlation and linear regression analyses. Results: The correlation between PPS and OS was strong (r = 0.88, P < 0.05, R2 = 0.87), while that between PFS and OS was weak (r = 0.60, P < 0.05, R2 = 0.15). The number of regimens administered after disease progression postsecond-line chemotherapy was significantly associated with PPS (P = 0.003). Conclusions:OS is more strongly linked to PPS than to PFS in refractory SCLC patients who undergo amrubicin monotherapy as a second-line treatment. These results suggest that treatments administered after second-line chemotherapy affect the OS of refractory SCLC patients treated with amrubicin monotherapy.
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A clinico-epidemiological, pathological, and molecular study of lung cancer in Northwestern India p. 771
HS Darling, Sundaram Viswanath, Rajeshwar Singh, Subhas Ranjan, Nikhil Pathi, Anvesh Rathore, Abhishek Pathak, Rahul Sud
DOI:10.4103/jcrt.JCRT_473_17  PMID:32930117
Introduction: Lung cancer is the most common malignant disease and is the topmost cause of cancer deaths in the world across all age groups and in both sexes. It is the most common cause of cancer deaths in developed countries and is also rising at an alarming rate in the developing countries. Objective: The present study was undertaken to explore the clinicopathological and molecular profile of bronchogenic carcinoma in northwestern population of India. Materials and Methods: A total of 136 consecutive patients with histologically proven bronchogenic carcinoma, registered between May 2014 and April 2016 at a tertiary care hospital in New Delhi, India, were analyzed. Results: Out of a total of 136 diagnosed cases, 6% were in the third to fourth decade of life, 49% in the fifth to sixth decade, and 45% in the seventh decade and above. Seventy-one percent of patients were male. Smoking was the major risk factor in 65.40% of patients. About 33% of female patients were smokers with a significant overlap in the use of smoking objects. Twenty-one percent of patients had been initially empirically treated with antitubercular therapy. Most common symptoms at presentation were cough, dyspnea, weight loss, and chest pain. Pleural effusion, paraneoplastic phenomenon, clubbing, peripheral lymphadenopathy, and Pancoast syndrome were the major signs at presentation. Twenty-one percent of nonsmokers and 40% of smoker patients presented with ECOG Performance Status 3 or 4. Ninety-three percent of patients presented in stage III or IV. Metastases to skeleton, brain, liver, pleura, adrenals, lung, and distant lymph nodes were present in 30.8%, 16.9%, 15.4%, 15.4%, 14.7%, 13.2%, and 11.8%, respectively. Fiberoptic bronchoscopy was found to be the most efficient diagnostic procedure as compared to transthoracic and thoracoscopic methods. Histologically, squamous cell carcinoma, adenocarcinoma, and small cell carcinoma and its variants were seen in 35.30%, 44.9%, and 15.40% cases, respectively. Nearly 4.4% of patients were diagnosed as poorly differentiated carcinoma. Driver mutations (epidermal growth factor receptor or anaplastic lymphoma kinase) were detected in 48% (25 of 52 tested) of adenocarcinomas and 55.55% (5 of 9 tested) of young, nonsmoker, female squamous cell carcinoma patients. Conclusion: This study highlights that the adenocarcinoma incidence is surpassing squamous cell carcinoma in Indian lung cancer patients also, as observed in Western population. Mean age at diagnosis is about one decade earlier than in the Western population. Driver mutations are more common in India than in the West as also reported in other Asian studies.
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Cause determination of missed lung nodules and impact of reader training and education: Simulation study with nodule insertion software p. 780
Subba R Digumarthy, Roberto Lo Gullo, Marie-Helene Levesque, Karl Sayegh, Sishir Rao, Scott B Raymond, Alexi Otrakji, Mannudeep K Kalra
DOI:10.4103/jcrt.JCRT_312_17  PMID:32930118
Background: There are “blind spots” on chest computed tomography (CT) where pulmonary nodules can easily be overlooked. The number of missed pulmonary nodules can be minimized by instituting a training program with particular focus on the depiction of nodules at blind spots. Purpose: The purpose of this study was to assess the variation in lung nodule detection in chest CT based on location, attenuation characteristics, and reader experience. Materials and Methods: We selected 18 noncalcified lung nodules (6–8 mm) suspicious of primary and metastatic lung cancer with solid (n = 7), pure ground-glass (6), and part-solid ground-glass (5) attenuation from 12 chest CT scans. These nodules were randomly inserted in chest CT of 34 patients in lung hila, 1st costochondral junction, branching vessels, paramediastinal lungs, lung apices, juxta-diaphragm, and middle and outer thirds of the lungs. Two residents and two chest imaging clinical fellows evaluated the CT images twice, over a 4-month interval. Before the second reading session, the readers were trained and made aware of the potential blind spots. Chi-square test was used to assess statistical significance. Results: Pretraining session: Fellows detected significantly more part-solid ground-glass nodules compared to residents (P = 0.008). A substantial number of nodules adjacent to branching vessels and posterior mediastinum were missed. Posttraining session: There was a significant increase in detectability independent of attenuation and location of nodules for all readers (P < 0.0008). Conclusion: Dedicated chest CT training improves detection of lung nodules, especially the part-solid ground-glass nodules. Detection of nodules adjacent to branching vessels and the posterior mediastinal lungs is difficult even for fellowship-trained radiologists.
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Evaluation of spirometry as a parameter of response to chemotherapy in advanced lung cancer patients: A pilot study p. 788
Deepak Aggarwal, Prasanta R Mohapatra, Ashok K Janmeja, Varinder Saini
DOI:10.4103/jcrt.JCRT_919_17  PMID:32930119
Context: Spirometry is an important tool to monitor treatment response in diseases such as chronic obstructive pulmonary disease and asthma. However, there is lack of evidence to support its application to evaluate response to chemotherapy in advanced lung cancer. It might be a useful adjunct to the imaging-based response evaluation which lacks functional assessment of lungs. Aims: The study was conducted to evaluate the change in spirometry in lung cancer patients after chemotherapy and to find its correlation with change in physical tumor size. Subjects and Methods: Sixty-two advanced lung cancer patients who were eligible for palliative chemotherapy were enrolled. Baseline tumor size evaluation using Response Evaluation Criteria in Solid Tumor (RECIST)-based scoring system, and spirometry was done. Four cycles of double agent (platinum doublets) chemotherapy were administered, after which treatment response was evaluated. Repeat spirometry was analyzed and correlated with changes in physical tumor size. Results: Twenty-five patients showed a response (all partial response) to four cycles of chemotherapy. Small cell carcinoma showed a better response rate than non-small cell carcinoma (78% vs. 39%). There was statistically significant improvement in forced expiratory volume in 1 (FEV1) (P = 0.01) and forced vital capacity (P = 0.03) in responders as compared to nonresponders. Change in FEV1 showed a statistically significant correlation with the change in tumor size (RECIST score) (r = –0.34; P = 0.04). Conclusions: Improvement in spirometry correlates with the tumor response as judged using RECIST criteria after chemotherapy. Further studies with bigger sample size are required to consolidate the results.
