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   Table of Contents - Current issue
Coverpage
January-June 2022
Volume 2 | Issue 1
Page Nos. 1-55

Online since Tuesday, May 3, 2022

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EDITORIAL  

Transitional oncology and the evidence hyperloop Highly accessed article p. 1
US Vishal Rao
DOI:10.4103/jpo.jpo_10_22  
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ORIGINAL ARTICLES Top

Kirsten rat sarcoma mutation in South Indians with non-small lung cancer: A cause for concern? Highly accessed article p. 3
Gautam Balaram, Renjan Thomas, Suhas N Ghorpade, Prarthana V Kowsik, Baby Dharman, Yogesh Shivakumar, Shekar Patil, Satheesh Chiradoni Thungappa, HP Shashidhara, Somorat Bhattacharjee, Sridhar Papaiah Susheela, Radheshyam Naik, Srinivas Belagutty Jayappa, Tejaswini Bangalore Nanjaiah, Shivakumar Swamy Shivalingappa, Mithua Ghosh, BS Ajaikumar
DOI:10.4103/jpo.jpo_7_22  
Background: Lung cancer is the poster child for advances in molecular oncology with a myriad of targeted therapies in NSCLC (non-small cell lung cancer) management. Kirsten rat sarcoma (KRAS) mutations are routinely isolated in NSCLC and account for a third of NSCLC oncogene driver tumors in Caucasian populations. The mutation is classically notorious to target with most therapies employed in management of KRASmut NSCLC being inhibitors of downstream signaling such as mitogen-activated protein kinase inhibitors (trametinib and selumetinib). There is a lacuna of information regarding prevalence and molecular epidemiology of KRAS mutations in NSCLC from an Indian context. Materials and Methods: The following study is a retrospective analysis of the incidence of KRAS epidemiology in high concentration epidermal growth factor receptor (EGFR) samples at a tertiary care hospital in South India from 2015 to 2017. Samples were selected following histopathological assessment and were subjected to nucleic acid extraction. KRAS mutation testing was performed using real-time polymerase chain reaction to ascertain the molecular epidemiology of KRAS in NSCLC patients. Results: KRAS mutations were observed in 15/44 NSCLC patients (34.09%) with a M:F ratio of 2:1. Majority of the mutations were single mutations, with 3 cases showing double mutations. Codon 12 mutations were observed in 6 cases followed by codon 146 mutations seen in 5 cases. Exon 3 (codon 59 and codon 61) and exon 4 (codon 117 and codon 146) were isolated in 5 and 3 cases, respectively. The current study demonstrated an elevated frequency for KRAS mutations in comparison to Asian cohorts. Conclusion: The advent of directly targeting KRAS inhibitors such as sotorasib (KRAS G12C inhibitor) necessitates KRAS mutation testing and warrants inclusion in the initial molecular workup of NSCLC.
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An experience of Methylguanine-DNA Methylation Assay (MGMT) characterization in glial tumors p. 9
Amrit Kaur Kaler, Renjan Thoma, NG Suhas, VK Prarthana, Baby Dharman, Gautam Balaram, Mithua Ghosh, R Veena, Shekhar Patil, PS Sridhar, Shivakumar Swamy, CT Satish, S Bhattacharjee, BS Ajaikumar
DOI:10.4103/jpo.jpo_4_22  
Background: MGMT (O6-methylguanine DNA methyltransferase) is a DNA repair enzyme, that rescues tumor cells from damage by alkylating agents like temozolomide (TMZ). Promotor methylation of MGMT leads to epigenetic silencing and potentially increased sensitivity to TMZ. MGMT methylation (mMGMT) is an independent favorable prognostic factor, and has confounded its role as a predictive biomarker in making therapeutic decisions for glial tumors, particularly glioblastoma multiforme (GBM). Materials and Methods: This retrospective cross-sectional study was conducted for 5 years in high-grade tumors (HCG) Cancer Hospital between January 2016 and December 2020. Methylation-specific polymerase chain reaction of MGMT gene using bisulfite modification of tumor DNA was utilized to ascertain the methylation status of cases in the cohort. Results: A total of 54 glial tumors comprising 35 males and 18 females between the age group 11 years to 76 years underwent mMGMT testing. About 64.8% (35 cases) of all glial tumors demonstrated mMGMT in the cohort; GBM accounting for a majority of the cases (80.0%; 28 cases). The percentage of mMGMT cases in males and females was found to be 60.0% and 73.0% of cases, respectively. The confluent necrosis commonly seen in GBM is present in 41.0% of methylated cases and minimal in 77.3% of unmethylated cases with a significant P < 0.05. Conclusion: MMGMT is a valuable predictive biomarker and is essential in taking the therapeutic decision in newly diagnosed glial tumors. Necrosis can be used as an indicator of mMGMT status according to the present study.
