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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 PDL-1 Receptors in Prostate Cancer Patients and its Association with Tumour Aggressiveness: A Cross-sectional Study
Correspondence Address :
Dr. Hemant Goel,
Room 31, OPD Block, RML Hospital, Baba Khragh Singh Marg,
Near GPO, New Delhi-110001, India.
E-mail: hemant.doc81@gmail.com
Introduction: Prostate cancers are infiltrated with Programmed Death-1 (PD-1) expressing Cluster of Differentiation (CD)8+ T-cells which interact with Programmed cell Death Ligand-1 (PDL-1) receptors on Tumour Cells (TC). However, in many studies, male with prostate cancer did not respond to monotherapy (PDL blockade). This unresponsiveness could be due to the fact that prostate cancer usually does not express PDL-1. The PDL-1 expression has demonstrated a significant correlation with increased risk of disease progression in various tumours but data regarding its role in prostate cancer is conflicting.
Aim: To study the occurrence rate of PDL-1 expression and its association with tumour aggressiveness in prostate cancer.
Materials and Methods: This cross-sectional observational study was conducted at ABVIMS and Dr. Ram Manohar Hospital, New Delhi, India, from October 1st, 2018 to April 30th, 2020. A total of 120 males with prostate cancer who had their diagnosis established by a prostate biopsy were included. Histopathology reports were analysed and PDL-1 immunohistochemical staining was carried out with PDL-1 monoclonal antibodies. PDL-1 expression on TCs was defined by the percentage of PDL-1 positive TCs (<1%=0 or negative, 1 to 5%=+1, ≥5%=+2). The relationship between PDL-1 expression in prostate cancer cells and clinicopathological factors like Gleason grade, lymph node positivity, perineural invasion, lymphovascular invasion, distant metastasis and Prostate Specific Antigen (PSA) level was investigated using univariate tests and multivariate logistic regression analyses.
Results: Overall, high PDL-1 expression was observed in 21.7% of patients. PDL-1 positivity 1+ and 2+ was found among 11.67% and 10% cases, respectively. Significantly higher expression (p-value <0.05) of PDL-1 was noted in cases with higher preoperative PSA levels (>40), high Gleason score (≥7), distant metastasis and cases with lymphovascular invasion.
Conclusion: Present study suggests that PDL-1 is associated with the tumour aggressiveness in prostate cancer patients and can be used for the identification of more aggressive diseases.
Body mass index, Lipid peroxidation, Reactive oxygen species, Thyroid hormone, Total iron binding capacity
Programmed cell Death Ligand 1 (PDL-1) is a cell surface glycoprotein that functions as an inhibitor of the immune response through promoting T-cell apoptosis by binding to programmed cell death-1 (PD-1) receptor on the surface of T lymphocytes (1). Although prostate tumours generally have low PDL-1 expression, PDL-1 expression is clearly not a universal marker of response as demonstrated by the experience in renal cell carcinoma and urothelial carcinoma (2). Efforts to enhance the immunogenicity of prostate cancer by combining chemotherapy, androgen deprivation, radiation, Deoxyribonucleic Acid (DNA) damaging agents, and vaccines with PD-1/PDL-1 inhibitors are all in clinical development (3).
Previous research has discovered wide variability in PDL-1 expression in prostate cancer, ranging from 14-92% (4),(5),(6),(7). PDL-1-positive expression has demonstrated a significant correlation with increased risk of disease progression and cancer death in various tumours like hepatocellular carcinoma, melanoma, colorectal carcinoma, etc., (8),(9), but data regarding the prognostic role of PDL-1 expression in prostate cancer are conflicting. These findings prompted researchers to investigate the relevance of PDL-1 as a prognostic marker in prostate cancer. PDL-1 could be a potential biomarker for prostate cancer risk stratification. In the future, providing additional meaningful predictive information to the existing clinical characteristics. Future research are required to investigate the response of PDL-1 therapy in such patients (PDL-1 and high-risk patients). Hence, present study aimed to assess the PDL-1 expression in prostate cancer and its relation with clinicopathological factors of cancer.
This was a cross-sectional observational study conducted from 1st October 2018 to 30th April 2020 in ABVIMS and Dr. Ram Manohar Hospital, New Delhi after obtaining Ethical Committee approval (No. TP(MD/MS) (09/2018) /IEC/PGIMER/RMLH 3004/18) and informed written consent.
Inclusion criteria: Patients who were diagnosed with prostate cancer on Transrectal Ultrasound (TRUS) guided prostate biopsy or who underwent radical prostatectomy were included in the present study.
Exclusion criteria: Those who had previously received immune-modulator or checkpoint inhibitor therapy were excluded.