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Identification of activated pathways in lung adenocarcinoma based on network strategy p. 793
Bo Yu, Tao Li, Juan Chen, Feng-Qiang Wang, Jian-Hua Fu, Shu-Mei Liu, Yan Wang, Xin Zhang, Hai-Tao Yang
DOI:10.4103/0973-1482.199458  PMID:32930120
Background: Lung adenocarcinoma has increased incidence over the past years and is the cause for almost 50% of deaths attributable to lung cancer. The objective of this paper is to identify activated pathways associated with lung adenocarcinoma based on gene co-expression network analysis. Materials and Methods: Kyoto Encyclopedia of Genes and Genomes pathway analysis of dysregulated genes was performed based on Expression Analysis Systematic Explorer test to illuminate the biological pathways. Co-expression networks of lung adenocarcinoma in different tumor Stages (IA, IB, IIA, IIB, IIIA, IIIB, and IV) were constructed by Empirical Bayes approach to reweight gene pair scores. Pathway activity analysis was conducted to compute the distribution of pathways in different stages and to identify “activated” pathways in lung adenocarcinoma. Results: We evaluated 211 dysregulated genes between lung adenocarcinoma patients and normal controls. Pathway activity analysis was performed and P values of pathways, which obtained from co-expression networks (Stage IA, IB, IIA, IIB, IIIA, IIIB, and IV), were calculated. Cell cycle, progesterone-mediated oocyte maturation, and oocyte meiosis were activated during all stages in lung adenocarcinoma. Conclusions: We successfully identified three activated pathways (cell cycle, progesterone-mediated oocyte maturation, and oocyte meiosis) in different Stages (IA, IB, IIA, IIB, IIIA, IIIB, and IV) of lung adenocarcinoma.
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Nestin is significantly associated with the overall survival of nonsmall cell lung cancer: A meta-analysis p. 800
Dehai Zhang, Jian Wang
DOI:10.4103/0973-1482.204901  PMID:32930121
Aims: Some studies investigated the association between nestin and the overall survival (OS) of nonsmall cell lung cancer (NSCLC). However, the results were conflicted and inconclusive. Therefore, we performed this meta-analysis to determine the association between nestin and OS of NSCLC. Materials and Methods: PubMed and EMBASE were searched to find relevant studies. The strength of the association was calculated with the hazard ratios (HRs) and respective 95% confidence intervals (CIs). Results: High expression of nestin was significantly associated with OS of NSCLC (HR = 2.09; 95% CI = 1.59–2.77). In the stratified analysis by race, we found that the expression of nestin was significantly associated with OS of NSCLC in Asians (HR = 3.02; 95% CI = 1.80–5.07) and Caucasians (HR = 1.81; 95% CI = 1.21–2.71). In addition, when we limited the meta-analysis to studies that controlled for clinical parameters, a significant association between nestin and OS of NSCLC remained (HR = 2.19; 95% CI = 1.54–3.11). A sensitivity analysis showed no substantial modification of the estimates after exclusion of individual studies. Conclusions: In conclusion, this meta-analysis suggested that high expression of nestin was significantly associated with OS of NSCLC.
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Putative stemness markers octamer-binding transcription factor 4, sex-determining region Y-box 2, and NANOG in non-small cell lung carcinoma: A clinicopathological association p. 804
Vinal A Upadhyay, Kanisha A Shah, Dimple P Makwana, Apexa P Raval, Franky Dhaval Shah, Rakesh M Rawal
DOI:10.4103/jcrt.JCRT_213_18  PMID:32930122
Background: The promising improvement in the clinical outcome of lung cancer can be possibly achieved by identification of the molecular events that underlie its pathogenesis. Cancer stem cell (CSC) being one of the subsets of tumor majorly participates in drug resistance and treatment failure because of the moderate cell cycle, lower proliferation, and increased expression of DNA repair and anti-apoptosis genes. Although many putative CSC markers exist, a precise characterization for non-small cell lung cancer is of utmost importance due to increased mortality rate and lack of targeted therapies. Hence, the article focuses on the expression of stemness-associated markers, namely octamer-binding transcription factor 4 (OCT4), NANOG, and sex-determining region Y-box 2 (SOX2) in non-small cell lung cancer (NSCLC) patients. Methods: The expression of OCT4, NANOG, and SOX2 were evaluated in 32 histopathologically confirmed NSCLC tissues using real-time polymerase chain reaction. The obtained expression was correlated with clinical and pathological manifestations using the statistical test such as Student's t-test and Pearson correlation in varied statistical software. Results: Results showed a significantly higher expression of OCT4 and NANOG compared to SOX2 in the tumor tissues. When the expression of these markers was correlated with the clinical parameters, higher expression was seen in males, patients with age above 60 years, and in adenocarcinoma subtype. In correlation with the habit, higher expression of OCT4 and SOX2 was observed in habituated patients. Expression of NANOG and OCT4 was higher even in patients with poor differentiation. Conclusion: The expression and prognostic significance of CSC markers obviously vary depending on histological NSCLC subtype. Importantly, our findings suggest that OCT4, SOX2, and NANOG network together may be promising for ongoing targeted therapies in specific NSCLC subgroups.
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Association of cytokines levels with epidermal growth factor receptor mutation in lung cancer patients p. 811
Priyanka Gaur, Sandeep Bhattacharya, Surya Kant, R A. S. Kushwaha, Gaurav Singh, Sarika Pandey
DOI:10.4103/jcrt.JCRT_632_18  PMID:32930123
Background: Lung cancer is one of the most frequent types of cancer and the leading cause of cancer-related deaths. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) being highly expressed in lung cancers. Activation of EGFR through oncogenic mutations leads to upregulation of gene expression that may heighten the inflammatory response in certain situations. EGFR acts as a key regulator and a cellular hub for inflammatory cytokine signaling, thereby promoting tumor cell proliferation, invasion, migration, metastases, and survival. The aim of the present study is to determine the serum cytokines levels and EGFR mutation status in lung cancer patients to investigate the association between the EGFR mutation status and cytokines levels with lung cancer patients. Materials and Methods: Blood and tissue samples of lung cancer patients were collected. The EGFR mutations of lung cancer patients were determined by the immunohistochemistry (IHC) and serum cytokines levels of lung cancer patients were determined using ELISA. Results: Statistically significant association of EGFR mutations with adenocarcinoma subtypes and non-smokers were found (P < 0.05). Lung cancer patients with EGFR mutations had significantly higher tumor necrosis factor-alpha levels when compared to lung cancer patients without EGFR mutations (P < 0.01), and EGFR mutation status was not significantly associated with interleukin-6 levels (P = 0.24). Conclusion: EGFR mutation detection by the IHC method is a potentially useful tool to guide clinicians for personalized treatment of lung cancer patients of adenocarcinoma subtype, and cytokines are good biomarkers for the diagnosis, prognosis, and prediction of treatment responses in lung cancer patients as well as act as therapeutic targets. This study will provide biomarkers for lung cancer diagnosis and treatments.