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Cost-effectiveness of cervical cancer screening in rural Bengaluru with demographic analysis of epithelial cell abnormalities: A cross-sectional descriptive study p. 14
Amrit Kaur Kaler, M Shilpa Rao, M Roopamouli, Y Srinivasalu, SN LV Narasimha Raju, US Vishal Rao
DOI:10.4103/jpo.jpo_5_22  
Aim: Cervical cancer is the fourth-most common cancer in women worldwide and ranks third among all the malignancies for women. In contrast to developed countries, cervical cancer is a public health problem in developing countries like India and accounts for a quarter of the global disease burden. It is also one of the leading causes of cancer mortality in India, accounting for 17% of all cancer deaths among women aged between 30 and 69 years. The aim of this study is to perform a demographic analysis of cervical cancer by using Papanicolaou (PAP) test as a screening modality in Doddaballapur, rural Bengaluru, Karnataka. Materials and Methods: A cross-sectional descriptive study was conducted on cervical cancer screening utilizing PAP smear screening. Camps were organized in Doddaballapur, rural Bengaluru, organized by Non-Profit Organization, Sahaya Hastha Trust between December 2017 and 2018. The PAP smears were stained and evaluated for epithelial cell abnormality using Bethesda System criteria free of cost at The Oxford Medical College and Hospital, Bengaluru. Results: A total of 647 patients were evaluated in this prospective study and abnormal epithelial cell abnormalities (ECA) were observed in 24 (3.7%) cases. Among the 24 cases, 2 cases (8.3%) of squamous cell carcinoma, 11 cases (45.8%) of atypical squamous cell of undetermined significance, 5 cases (20.8%) of Atypical Squamous cells - cannot rule out high-grade squamous intraepithelial lesion (HSIL), 3 cases (12.5%) of low-grade squamous intraepithelial lesion (3), 2 cases (8.3%) of high-grade squamous intraepithelial lesion (HSIL), and a single case (4.2%) of atypical glandular cells of undetermined significance were noted. Of the remaining 623 smears (96.2%) diagnosed with negative for intraepithelial lesion or malignancy, 428 cases (68.7%) were reported as nonspecific inflammation, while 56 smears (8.9%) showed atrophic smears and 20 cases (3.1%) were unsatisfactory for evaluation. 119 cases (19.1%) displayed a specific infectious etiology; coccobacilli (bacterial vaginosis) being the most common 66 cases (55.5%), followed by Trichomonas vaginalis 46 cases (38.6%) and Candida infection has 7 cases (5.8%). Conclusions: In Dodabullapur, a rural Bengaluru suburb, 3.7% of cervical cancer patients had ECA. It is hypothesized that a low-cost screening program is exceptionally beneficial in lowering the disease burden of cervical cancer, especially among middle-aged women and those living in low-income areas. This humanitarian purpose might motivate women in rural regions to be educated with the sole goal of uplifting the impoverished.
