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Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."
Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011
Dr. Shankar P.R.
"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."
Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011 Anuradha
Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.
Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020
Original article / research
Full Version
Expression of IDH1, ATRX, p53 in Diagnosis of Gliomas as Per 2016 WHO Classification
Correspondence Address :
Dr. Manjiri Karandikar,
Professor, Department of Pathology, Bharati Vidyapeeth Deemed to be University, Medical College, Hospital and Research Centre, Pune-411043, Maharashtra, India.
E-mail: mnkarandikar@gmail.com
Introduction: The 2016 World Health Organisation (WHO) classification of tumours of the Central Nervous System (WHO CNS 2016 classification) is used to classify diffuse gliomas as astrocytoma, Oligodendroglioma (ODG), glioblastoma which are three prognostically distinct groups based on Isocitrate Dehydrogenase (IDH1), alpha thalassaemia/mental retardation, x-linked (ATRX) mutations, p53 and 1p/19q co-deletion status. Although WHO CNS 2022 classification has been brought in use, it is based on molecular studies. In a resource limited setting like in many Indian diagnostic centres it’s difficult to apply the WHO CNS 2022 classification. It is felt that WHO CNS 2016 classification has not lost its utility.
Aim: To investigate the Immunohistochemistry (IHC) status of IDH1, ATRX, p53 in diagnosis of diffuse glial tumours and to classify them according to WHO 2016.
Materials and Methods: The present cross-sectional study was conducted at Department of Pathology, Bharati Vidyapeeth Medical College, Hospital and Research Centre, Pune, Maharashtra, India for two years and six months (July 2020 to December 2022). Thirty-two diffuse glioma cases and IHC markers IDH1, ATRX, p53 were evaluated. Ki-67 index was additionally done.
Results: Total 32 cases were studied, 19 cases were male. Mean age of the patients was 40.13 years. Fourteen patients belonged to WHO Grade-II, six to Grade-III, and 12 to Grade-IV. As per the IHC findings and histopathological features, there were 16 (50%) patients with diffuse astrocytoma, while 12 (37.5%) and 4 (12.5%) patients were diagnosed as glioblastoma and ODG, respectively. Reclassification of these cases was done depending on IHC results where IDH1 was positive in 71.9% cases, ATRX was positive in 40.6% cases and p53 was positive in 15.6% cases. This result includes all the cases where these IHC markers showed reactivity. The diagnosis of four patients was modified based on findings of IHC markers.
Conclusion: The study demonstrates subgrouping of gliomas based on IDH1, ATRX, p53. There was no significant association between grade of tumour and Ki-67 expression.
Astrocytoma, Isocitrate dehydrogenase, Oligodendroglioma, World health organisation
The annual incidence of primary intracranial tumours is 5 to 10 cases per 100,000 people in India, where it represents 2% of all malignancies (1),(2). Gliomas are the most common and are responsible for nearly 30% deaths due to primary brain tumours (3). The 2007 WHO classification system puts both diffuse and well-circumscribed gliomas in the same category (4). However, the 2016 update to the 2007 classification categorises them into well-circumscribed tumours as pilocytic astrocytoma, Pleomorphic Xanthocytoma (PXA), Subependymal Glial Astrocytoma (SEGA) and diffuse tumours as astrocytoma, ODG, and glioblastoma (5). This updated classification system allows more accurate diagnosis, predicts patient prognosis and better management (6).
The IHC staining of tissue sections can be used to evaluate the expression of mutant proteins such as IDH1, ATRX and p53, which can subtype gliomas. IDH1 mutation, ATRX mutation (loss) and p53 mutation is common in mutant type astrocytoma. IDH1 wild type, ATRX mutation (loss) and p53 mutation is common in wild type glioblastoma. IDH1 mutation, ATRX retained and p53 variable expression is common ODG (7),(8). A 1p19q co-deletion status using Fluorescence In-situ Hybridisation (FISH) is additionally done to confirm ODG. Therefore, the present study was planned to investigate the IHC status of diffuse glial tumours and to utilise the 2016 WHO classification of tumours of the CNS to classify them.
The present cross-sectional study was conducted in the Department of Pathology at Bharati Vidyapeeth, Deemed to be University, Medical College, Pune, Maharashtra, India after approval by the Institutional Ethics Committee (IEC) (BVDUMC/IEC/141). The period of the study was two years and six months (July 2020 to December 2022).
Inclusion criteria: All cases of diffuse glioma were included in the study.
Exclusion criteria: Inadequate and non representative samples were excluded from the study.