A total of 120 patients were subjected to standard tests, for e.g., routine blood and urine tests, serum PSA, Multiparametric-Magnetic Resonance Imaging (mpMRI) for local staging. Radiographic staging with Computed Tomography (CT) scan whole abdomen, chest plus spine screening or Prostate-Specific Membrane Antigen-Positron Emission Tomography (PSMA-PET) scan was done for patients with suspected locally advanced disease, Gleason score of 8 or greater (as per World Health Organisation (WHO) 2016 modified Gleason scoring system) (10), or PSA level greater than 20 ng/mL,
as per 2018 clinically localised prostate cancer: American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology (AUA/ASTRO/ SUO) guideline (11).
Histopathological Examination
The patients underwent either TRUS biopsy or radical prostatectomy. Out of 120 cases, 96 patients underwent TRUS biopsy, while 24 patients underwent radical prostatectomy with pelvic lymph node dissection for clinically organ confined prostate cancer at present Institution. The limits of pelvic lymph node dissection included all lymphatic tissue along the external iliac vein from the lymph node of cloquet distal to the bifurcation of the common iliac vein proximal, including all lymphatic tissue in the obturator fossa. The tissue samples with adjacent normal tissue samples were fixed in 10% phosphate buffered formalin and embedded in paraffin. About 5 mm thick sections were stained by Haematoxylin and Eosin (H&E) (Table/Fig 1) for routine histopathological analysis/Gleason grading (as per WHO 2016 modified Gleason scoring system) (10). PDL-1 immunohistochemical staining was carried out with the following antibodies: PDL-1 (Rabbit) ZR3 (438R-25) monoclonal antibodies (Table/Fig 2). Other histopathological markers like lymph nodes positivity, perineural and lymphovascular invasion were also analysed. (TNM staging-T (primary tumour), N (lymph nodes) and M (metastasis) as per American Joint Committee on Cancer (AJCC) 8th Edition, 2016) (12).
Immunohistochemical (IHC) Expression Analysis of PDL-1 in Tumour Samples
PDL-1 expression was evaluated based on immunostaining in the membrane of TCs in carcinoma prostate according to the intensity and extent on a semiquantitative scale as follows: PDL-1 expression on TCs was defined by the percentage of PDL-1 positive TCs (6):
(<1%=0 or negative, ≥1% but <5%=+1, ≥5%=+2).
Statistical Analysis
Data so collected were tabulated in an excel sheet, under the guidance of a statistician. The means and standard deviations of the measurements per group were used for statistical analysis (Statistical Package for the Social Sciences (SPSS) 22.0 for windows; SPSS inc, Chicago, USA). Normality of data was tested by Kolmogorov-Smirnov test. Student’s t-test, Mann-Whitney U test, Pearson’s Chi-square test, Fisher’s-Exact test and the Receiver Operating Characteristic (ROC) curve test were used to analyse the data and the level of significance was set at p<0.05. Moreover, multivariate logistic regression analysis was also conducted to determine the relationship of PDL-1 expression in prostate cancer with different clinicopathological factors of the malignancy.
The mean age of the study group was 59.6 years. There was no significant difference among subjects with diabetes, hypertension and Body Mass Index (BMI) as compared to their counterparts in terms of PDL-1 positivity.
The association of various clinicopathological factors of enrolled patients with PDL-1 expression is shown in (Table/Fig 3). There were a total of 120 cases out of which 96 and 24 subjects underwent TRUS Biopsy and radical prostatectomy respectively. A total of 26 (21.7%) samples of tumour tested positive for PDL-1 (Table/Fig 4).
PDL-1 positivity 1+ and 2+ was found among 14 (11.67%) and 12 (10%) cases respectively. Significantly higher expression (p-value <0.05) of PDL-1 (+1 or +2 in comparison to 0) was noted in cases with higher T stage, distant metastasis, higher preoperative PSA levels, high Gleason score (≥8), perineural invasion, and cases with lymphovascular invasion. No significant difference was found between PDL-1 expression with prostate size, and lymph node staging (Table/Fig 3). PDL-1 (+2) was found to have significantly higher expression than PDL-1 (+1) in cases with distant metastasis (M1) and lymphovascular invasion, but no such significant difference was found between PDL-1 (1+) and (2+) expression in cases with high Gleason score (8), T stage (T4), N stage (pN1), and perineural invasion (Table/Fig 4).
Likewise, multivariate analysis confirmed that higher preoperative PSA levels (>40), high Gleason score (7 or more), distant metastasis, and cases with lymphovascular invasion had significantly higher expression (p-value <0.05) of PDL-1. Conversely, no significant associations were found between the expressions of PDL-1 in TCs with other factors as depicted in (Table/Fig 5).