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The prognostic significance of the 18F-fluorodeoxyglucose positron emission tomography/computed tomography in early-stage nonsmall cell lung cancer p. 816
Caglayan Geredeli, Mehmet Artac, Ismail Kocak, Lokman Koral, Abdullah Sakin, Tamer Altinok, Bugra Kaya, Mustafa Karaagac
DOI:10.4103/jcrt.JCRT_911_17  PMID:32930124
Context: The prognostic criteria for early-stage nonsmall cell lung cancer (NSCLC) wait to be explored. Aim: In this study, our aim was to evaluate the prognostic significance of the positron emission tomography/computed tomography (PET/CT) maximum standardized uptake value (SUVmax) value of the primary tumor in patients with a diagnosis of early-stage NSCLC who received surgical treatment. Settings and Design: This was a multicenter retrospective design. Materials and Methods: Patients who had been diagnosed with early-stage NSCLC and who underwent surgery for the condition were included in this study. The preoperative fluorodeoxyglucose (18F-FDG) PET/CT results of the patients were retrospectively accessed from their medical files. The disease-free survival (DFS) rates of patients who had SUVmax values above and below the determined cutoff value were compared. Statistical Analysis Used: SPSS version 22 and Kaplan–Meier method were used for statistical analysis. Results: A total of 92 patients were included in the study. The median age of the patients was 60 years (range: 36–79). The determined cutoff SUVmax value of the primary tumor was 13.6. A comparison of the DFS rates of the patients with an SUVmax value above and below 13.6 revealed a significant difference in patients with Stage I (22.9 months vs. 50.3 months; P = 0.02) and Stage II (28 months vs. 40.4 months; P = 0.04), Stage I + II (43.5 months vs. 26.1 months; P = 0,02), and Stage IIIA (14.7 months vs. 13.6 months; P = 0.92) NSCLC. Conclusions: We found that in early-stage NSCLC patients, the SUVmax value of the primary mass in 18F FDG PET/CT was a prognostic indicator for the DFS rates.
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Evaluation of antioxidant and anticancer effects of Thymbra sintenisii subsp. isaurica extract Highly accessed article p. 822
Ceylan Hepokur, Sema Misir, Mehmet Çiçek, Ilhan Yaylim, Umit Zeybek
DOI:10.4103/jcrt.JCRT_355_17  PMID:32930125
Background: The purpose of this study was to investigate the phenolic composition and antioxidant activity of Thymbra sintenisii subsp. isaurica extract (TSIE) and, to evaluate, for the first time, anticancer effect on human MCF-7 (breast carcinoma) cells. Materials and Methods: The antioxidant capacity of TSIE was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and total polyphenol assays. The anticancer activities of TSIE were tested on MCF-7 (breast carcinoma) cells. Results: Total polyphenol value of extracts TSIE was found as 73.02 mg gallic acid /g powder. DPPH result of IC50 value of TSIE was found to be 27.15 μg/mL. To examine anticancer effect of TSIE at different concentrations were given on MCF-7 cells. TSIE was observed to reduce the cell viability in a dose-dependent manner. This anticancer property of the TSIE provides a highlights the importance of plant research for drug design. Conclusion: In this study, anticancer effects and antioxidant level of endemic species, that is TSIE, are evaluated on MCF-7 cells. Thus, an effective therapeutic agent for cancer treatment is aimed to develop. Further studies are needed to better understand the molecular mechanisms underlying this effect of TSIE.
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Checkpoint inhibitors in advanced nonsmall-cell lung cancer; a Bayesian network meta-analysis p. 828
Hakan Bozcuk, Mustafa Yıldırım, Özlem Sever, Hasan Mutlu, Mehmet Artaç
DOI:10.4103/jcrt.JCRT_450_19  PMID:32930126
Background: Checkpoint inhibitors (CPIs) have improved survival compared to chemotherapy alone in advanced nonsmall-cell lung cancer (NSCLC). This article aims to compare indirect evidence and rank the effect of different CPIs in this setting. Materials and Methods: In this network meta-analysis, we searched for trials comparing CPIs in advanced NSCLC. Figures for survival endpoints were extracted. In addition, a network meta-regression analysis was carried out. Results: A total of 9220 patients from 16 trials were included in the analysis. In the first-line setting, for the overall survival endpoint, the chemotherapy + Pembrolizumab combination had the highest effectivity rank probability as compared to chemotherapy (hazard ratio = 0.788, 95% credential interval = 0.728–0.855). For the second-line setting, and also for the efficacy in terms of progression-free survival, various CPIs and their combinations were ranked. Conclusion: Some degree of differences in terms of efficacy exists between different types, dosages, settings, and combinations of CPI. We quantify these differences to guide clinical practice.
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Hospital-based study on demographic, hematological, and biochemical profile of lung cancer patients p. 839
Priyanka Gaur, Sandeep Bhattacharya, Surya Kant, RA S. Kushwaha, Rajiv Garg, Sarika Pandey, Abhishek Dubey
DOI:10.4103/jcrt.JCRT_185_18  PMID:32930127
Background: Lung cancer is considered as the most commonly diagnosed cancer. It is the leading cause of cancer-related mortality. Smoking and environmental pollutants act as important risk factors in majority of lung cancer cases (80%–90%). Material and Methods: This is a hospital-based study carried on in lung cancer patients of North India. Demographic profile of lung cancer patients was recorded. Hematological and biochemical profiles of lung cancer patients and healthy controls were compared. Results: Highest proportion of lung cancer was found in the age group of 46–60 years. Lung cancer was seen in highest number in male gender (76.63%) and also in those patients belonging to the rural category (84.58%). In this study, only 3.98% lung cancer patients having the past history of cancer and 5.47% showing the family history of cancer. Significant differences were found in weight and body mass index (BMI) of lung cancer patients when compared to healthy control (P < 0.0001). Hemoglobin (Hb) was found lower in lung cancer patients as compared with healthy controls. Significant difference was also observed in Hb levels of these two groups (P < 0.000). The serum protein level was lower in lung cancer patients than healthy controls. A significant difference was also observed in the protein levels of these two groups (P < 0.0001). Serum alkaline phosphatase (ALP) levels were higher in lung cancer patients in comparison to healthy controls. A significant difference was also observed in serum ALP levels in lung cancer patients as compared with healthy controls (P < 0.0001). Conclusions: Significant difference between BMI, Hb, serum albumin, and total protein was found in this study. These biomarkers may be helpful in the diagnosis of lung cancer at early stage and also in the follow-up assessment of the effects of treatment.