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Evaluation of tumor-infiltrating lymphocytes as a prognostic indicator of head-and-neck squamous cell carcinomas: A prospective study p. 19
N Apoorva Reddy, BM Joshna, Abhijith George, VP Indu, Shalini Thakur, Anand Subash, Akshay Kudpaje, US Vishal Rao
DOI:10.4103/jpo.jpo_4_21  
Introduction: The incidence of Head-and-Neck Squamous Cell Carcinomas (HNSCC) is on the rise in our country and worldwide, with a worsening prognosis. The abundance of tumor-infiltrating lymphocytes (TILs) is evolving to be a novel prognostic indicator in assessing treatment response of HNSCC. TILs mainly comprise T lymphocytes, which migrate from blood into the tumor as part of the body's immune response. In this context, targeting the tumor microenvironment with the help of immunotherapy may present a potential approach for better cure of head-and-neck cancers. In the present study, we evaluated the potential TILs parameters which can be used in clinical practice to predict treatment outcomes in HNSCC. Materials and Methods: This is a prospective observational study of 41 patients conducted at a tertiary cancer center between September 2019 and September 2020. All patients with biopsy proven, primary/recurrent HNSCC, without distant metastasis, and complete clinicopathological data were included in the study. Patients with a nonsquamous cell carcinoma, patients who underwent upfront chemotherapy or chemoradiotherapy were excluded from the study. Patients who had follow-up of <1 year or lost to follow-up were excluded from the study. Parameters analyzed include mean age; percentage of cluster of differentiation 3 (CD3) cells; CD4, CD8, and FOXP3cell counts; distribution of CD57 and CD3/FOXP3 ratio. Results: A total number of 19 patients were grouped under the nonrecurrence TILs and 22 patients under recurrent TILs category. Majority of the patients (90.2%) had oral cavity squamous cell carcinoma. 68.42% of nonrecurrent cases and 36.36% of recurrent cases were found to be harboring Hot tumors. Using odds ratio, it was noted that the odds of having Hot tumor is 3.79 times (95% confidence interval: [1.03,13.91]) higher in nonrecurrent TILs than in recurrent TILs group. CD3 cell count was higher in nonrecurrent cases (54.74 ± 18.37) than in recurrent cases (42.73 ± 16.09) with P = 0.0157. Using two tailed t-test, it was noted that the mean of CD4, CD8, and FOXP3 is not significantly different between nonrecurrent and recurrent tumor TILs groups. Conclusion: To summarize, we have shown that the CD3/FOXP3 cell ratio, rather than the individual proportion of TILs, is a significant prognostic indicator in HNSCC. It's also been shown that people with Cold tumors have a higher risk of recurrence than those with Hot tumors. Our findings confirm the importance of host immunity in prognosis and suggest that the degree of immune cell infiltration in the tumor microenvironment is a major independent prognostic factor that merits further investigation as a potentially valuable biomarker in HNSCC patients.