The median PSA level was significantly higher among PDL-1 positive as compared to PDL-1 negative patients {41.7 (15.1-53) vs. 17.3 (9.8-37.5) ng/mL; p<0.001}. An optimal PSA cut-off of ≥30.75 ng/mL had a sensitivity of 69.2%, specificity of 72.3%, accuracy of 71.7%, positive predictive value of 40.9% and negative predictive value of 89.5% in detecting PDL-1 positivity. It has an area under the ROC curve of 0.708 (95% CI: 0.579-0.838); p<0.001 as shown in (Table/Fig 6).
Prostate cancer has been shown to have little response to immune checkpoint inhibitors. In order to reveal the underlying mechanisms of resistance, many investigators have examined the expression of PDL-1 in primary prostate tumours. Martin AM et al., speculated that the likely reason for the failure of anti-PD-1 monotherapies in prostate cancer is due to paucity of PDL-1 expression in the prostate tumour microenvironment, as only three out of 20 prostate tumours in their study showed positive PDL-1 staining (4). In present study, 21.7% of cases were tested positive for PDL-1. However, previous studies found huge variations in terms of PDL-1 expression. PDL-1 positive rates vary from 15%, 14%, 35% to 52.2%, and even 92% (4),(5),(6).
Baas W et al., found no significant association between expression of PDL-1 and patient or disease characteristics (13) while some published studies (7),(14),(15),(16) reported that PDL-1 expression was a negative predictor for prognosis. Sharma M et al., found that PDL-1 expression was not very helpful in predicting tumour recurrence in prostate cancer patients who underwent radical prostatectomy (14). Because of these conflicting results in different studies, one might be able to question the role of PDL-1 in local immune suppression in prostate cancer.
Li Y et al., in their meta-analysis revealed that the prevalence of PDL-1 in prostate cancers was 35% (15). They also revealed that PDL-1 tends to have high expression levels in high Gleason score cases. However, PDL-1 had a relatively weak correlation with age, pathologic stage, lymph node metastasis, and preoperative PSA level. Xian P et al., in their study found that PDL-1 positive tumours were found in patients with advanced tumour stage, lymph node metastasis, and high Gleason score, which was similar to present study (17). However, they did not find a significant association with PSA levels. Petitprez F et al., found that expression of PDL-1 by TCs was associated with a higher risk of clinical progression in men with node-positive prostate cancer (18). He J et al., reported that the PDL-1 expression in TCs or lymphocytes was associated with Gleason score, but not related to age, preoperative PSA level, clinical T-stage, lymph node metastasis and grade of risk factors (19).
Present study also explored the relationship of PDL-1 expression with clinicopathological features in prostate cancer. The results present study revealed that high PDL-1 expression was more likely to be observed in patients with higher preoperative PSA levels (>40), high Gleason score (7 or more), distant metastasis, and cases with lymphovascular invasion. Although nodal involvement was not found significant, this must have happened because of a low number of cases (24 cases) who underwent pelvic lymph node dissection during radical prostatectomy. These findings indicated that patients with PDL-1 overexpression showed more aggressive and advanced disease than those without PDL-1 expression and might obtain a survival benefit from anti-PDL-1 immunotherapy. In the future, PDL-1 may be a promising biomarker for risk stratification of prostate cancer and might offer additional relevant prognostic information to the implemented clinical parameters. The response of PDL-1 therapy in such patients (PDL-1 positivity 1+ and high-risk patients) need to be assessed in future studies. The cut-off values distinguishing negative and positive PDL-1 expression varied in different studies. The different antibodies used in the previous studies might also affect the precision of the positive rate of PDL-1 expression and might therefore affect the estimation of the prognostic and clinicopathologic value of PDL-1 expression (14),(15),(16).
Limitation(s)
The main limitation of present study was its observational nature, single-Institution data with a limited number of cases. Secondly, the present study did not evaluate the response of anti-PDL-1 therapy in these patients. Thus, a large multicentric study employing the same antibody and cut-off value is expected to provide more precise and reliable results.
The present research reveals that PDL-1 expression is linked to high-risk prostate cancer patients. PDL-1 expression by prostate cancer cells could be utilised in the future to identify more aggressive diseases and hence, guide the use of anti-PDL-1 therapy. The current investigation was carried out in a single facility with a modest number of patients. To corroborate the findings of the present study, more research with a bigger sample size and multicentre population is required.
DOI: 10.7860/JCDR/2022/52587.15978
Date of Submission: Sep 25, 2021
Date of Peer Review: Oct 09, 2021
Date of Acceptance: Jan 27, 2022
Date of Publishing: Feb 01, 2022
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? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes
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