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Correlation of epidermal growth factor receptor mutation status in plasma and tissue samples of patients with non-small cell lung cancer p. 843
Mee-Sook Roh, Neul-Bom Yoon, Seul Lee, Bo-Hyoung Kang, Soo-Jung Um, Dong-Hyun Lee, Choonhee Son
DOI:10.4103/jcrt.JCRT_515_18  PMID:32930128
Background: Somatic mutations of the gene encoding epidermal growth factor receptor (EGFR) are detected in approximately 30%–50% of patients with non-small cell lung cancers (NSCLC), so detection of EGFR mutation is the pivotal step of treatment in patients with advanced NSCLC. However, difficulty in obtaining sufficient tissue and bias from the heterogeneity of the tumor samples are the major obstacles. Although analyzing EGFR with circulating tumor DNA (ctDNA) in plasma is a breakthrough, accuracy is the problem in variable methods. Peptide nucleic acid (PNA) clamping-assisted fluorescence melting curve analysis (PANAMutyper®) is a novel and highly sensitive method of detecting EGFR mutation in tumor tissues. Aims and Objectives: This study was designed to evaluate PANAMutyper® for detecting EGFR mutation with ctDNA of patients with lung cancer. Materials and Methods: EGFR mutation status detected by PNA clamp with tissue samples and by PANAMutyper® with ctDNA was compared. Tissue biopsy was done in 158 patients with lung tumor, in which 23 cases were excluded and 135 cases were enrolled. EGFR mutation rate was 23.0% (31/135) in overall patients. All the plasma samples of the cases with mutant EGFR in tissue samples were verified by an already known highly sensitive method of droplet digital polymerase chain reaction (ddPCR). Results: The concordance rate of tissue and plasma samples was 91.9% (124/135). The sensitivity, specificity, negative predictive value, and positive predictive value were 64.5%, 100%, 90.4%, and 100%, respectively, according to the tissue samples as a standard. PANAMutyper® method was not inferior to ddPCR for the detection of EGFR mutation including T790M with ctDNA. These results suggest that the detection of EGFR mutation status using ctDNA in plasma by PANAMutyper® is a feasible test prior to tissue biopsy.
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Concomitant echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase rearrangement and epidermal growth factor receptor mutation in non-small cell lung cancer patients from eastern India p. 850
Prasanta Raghab Mohapatra, Satyajeet Sahoo, Sourin Bhuniya, Manoj Kumar Panigrahi, Saroj Kumar Das Majumdar, Pritinanda Mishra, Susama Patra
DOI:10.4103/jcrt.JCRT_678_18  PMID:32930129
Background: In non-small cell lung cancer common driver mutations such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are usually mutually exclusive. This study aimed to elucidate the concurrence of EGFR mutation and ALK rearrangement in eastern India patients with primary lung adenocarcinoma and assess the response of EGFR tyrosine kinase inhibitor (TKI) therapy after 6 months in primary lung adenocarcinoma. Methods: We retrospectively analyzed 198 adenocarcinomas for EGFR and ALK mutations. EGFR and ALK tests were done by real-time polymerase chain reaction and immunohistochemistry (IHC) techniques, respectively. Radiological response was assessed by Response Evaluation Criteria in Solid Tumors (version 1.1). Results: EGFR/ALK co-alteration was found in 4 adenocarcinoma patients. All were males with advanced disease. Younger patients had exon 19 deletion whereas older ones showed exon 21 mutation. The initial option of ALK-TKI in all four patients was excluded straightaway due to the high-cost burden of ALK-TKI. Two of them showed a partial response while other two had stable disease after 6 months of EGFR TKI therapy. Conclusion: EGFR/ALK co-alterations in adenocarcinomas albeit rare do exist. The challenge of monetary hurdle in developing countries with ALK TKI therapy can be handled by giving only EGFR TKI in these cases of concomitant mutations. Future perspective in research could be finding an agent with the potential of dual inhibition of ALK and EGFR.
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Evaluation of the relationship between serum ghrelin levels and cancer cachexia in patients with locally advanced nonsmall-cell lung cancer treated with chemoradiotherapy p. 855
Pelin Uysal, Cigdem Usul Afsar, Volkan Sozer, Berrin Inanc, Fulya Agaoglu, Zeynep Gural, Nevin Yaman Fazlıoglu, Caglar Cuhadaroglu, Hafize Uzun
DOI:10.4103/jcrt.JCRT_10_19  PMID:32930130
Background: Ghrelin plays a role in mechanisms related to cancer progression – including cell proliferation, invasion and migration, and resistance to apoptosis in the cell lines from several cancers. We investigated the role of ghrelin levels in cancer cachexia-anorexia in patients with locally advanced nonsmall-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT). Materials and Methods: This study involved 84 NSCLC patients who had received concomitant CRT. Blood ghrelin levels were compared before and 3 months after CRT. Meanwhile, changes in body weight of the patients were also investigated with changes in ghrelin levels before and after CRT. Results: Ghrelin levels were significantly decreased in line with changes in patients' weights in patients receiving CRT (P < 0.001). Serum albumin levels and inflammatory-nutritional index were significantly decreased after radiotherapy (RT) (3.01 ± 0.40 g/dL, 0.38 ± 0.20) when compared with its baseline levels (3.40 ± 0.55 g/dL,P < 0.001; 0.86 ± 0.71,P < 0.001, respectively). Serum C-reactive protein levels were significantly increased after CRT (7.49 ± 6.53 mg/L) when compared with its baseline levels (9.54 ± 3.80 mg/L,P = 0.038). After RT, ghrelin levels in patients were positively correlated with body mass index (r = 0.830,P < 0.001) and albumin (r = 0.758,P < 0.001). Conclusion: Ghrelin may play a role in the pathogenesis of weight loss in NSCLC patients. Ghrelin seems to be implicated in cancer-related weight loss. Ghrelin, cancer, and RT all together have a role in tumor-related anorexia-cachexia in patients with NSCLC. Results of this study need further evaluation as regards to its potential role as an adjuvant diagnostic or prognostic marker.