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Multigene profiling to identify clinically relevant actionable mutations in head and neck cancers: An Indian study p. 25
Sateesh S Kunigal, Shalini Thakur, Yogesh Shivkumar, ML Sheela, CR Krishna, Anindita Kundu, Jaya Jain, Urvashi Bahadhur, KS Gopinath, Gururaj Arakeri, Mithua Ghosh, US Vishal Rao, BS Ajaikumar
DOI:10.4103/jpo.jpo_3_22  
Background: Head and neck squamous cell carcinoma (HNSCC) represents approximately 5%–10% of malignancies worldwide. The most appropriate treatment approach for HNSCC varies with the disease stage and disease site in the head and neck (H&N). Radiotherapy (RT) combined with chemotherapy has become the standard of care for patients having locally advanced tumors. However, there is significant morbidity associated with these treatments, and recurrent or metastatic diseases will occur in 50%–60% of patients. Moreover, the detection of residual viable tumor at the end of therapy remains an important issue. It is therefore an unmet need to improve the outcome of therapy by identifying predictive (prognostic) indicators at the molecular level and radioresistance that will enable the clinicians to select the logical treatment modality. Materials and Methods: Fifty H&N cancer patients aged 27 to 85 years diagnosed at HCG between April 2015 and 2017 were screened using Illumina's TSCAP panel and MiSeq technology for hotspot mutations in 48 cancer-related genes. All the cases had histopathological reviews and comprised tumors from the following sites – oral, nasopharynx, throat, hypopharynx, larynx, thyroid, or nasal cavity and paranasal sinuses. The average coverage across 220 hotspots was >1000X. Data were processed using Strand Avadis NGS™. Mutations identified in the tumor were assessed for “actionability,” i.e., response to therapy and impact on prognosis. Results: Somatic variants were detected in 65% of cases with direct impact on therapy and/or prognosis. Genetic aberrations were identified in major RAS/RAF signaling pathways in nearly 15% of H&N cancers, out of which HRAS activating mutations were the most common (n = 5). HRAS was also found to be co-mutated with phosphatidylinositol 3-kinase (n = 3) and PTEN deletions (n = 3). In contrast to the MAPK signaling pathways, mutant HRAS is able to signal exclusively through PI3K-AKT, reducing the response to cetuximab and increasing the response to MEK inhibitors including selutinib and tramatinib. Based on the results, cetuximab was discontinued in two patients who had presented with metastatic HNSCC. Other targetable mutations included PIK3CA (n = 3), EGFR (n = 1), cKIT (n = 1), RB1 (n = 1), and PTEN (n = 3) were reported. Further, disruptive and nondisruptive mutations in TP53 alone were found in 45% of H&N cancers, varying widely among different histologies, indicating a poor response to cisplatin- and 5FU-based chemotherapy. Interestingly, all metastatic/recurrent patients treated with cisplatin presented with very short progression-free survival of 9–12 months were found to have TP53. TP53 was also found to be co-mutated with ATM gene (n = 1), an important prognostic marker indicating poor response to chemotherapy and RT. Conclusion: This study validates the utility of multigene profiling in H&N cancer patients, both early diagnosed and advanced cases, to stratify based on their molecular profile that could potentially benefit/not benefit from targeted therapy and chemoradiation. Few ongoing prospective studies and randomized clinical trials may help us confirm the independent prognostic and therapeutic value of the mutations in a larger cohort of Indian population.
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MINI REVIEWS Top

Image “OMICS” in cancer - Synergy of qualitative and quantitative data analytics for futuristic precision medicine p. 33
G Lohith, Kritika Murugan, Krithikaa Sekar, Sudhakar Sampangi, Mahesh Bandemagal, Shivakumar Swamy
DOI:10.4103/jpo.jpo_12_22  
There are several methods for generating and analyzing big data in oncology, the most well-known of which are genomics, proteomics, and metabolomics. Similarly, “omics” clusters in imaging are frequently referred to as “radiomics.” A quantitative approach to medical imaging that tries to improve current qualitative data with modern computation and often counterintuitive mathematical analysis. This paper describes the breakthroughs in the use of radiomics in breast cancer, as well as the future challenges of radiomics research.
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Detection of antinuclear antibodies in oncology from slide to multiplexing: An overview p. 36
Amrit Kaur Kaler, Ravi Gaur, Anita Jain, Junu Rajan, US Vishal Rao
DOI:10.4103/jpo.jpo_11_22  
Antinuclear antibodies (ANA) are autoantibodies considered as the immune biomarkers of systemic autoimmune diseases. ANAs are directed against antigens of the cell nucleus and are named after their biochemical characteristics (deoxyribonucleic acid [DNA], histones, ribonucleoprotiens), the disease is associated with the corresponding autoantibody, e.g., Sjögren syndrome antigen A [SS-A] and Systemic Sclerosis (SS-B); progressive systemic sclerosis, polymyositis, or occasionally after the patient in whom the corresponding antibody was first detected (Sm, Ro, La). Positive ANA can also be used as an aid to early diagnosis of solid tumors and prognosis in hematological malignancies such as non-Hodgkin's lymphoma patients. Positive ANA has been found in the sera from patients with head and neck, lung, breast cancers by multiple studies. Most commonly patients with chronic lymphocytic leukemia (CLL) frequently present with autoimmune disorders (AIDs) which include autoimmune hemolytic anemia (AIHA), immune thrombocytopenia, pure red cell aplasia and autoimmune granulocytopenia, and nonhematological AIDs such as paraneoplastic pemphigus, neuropathies, SS, rheumatoid arthritis, and systemic lupus erythematosus. The presence of AIHA was previously demonstrated to be a poor prognostic indicator and also proved the negative survival impact of positive direct antiglobulin test on CLL patients.