Study Procedure
Data for age, sex and location of tumour was collected from histopathology registers and test requisition forms. All retrospective cases were reviewed to confirm diagnosis of diffuse glioma. For the prospective study, specimens were collected in 10% buffered formalin and processed using routine histotechnique and stained with Haematoxylin and Eosin (H&E) for histopathological diagnosis. IHC was done using IDH1 (IDH1 R132H point mutated form, H09, RTU master diagnostic), ATRX (Flex mono, MAD-0007826D-R-3, polyclonal master diagnostica), p53 (MAD-000479QD, polyclonal master diagnostica), Ki-67 (clone SP6, MAD-000310QD, master diagnostica). All four IHC markers were studied in all cases. Preparation of the tissue, antigen retrieval, inhibition of non-specific binding sites, incubation with primary and secondary antibodies, and detection of the labelled antibodies are the fundamental steps in IHC staining.
Using antibodies that recognise these proteins, IHC markers were evaluated by examining the presence and distribution of particular proteins in tissue samples. These antibodies are frequently marked with a chromogen or a fluorescent chemical, enabling microscopic observation of the target protein. Grading of CNS tumours was done according to WHO 2016 classification (4).
Statistical Analysis
The data was analysed using Statistical Package for Social Sciences (SPSS) version 26.0 software. For qualitative data various rates, ratios, and percentages (%) were calculated. Chi-square test/Fisher’s-exact test was used to find the association between two or more attributes for qualitative data variables. The p-value <0.05 was considered as significant.
A total of 32 cases with diffuse gliomas were studied. The mean age of the patients was 40.13 years with age range from 7-70 years and male to female ratio of 1.46:1. Maximum tumours were located in the frontal lobe (37.5%) followed by temporal lobe (12.5%), parietal lobe (9.4%), Insular region (9.4 %), parasagittal region (9.4%), thalamus (9.2%), Cerebro-pontine (CP) angle angle (6.3%), brain stem (6.3%), cases were diagnosed as diffuse astrocytoma (50%), 12 as glioblastoma (37.5%) and 4 as ODG (12.5%). Fourteen patients belonged to WHO Grade-II (43.8%) and 6 (18.7%) patients belonged to WHO Grade-III while there were 12 patients who belonged to WHO Grade-IV (37.5%). The IHC expression of IDH1, ATRX and p53 was positive in 23 (71.9%), 13 (40.6%) and 5 (15.6%) of patients, respectively. The distribution of patients according to IHC findings is shown in (Table/Fig 1).
IHC findings related to IDH1 mutation status of diffuse glioma cases: The IHC findings revealed that IDH1 was mutant in 23 (71.9%) patients, while in 9 (28.1%) was wild type. Ideally, genetic testing should be done before labelling cases as IDH wild type. But when patient age is more than 54 years and there is no previous history of glioma, absence of IDH1 mutation can be treated as IDH1 wild. Hence, three cases could be labelled as glioblastoma wild type. Rest 6 (18.8%) patients, the IDH1 was labelled as Not Otherwise Specified (NOS).
The association between diagnosis and expression of IDH1, ATRX, p53 and Ki-67: (Table/Fig 2) shows the IHC diagnosis results and p-values for diffuse gliomas. The results are based on the analysis of three antibodies-IDH1, ATRX, p53. The p-values indicate the statistical significance of the differences between the groups. For IDH1, the positive result was seen in a higher percentage of diffuse astrocytoma cases (87.5%) compared to glioblastoma (41.7%). The difference in IDH1 positivity between diffuse astrocytoma and glioblastoma was statistically significant (p-value=0.012). ATRX loss was seen in a higher percentage of diffuse astrocytoma cases (87.5%) compared to glioblastoma (33.3%) and ODG (25%) cases. The difference in ATRX negativity between diffuse astrocytoma and glioblastoma was statistically significant (p-value=0.005). p53 was negative in all cases of diffuse astrocytoma (100%), in a higher percentage of glioblastoma cases (75%) compared to ODG cases (50%). The difference in p53 negativity between diffuse astrocytoma and glioblastoma was statistically significant (p-value=0.025). Ki-67 was between 5-10% in most gliomas irrespective of their grades.
Among 16 cases of astrocytoma, diagnosis of two cases was modified to ODG because IDH1 and ATRX expression were positive in both cases. Among four cases of ODG, diagnosis of two cases was modified to astrocytoma because IDH1 mutation and ATRX mutation was present in both cases (Table/Fig 3),(Table/Fig 4),(Table/Fig 5). Histopathological and IHC diagnosis was similar in all 12 cases of glioblastoma (Table/Fig 3),(Table/Fig 6).
The understanding of molecular changes in CNS tumours has significantly grown over the past 10 years. Due to these efforts, the classification of CNS tumours has undergone a fundamental change. Now, the definition of several diagnostic categories may be partially based on genotype, and in some cases, genotype may even take precedence over a histological diagnosis.