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Neo-adjuvant chemotherapy followed by either continuous hyper-fractionated accelerated radiation therapy week-end less or conventional chemo-radiotherapy in locally advanced NSCLC-A randomised prospective single institute study p. 860
Rajesh Kumar, HS Kumar, Murali Paramanandhan, Ramesh Purohit, Neeti Sharma, SL Jakhar, Satynarayan Sharma, Sitaram Maharia, Rahul Kumar Rai
DOI:10.4103/jcrt.JCRT_377_16  PMID:32930131
Context: Better locoregional control and increased overall survival by continuous hyper fractionated accelerated radiotherapy have been shown in unresectable nonsmall cell lung carcinoma (NSCLC). Dose escalation and neoadjuvant chemotherapy (NACT) along with continuous hyperfractionated accelerated radiotherapy week end-less (CHARTWEL) were also tried for improved survival. In this present study, we compared the results of NACT followed by CHARTWEL against NACT followed by conventional concurrent chemo-radiation therapy. Aims: The aim of this study is to compare the locoregional control and toxicities in NSCLC Stage IIIA and B in both arms. Settings and Design: Randomized, prospective single-institutional study with a study population comprising all locally advanced unresectable NSCLC patients enrolled in 2014 at our institute. Subjects and Methods: All enrolled patients were randomized into two arms-CHARTWEL and concomitant chemo-radiotherapy (CCRT), after three weeks of the fourth cycle of NACT. In CHARTWEL arm 30 patients received two-dimensional radiotherapy (RT) 58.5 Gy/39 fr/2.5 weeks while in CCRT arm 30 received 66 Gy/33 fr/6.5 weeks. Disease response was evaluated at 6 months and toxicity assessment during and after treatment completion. Data were analyzed using tools such as percentage, mean, Chi-square test and P value. Chi-square and P value was calculated by statistical online software (http://quantpsy.org). Results: 28% of patients in study arm and 20% in control arm had complete response at 6 months after RT. Locoregional disease control was observed in 44% in study arm and 32% in control arm of patients. There was no statistical difference in grades of toxicities or overall survival (OS)/disease-free survival except persistent esophagitis Grade III seen in two patients of study arm. Conclusions: Study suggests that CHARTWEL in combination with NACT is an effective strategy to treat patients with locally advanced lung cancer with the advantage of a smaller dose and shorter duration. Although large multivariate studies still needed.
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Utilizing benchmarked dataset and gene regulatory network to investigate hub genes in postmenopausal osteoporosis p. 867
Xiao-Lu Wang, Yi-Ming Liu, Zhi-Dong Zhang, Shan-Song Wang, Yi-Bin Du, Zong-Sheng Yin
DOI:10.4103/0973-1482.204842  PMID:32930132
Objective: The objective of this paper was to investigate hub genes of postmenopausal osteoporosis (PO) utilizing benchmarked dataset and gene regulatory network (GRN). Materials and Methods: To achieve this goal, the first step was to benchmark the dataset downloaded from the ArrayExpress database by adding local noise and global noise. Second, differentially expressed genes (DEGs) between PO and normal controls were identified using the Linear Models for Microarray Data package based on benchmarked dataset. Third, five kinds of GRN inference methods, which comprised Zscore, GeneNet, context likelihood of relatedness (CLR) algorithm, Partial Correlation coefficient with Information Theory (PCIT), and GEne Network Inference with Ensemble of trees (Genie3), were described and evaluated by receiver operating characteristic (ROC) and precision and recall (PR) curves. Finally, GRN constructed according to the method with best performance was implemented to conduct topological centrality (closeness) for the purpose of investigate hub genes of PO. Results:A total of 236 DEGs were obtained based on benchmarked dataset of 20,554 genes. By assessing Zscore, GeneNet, CLR, PCIT, and Genie3 on the basis of ROC and PR curves, Genie3 had a clear advantage than others and was applied to construct the GRN which was composed of 236 nodes and 27,730 edges. Closeness centrality analysis of GRN was carried out, and we identified 14 hub genes (such as TTN, ACTA1, and MYBPC1) for PO. Conclusion: In conclusion, we have identified 14 hub genes (such as TN, ACTA1, and MYBPC1) based on benchmarked dataset and GRN. These genes might be potential biomarkers and give insights for diagnose and treatment of PO.
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Heme oxygenase-1 in osteosarcoma p. 874
Simmi Kharb, M Halder, ZS Kundu
DOI:10.4103/jcrt.JCRT_419_17  PMID:32930133
Aim of Study: The present study was planned to analyze serum heme oxygenase-1 levels in osteosarcoma patients. Materials and Methods: Twenty five histopathologically confirmed cases of osteosarcoma localized without metastasis of all the ages attending the Orthopedic Clinics were included in the study group and twenty five patients having musculoskeletal pain (age and sex matched) served as control. Five ml of venous blood was collected aseptically from antecubital vein and serum was be separated by centrifugation and analyzed the same day. Routine biochemistry investigations were performed as per standard enzymatic methods by autoanalyzer. Serum Heme oxygenase-1 was analyzed by enzyme-linked immunosorbent assay. Results: In osteosarcoma patients, serum HO-1 levels were increased as compared to patients having musculoskeletal pain (P < 0.05). Workers have found that HO-1 induction in prostate cancer cell lines (PC3) cells restored the proliferation of osteoblasts, which was inhibited during co-culture with parental prostate cancer cell line PC3 cells. However, no concrete data are available on blood levels of HO in osteosarcoma. Major role of HO-1 is the protection against oxidative injury, additionally, it regulates cell proliferation, modulates inflammatory response and facilitates angiogenesis. Conclusion: Findings of the present study suggests that pharmacological agents that regulate HO activity or HO-1 gene silencing may become powerful tools for preventing the onset or progression of various cancers and sensitize them to anticancer therapies.
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Improvement of metallic artifacts in computed tomography in the absence of artifact reduction algorithms for spinal treatment planning applications p. 878
Marjan Alinejad, Amir Pourmoghaddas, Alireza Amouheidari, Parvaneh Shokrani
DOI:10.4103/jcrt.JCRT_1446_16  PMID:32930134
Aim of Study: The goal of this research was to investigate if application of optimized imaging parameters, recommended in literature, would be effective in producing the image quality required for treatment planning of spinal radiation fields with metallic implants. Materials and Methods: CT images from an anthropomorphic torso phantom with and without spinal implants were acquired using different imaging protocols: raising kVp and mAs, reducing the pitch and applying an extended CT scale (ECTS) technique. Profiles of CT number (CT#) were produced using DICOM data of each image. The effect of artifact on dose calculation accuracy was investigated using the image data in the absence of implant as a reference and the recommended electron density tolerance levels (Δρe). Results: Raising the kVp was the only method that produced improvement to some degree in CT# in artifact regions. Application of ECTS improved CT# values only for metal. Conclusions: Although raising the kVp was effective in reducing metallic artifact, the significance of this effect on Δρe values in corrected images depends on the required tolerance for treatment planning dose calculation accuracy. ECTS method was only successful in correcting the CT number range in the metal. Although, application of ECTS method did not have any effect on artifact regions, its use is necessary in order to improve delineation of metal and accuracy of attenuation calculations in metal, provided that the treatment planning system can use an extended CT# calibration curve. Also, for Monte Carlo calculations using patient's images, ECTS-post-processed-CT images improve dose calculation accuracy for impure metals.