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CASE REPORTS Top

Management of the anuric patient after Robotic-Assisted Laparoscopic Prostatectomy (RALP): A case report p. 40
Antonio Devanti Bardoli, Amit Patel, Sebastian Chang, Christopher Lawrence, Alex Hampson, Gowrie Mohan Shan, Nikhil Vasdev
DOI:10.4103/jpo.jpo_1_21  
Robotic-assisted laparoscopic prostatectomy (RALP) has been linked to lower perioperative blood loss, lower transfusion rates, and shorter hospital stays. In addition, recent studies show that as compared to standard open prostatectomy surgery, there is less intraoperative blood loss. The authors report a unique case of anuric patients who have undergone RALP as well as the complications that arise when dealing with anuric patients after RALP.
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A novel technique of vascularised fibular epiphyseal transfer combined with cryosterilized autograft and 3D printing in a 2-year-old child with Ewing's sarcoma: A case report p. 44
Giovanni Beltrami, Pramod S Chinder, R Sreeraj, Suraj Hindiskere, Sohan Pothaganahalli Raghavendra, Srinath Doddarangappa
DOI:10.4103/jpo.jpo_2_21  
Vascularized fibular epiphyseal transfer (VFET) though technically challenging, is a technique which can be used in skeletally immature patients to preserve the limb length in tumors near physis. As limb salvage at a young age adds to the complexity of the procedure since the growth potential of the limb has to be considered to restore the optimal function of the salvaged limb. This case report documents the treatment of an Ewing's Sarcoma of the left proximal tibia in a 2-year-old boy, following VFET modified with free freezing liquid nitrogen and three-dimensional printing. We succeeded in improving the patient's oncological and functional outcome because our patient was mobilized early and no postoperative complications occurred. This technique can thus be considered for the biological reconstruction of very young children as it has the least influence on limb lengths and growth potential.
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Febrile neutropenia: An unusual cause of Pantoea Agglomerans bacteremia in acute myeloid leukemia p. 49
Sachin Suresh Jadhav, Jyothi Goutham Kumar, Priyank Tripathi, Anjali Matani, Shobha K Ganesan, Vishnupriya , Amey C Panchal, Chintan Kumar H.Kaswala, Nishit , Samuel L Koramati, BS Ajaikumar
DOI:10.4103/jpo.jpo_8_22  
We present a case of febrile neutropenia in a patient with acute myeloid leukemia caused by an uncommon bacterial species. The patient was treated with antibiotics for 14 days before being discharged. Pantoea agglomerans is a plant soil and water-dwelling agricultural organism. It is both a commensal and pathogen of animals and humans, according to earlier research. In conclusion, p. agglomerans should be considered a bacterial threat in cancer patients who are undergoing highly myelotoxic chemotherapy.
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COMMENT Top

The role of the pathologist in the next-generation era of molecular oncology p. 52
Amrit Kaur Kaler, US Vishal Rao
DOI:10.4103/jpo.jpo_9_22  
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SHORT COMMUNICATION Top

Gross picturesque: Case of the journal p. 54
Amrit Kaur Kaler
DOI:10.4103/jpo.jpo_13_22  
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