A total of 32 patients with diffuse gliomas were included in the present study. The mean age of the patients was 40.13 years. There were total 19 (59.4%) male patients and 13 (40.6%) females patients, with male to female ration of 1.46:1. Sarma S et al., included 53 glioma patients, 30 (56.60%) of whom were male and 23 (43.39%) were female with a mean age of 32 years (9). According to Arshad H et al., of the 50 glial cases evaluated, 35 (70%) cases were male, while 15 (30%) were female with mean age of 35 years (10).
Maximum tumours (12 cases) were located in the frontal lobe (37.5%). Sarma S et al., Wang Z et al., also found frontal lobe to be the commonest site (9),(11). In the present study, most common histological type was diffuse astrocytoma 16 (50%) followed by glioblastoma 12 (37.5%) and the least common type was ODG in 4 (12.5%) of patients. In the study by Wang Z et al., and Popova SN et al., showed 58% and 51% astrocytoma cases [11,12]. In the present study, 14 (43.8%), 12 (37.5%) and 6 (18.7%) patients belonged to WHO Grade-II, III and IV, respectively. In the study by Popova SN et al., 76 (42.22%), 32 (17.77%), 72 (40%) patients belonged to WHO Grade-II, III and IV, respectively (12).
The IHC expression of IDH1, ATRX, and p53 was positive in 23 (71.9%), 13 (40.6%), and 5 (15.6%) of patients, respectively. As per these IHC findings, there were 16 (50%) patients with diffuse astrocytoma, while 12 (37.5%) and 4 (12.5%) patients were diagnosed as glioblastoma and ODG, respectively. Present study results showed 14 cases (87.5%) with diffuse astrocytoma had IDH1 mutation and ATRX mutation (loss). Remaining two cases of astrocytoma IDH wild type were put in NOS category because IDH status could not be genetically assessed. In the studies by Sarma S et al., Wang Z et al., and Larjavaara S et al., IDH1 mutation was seen in 69.69%, 32.56% and 87% of cases, respectively (9),(11),(13). Present study results showed IDH1 mutation, IDH wild and ATRX loss in 41.7%, 58.3% and 33.3% of glioblastoma. The percentages of IDH mutation and ATRX mutation in other studies were different, possibly due to the small number of glioblastoma cases in the present study. The study suggests that genetic testing should ideally be performed before labelling cases as IDH wild type.
The present study found that 100% of the ODG cases had IDH1 mutation (positive) and 75% showed ATRX retention. In the study by Sarma S et al., Broggi G et al., and Dahuja G et al., (9),(14),(15). IDH1 mutation and ATRX retention was seen in 83.33% and 100%, 100% and 100%, 80% and 100% of ODG cases. Ideally cases with ATRX loss in ODG morphology should undergo 1p19q co-deletion by FISH, which was not done in the present study.
All 16 cases of diffuse astrocytoma showed p53 mutation. In glioblastoma, out of total 12 patients, 75% cases showed p53 mutation. Among four cases of ODG, 50% cases show p53 mutation. No significant association was found between tumour grade and Ki-67 expression. IDH1 mutation, ATRX mutation (loss) and p53 mutation is common in mutant type astrocytoma. IDH1 wild type, ATRX mutation (loss) and p53 mutation is common in wild type glioblastoma. IDH1 mutation, ATRX retained and p53 variable expression is common ODG.
Modification of diagnosis after IHC study: As per the findings of IHC in present study, the diagnosis of four patients was modified. All four cases showed IDH1 mutation. The diagnosis of diffuse astrocytoma was modified to ODG, IDH mutant, Grade-II, NOS in two patients. This was done because IHC expression of ATRX was positive (retained). As genetic study (1p,19q co-deletion) was not done in ODG cases they were classified as ODG, NOS type. Diagnosis of ODG Grade-II was modified to diffuse astrocytoma, IDH mutant, Grade-II because IHC expression of ATRX was negative (loss).
Limitation(s)
Genetic testing was not performed before labelling cases as IDH wild type. FISH for 1p19q co-deletion was not done for cases with ATRX loss in ODG morphology.
The study demonstrated subgrouping in diffuse gliomas based on IDH1, ATRX, p53. However, 1p19q co-deletion study using FISH is necessary to confirm diagnosis of ODG. Glioblastoma generally have high Ki-67 index as compared to astrocytoma and ODG. Ki-67 do not have a role in reclassification of CNS tumour.
DOI: 10.7860/JCDR/2023/64368.18256
Date of Submission: Mar 31, 2023
Date of Peer Review: May 10, 2023
Date of Acceptance: May 30, 2023
Date of Publishing: Jul 01, 2023
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. No
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ETYMOLOGY: Author Origin
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