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Q192R variant in paraoxonase 1 gene confers susceptibility to leiomyoma p. 884
Shirin Shahbazi, Soghra Zarei, Mahnaz Torfeh, Neda Fatahi
DOI:10.4103/jcrt.JCRT_923_16  PMID:32930135
Objective: Paraoxonase 1 (PON1) plays a defensive role against oxidative stress by destroying oxidized lipids. Q192R single nucleotide polymorphism of PON1 gene alters the enzyme's activity. Several investigations reported a link between Q192R and an increased risk of developing tumors including uterine leiomyomas. We assessed the antioxidant effects of Q192R on myoma which fluctuate in frequency between populations. Study Design: The cohort consisted of 68 unrelated uterine leiomyoma patients and 93 healthy controls that were randomly selected from women with no ultrasonographic evidence of myoma. Materials and Methods: Genotyping was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction. Chi-square test was selected to evaluate differences between the groups. Results: To analyze the correlation between PON1 Q192R and leiomyoma risk, the AA genotype was given as a reference genotype then the two other genotypes were compared with the reference. A significantly (P < 0.05) increased risk of myoma was observed with both Q192R homozygote GG and heterozygote AG genotypes. The odds ratio (OR) of AG genotype was calculated 1.8 (confidence interval [CI]: 0.94–3.62). A higher OR was seen with GG genotype (OR: 2.8; 95% CI: 0.98–8.18). Conclusion: Oxidative stress has been suspected of having a link with tumor development, and the role of endogenous-free radical scavenger is taken into consideration. Increased protein oxidative stress status and reduced antioxidant capacity have been observed in leiomyomas patients. Our study indicates that the low-antioxidant PON1 R192 allele correlates to leiomyoma development.
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Setting up a lung stereotactic body radiotherapy service in a tertiary center in Eastern India: The process, quality assurance, and early experience p. 888
Raj Kumar Shrimali, Animesh Saha, Balakrishnan Arun, Sriram Prasath, Chandran Nallathambi, Suchandana Bhoumik, Indranil Mallick, Rimpa Basu Achari, Sanjoy Chatterjee
DOI:10.4103/jcrt.JCRT_427_18  PMID:32930136
Context: Stereotactic body radiotherapy (SBRT) is increasingly being used for early-stage lung cancer and lung oligometastases. Aims: To report our experience of setting up lung SBRT and early clinical outcomes. Settings and Design: This was a retrospective, interventional, cohort study. Subjects and Methods: Patients were identified from multidisciplinary tumor board meetings. They underwent four-dimensional computed tomography-based planning. The ROSEL trial protocol, the Radiation Therapy Oncology Group (RTOG) 0236, and the UK-Stereotactic Ablative Body Radiotherapy Consortium guidelines were used for target volume and organs-at-risks (OARs) delineation, dosimetry, and plan quality assessment. Each SBRT plan underwent patient-specific quality assurance (QA). Daily online image guidance using KVCT or MVCT was done to ensure accurate treatment delivery. Statistical Analysis Used: Microsoft Excel 2010 was used for data analysis. Results: Fifteen patients were treated to one or more lung tumors. One patient received helical tomotherapy in view of bilateral lung oligometastases at similar axial levels. All the remaining patients received volumetric modulated arc therapy (VMAT)-based treatment. The prescription dose varied from 40 to 60 Gy in 5–8 fractions with alternate-day treatment. The mean and median lung V20 was 5.24% and 5.16%, respectively (range, 1.66%–9.10%). The mean and median conformity indexes were 1.02 and 1.06, respectively (range, 0.70–1.18). After a median follow-up of 17 months, the locoregional control rate was 93.3%. Conclusions: SBRT was implemented using careful evaluation of OAR dose constraints, dosimetric accuracy and plan quality, patient-specific QA, and online image guidance for accurate treatment delivery. It was safe and effective for early-stage nonsmall cell lung cancer and lung metastases. Prospective data were collected to audit our outcomes.
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Extra-abdominal aggressive fibromatosis treated with meloxicam and sorafenib: An encouraging option p. 900
Murat Sari
DOI:10.4103/jcrt.JCRT_169_19  PMID:32930137
Objective: Aggressive fibromatosis (AF), also called desmoid tumor, is an uncommon soft-tissue neoplasm. Characteristically, it expands locally without metastatic potential. However, its tendency of relapse after curative resections has been well documented. Effective treatment options have been limited and there is a clear need for novel treatment strategies. Methods: We used combination therapy including multikinase tyrosine kinase inhibitor for treating AF. Results: We presented a case of an extra-abdominal AF who was successfully treated with meloxicam and sorafenib combination in our clinic. She tolerated this therapy well with only mild side effects. To our knowledge, this is the first case report of an extra-abdominal AF with a major partial response to sorafenib and meloxicam combination. Conclusion: Due to the favorable toxicity profile of sorafenib and meloxicam, this combination might be an effective treatment option for patients with locally aggressive and inoperable AF.
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Prognostic factors and clinical course of extremity soft-tissue sarcomas p. 903
Gülsen Pinar Soydemir, Zümrüt Bahat, Mustafa Kandaz, Emine Canyilmaz, Adnan Yöney
DOI:10.4103/jcrt.JCRT_108_18  PMID:32930138
Purpose: Although soft tissue constitutes half of the body weight, soft-tissue sarcomas (STSs) are less common than any other types of tumors. Materials and Methods: In this retrospective study, the prognostic factors and clinical courses of 64 patients with extremity STSs treated at our clinic between 1996 and 2012 were investigated. Results: Of the 64 patients included in this study, 35 (55%) were male and 29 (45%) were female. By the end of follow-up, 29 (45%) of the patients remained alive while 35 (55%) deceased. The overall survival (OS) time of the patients was 89.1 months, and their 1-, 3-, 5-, and 10-year survival rates were 82.8%, 69.3%, 51.6%, and 39.4%, respectively. Univariate analysis revealed the following variables as prognostic factors: tumor stage (P < 0.001), surgical method applied (P = 0.009), radiotherapy (RT) application (P = 0.018), RT dose (P < 0.001), and development of metastasis during follow-up (P < 0.001). Multivariate analysis revealed only type of surgery to be a prognostic factor (P = 0.016). Conclusion: Besides surgery, RT plays a crucial role in the multimodal treatment of STSs and increases local control rates and OS. In our study, stage, surgery, and adjuvant RT were found to be effective factors indicating OS. However, more prospective work in this area is necessary.
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Prognostic value of the neutrophil-to-lymphocyte ratio and carbohydrate antigen 19-9 in estimating survival in patients with metastatic pancreatic cancer p. 909
Sirin Cetin, Isa Dede
DOI:10.4103/jcrt.JCRT_366_19  PMID:32930139
Background: The predictive value of different prognostic biomarkers has been studied in various cancer types. Aims and Objectives: The purpose of this study was to examine the degree of risk and prognostic significance of pretreatment neutrophil-to-lymphocyte ratio (NLR) and carbohydrate antigen (CA) 19-9 levels in patients with metastatic pancreatic cancer (PC) and reveal its relevance with survival. Materials and Methods: Clinical and laboratory data of 118 patients with metastatic PC at the time of diagnosis were retrospectively analyzed. The overall survival (OS) was estimated according to the Kaplan–Meier method. To determine the prognostic factors affecting PC, the Cox regression analysis was performed. Results: The average age of the patients was 67 ± 9.57 years. The patients were analyzed during the follow-up period, and their average OS was 12 months (95% confidence interval [CI] = 9.73–14.26). The cutoff value was 3.54 (area under the curve [AUC] = 0.653, 95% CI = 0.56–0.73, P = 0.006) for NLR and 437 (AUC = 0.670, 95% CI = 0.57–0.75, P = 0.002) for CA19-9. Statistically significant difference was found between CA19-9 (P < 000.1) and NLR (P < 000.1) and OS. Analysis of multivariate Cox regression showed that NLR (hazard ratio [HR] = 2.17, 95% CI = 1.17–4.03, P = 0.013) and CA19-9 (HR = 1.81, 95% CI = 1.08–3.03, P = 0.022) were important prognostic factors in OS analysis. Conclusion: Pretreatment NLR and CA19-9 levels were found to be reliable estimative markers for poor prognosis in patients with metastatic PC. Our findings revealed that NLR and CA19-9 levels can be used to estimate the survival of patients with PC. We believe that our findings will shed light on the management of treatment protocols for patients diagnosed with metastatic PC.
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BRIEF COMMUNICATION Top

A cutaneous metastasis of bronchogenic carcinoma: Milia-like lesions with dermatomal pattern p. 917
Esra Varnali, Ayse Kavak, Yasemin Özkan, Fatma Büsra Karahacioglu
DOI:10.4103/jcrt.JCRT_450_17  PMID:32930140
Clinical presentation of cutaneous metastases is often variable. Presented case had an intriguing cutaneous metastasis of bronchogenic squamous cell carcinoma. Lesions were characterized by dermatomal pattern with milia-like papules, plaques, and nodules.
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CASE REPORTS Top

Interstitial lung disease secondary to alectinib after interstitial injury induced by crizotinib p. 919
Kyoichi Kaira, Ichiro Naruse, Kimihiro Shimizu, Takayuki Asao
DOI:10.4103/jcrt.JCRT_985_15  PMID:32930141
An 84-year-old male had a recurrence after surgical resection against Stage IIIA pulmonary adenocarcinoma and was treated with crizotinib due to harboring the anaplastic lymphoma kinase fusion gene. The patient exhibited crizotinib-induced interstitial lung disease (ILD), and alectinib was administered because of progressive disease. However, ILD appeared in both lungs again after alectinib treatment. This is the first case of ILD, resulting from alectinib administration after crizotinib-induced ILD. We should pay careful attention to patients who are treated with alectinib after crizotinib-induced ILD.
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Coughing up: “Adenosquamous carcinoma lung with unusual initial presentation as an ulceroproliferative growth” - case report and review of literature p. 922
Rakesh Kumar, Gunjesh Kumar Singh, Pragya Singh
DOI:10.4103/jcrt.JCRT_694_17  PMID:32930142
Lung carcinoma is the most common carcinoma seen in males with the skin being a rare metastatic site. Adenosquamous carcinoma as a rare histologic subtype, showing cutaneous metastasis is an unusual event with no reports in the literature till date. Skin metastasis is an alarming sign, carries poor prognosis, and is associated with shortened survival. Herein, we report a case of 60-year-old male who presented with isolated cutaneous metastasis as a chronic nonhealing ulcer over the sternal region for 3 years (unusual) in the first place, without any other associated symptoms and clinical evidence of the primary. Wide local excision of the lesion was performed after proper workup which revealed metastatic adenosquamous carcinoma. The patient was advised systemic chemotherapy. A high index of suspicion along with clinico-radio-pathological correlation in these cases is of utmost importance and forms the basis of accurate diagnosis.
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Diagnostic dilemma of a thumb swelling: An unpropitious turn of events p. 926
Seetharama B Rao, Pooja K Suresh, Merwyn Fernandes, Laxman G G Prabhu, Saraswathy Sreeram, Rajendra Annappa
DOI:10.4103/jcrt.JCRT_624_18  PMID:32930143
Benign and malignant bone tumors arise in small bones of the hands and feet. Nevertheless, secondary deposits at these sites are extremely rare. We report a peculiar case of an adult man who presented with thumb swelling, which was later discovered to be a metastasis from renal cell carcinoma. Such cases have a sinister prognosis with a survival rate of 6–12 months from the time of diagnosis. We intend to discuss the diagnostic dilemma and treatment of acrometastases.
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Successful treatment of nonsmall cell lung cancer patients with leptomeningeal metastases using whole brain radiotherapy and tyrosine kinase inhibitors p. 930
Masakuni Sakaguchi, Toshiya Maebayashi, Takuya Aizawa, Naoya Ishibashi, Tsutomu Saito
DOI:10.4103/jcrt.JCRT_1343_16  PMID:32930144
The efficacy of treatments in patients with nonsmall cell lung cancer (NSCLC) with leptomeningeal metastases (LMs) remains unclear. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) play an important role in the treatment of patients with NSCLC. However, few studies have investigated the efficacy of combination therapy with TKIs and whole brain radiotherapy (WBRT) in patients with NSCLC/LM. We report here the case of a male patient in his 60s with adenocarcinoma who underwent lobectomy of the right upper lobe. The cancer was classified as pT1bN1M0 Stage IIA, and a mutational analysis revealed the presence of an EGFR mutation. However, 6 months after standard chemotherapy, LM had developed and WBRT was administered. Gefitinib (250 mg/day) was administered after WBRT. The patient remained free of significant recurrent disease for 57 months after WBRT was administered. Combination therapy with TKIs and WBRT is associated with relatively long survival times in patients with LM.
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Utility of medical thoracoscopy in diagnosis and treatment of hemothorax due to carcinoma: A case report p. 933
Qing-Hua Liu, Dian-Jie Lin
DOI:10.4103/jcrt.JCRT_1222_16  PMID:32930145
Hemothorax cannot always be treated by thoracic surgeon. Rapidly improved interventional pulmonology broadens the application of medical thoracoscopy. We attempt to share our experiences of medical thoracoscopy for hemothorax and discuss the value of medical thoracoscopy in pleural diseases. We reported a 76-year-old male with hemothorax who was cured by medical thoracoscopy under local anesthesia together with argon plasma coagulation. Moreover, final pathological diagnosis was acquired as pleural sarcomatoid carcinoma. The unusual manifestation under medical thoracoscopy of such a relative rare disease was also described in this paper. The medical thoracoscopy could be used successfully for hemothorax instead of treating with surgeon, especially for those who cannot tolerate procedure of operation or surgical thoracoscopy.
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Calvarial metastasis from adenocarcinoma of lung: An uncommon initial presentation diagnosed by cytology p. 935
Subrata Pal, Biswajit Biswas, Ranu Roy Biswas, Rajashree Pradhan, Abhishek Sharma
DOI:10.4103/jcrt.JCRT_1285_16  PMID:32930146
Bone metastasis from lung primary is not uncommon and about one-third of bone metastases originate from lung. However, skull bone metastasis is uncommon from lung carcinoma. Metastasis to skull bone and scalp as an initial presentation of lung carcinoma is a very rare phenomenon. We have diagnosed a case of calvarial metastasis with scalp swelling as an initial presentation of adenocarcinoma of lung by fine-needle aspiration cytology in an aged female. Radiologically, it was suggested as tuberculous lesion but cytology gave the correct diagnosis. Here, we present a rare case of calvarial metastasis as a presentation of adenocarcinoma of lung in an elderly female.
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Intrathoracic hemangioma p. 938
Gaurav Patel, Suyash Agrawal, Prakash Patil
DOI:10.4103/jcrt.JCRT_357_19  PMID:32930147
We report the very rare case of recurrent unilateral pleural effusion in a 53-year-old male. Computed tomography (CT) scan and magnetic resonance imaging revealed a left-sided paravertebral mass at D3 level. Multiple biopsy and CT scan lead us to the diagnosis of “Angiomatous Malformation.” The lesion was excised surgically which on final histopathological report termed hemangioma.
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Long-term survival of a patient with programmed death ligand 1-negative lung adenocarcinoma and oligoprogressive disease treated with nivolumab and stereotactic body radiation therapy p. 941
Miguel J Sotelo, Santiago Cabezas-Camarero, Alejandro Riquelme, Coralia Bueno
DOI:10.4103/jcrt.JCRT_81_19  PMID:32930148
Immune-checkpoint inhibitors have shown to prolong survival in patients with metastatic non-small cell lung cancer. Programmed death ligand 1 (PD-L1) expression is associated with a higher probability of response, although some patients with PD-L1 negative tumors may also respond or show durable stabilizations. However, the optimal strategy after progression to immunotherapy (IO) is not yet defined. Patients with oligometastatic disease may benefit from local treatments such as radiotherapy (RT), achieving significant local control rates. In addition, RT is claimed to have numerous immunogenic effects that could synergize with IO. We present the case of a complete responder to nivolumab that after a monotopic adrenal relapse received stereotactic body radiation therapy, followed by maintenance nivolumab achieving a partial response that is still ongoing. Aspects such as mechanisms of acquired resistance to PD-L1 inhibitors, the optimal management after progression, and the potential interplay between IO and RT are briefly reviewed and discussed.
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Synchronous thoracic and head-and-neck malignancies-double trouble-challenges, pitfalls, and lessons learnt p. 946
Kanika Sharma Sood, Manisha Himthani, Aditi Tanwar, S Lakshmana Perumal
DOI:10.4103/jcrt.JCRT_911_18  PMID:32930149
Synchronous malignancies arising from head and neck and thorax are rare presentation, and only few cases are reported in the scientific literature. We report three cases of double primary malignancies treated at our hospital.
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Epidermal growth factor receptor-activating mutation(E746_T751>VP) in pancreatic ductal adenocarcinoma responds to erlotinib, followed by epidermal growth factor receptor resistance-mediating mutation (A647T): A case report and literature review p. 950
Girijesh Kumar Patel, Josiah B Perry, Osama Abdul-Rahim, Arthur E Frankel, Daniel Cameron, William Taylor, Rodney P Rocconi, Laith Abushahin, Cindy Nelson, Ajay P Singh, Moh'd Khushman
DOI:10.4103/jcrt.JCRT_729_18  PMID:32930150
Despite recent advances in treatment with multidrug chemotherapy regimens, outcomes of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain very poor. Treatment with targeted therapies has shown marginal benefits due to intrinsic or acquired resistance. Actionable mutations, while detected infrequently in patients with PDAC, are becoming increasingly used in personalized medicine. Here, we describe an epidermal growth factor receptor (EGFR)-activating mutation (E746_T751>VP) to erlotinib, a first-generation tyrosine kinase inhibitor (TKI), in a patient with metastatic PDAC. After an initial partial response to erlotinib for 12 months, the patient's disease progressed with emergence of the EGFR A647T mutation. Certainly, the patient also progressed after switching therapy to a third-generation EGFR TKI (osimertinib). This case illustrates the posttreatment evolution of EGFR A647T-mediated resistance to the first- and third-generation TKIs. To our knowledge, this is the first case to report the aforementioned activating and resistance-mediated mutations. In summary, genomic analysis performed in this patient with PDAC on the tumor biopsy and peripheral blood provided tools to understand mechanisms of response and resistance to targeted therapy with EFGR TKIs.
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COMMENTARY Top

“Choosing Wisely” for cancer care in India p. 955
CS Pramesh, Harit Chaturvedi, Vijay Anand Reddy, Tapan Saikia, Sushmita Ghoshal, Mrinalini Pandit, K Govind Babu, KV Ganpathy, Dhairyasheel Savant, Gunita Mitera, Richard Sullivan, Christopher M Booth, On behalf of the National Cancer Grid of India
DOI:10.4103/0973-1482.294950  PMID:32930151
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