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   2016| May  | Volume 143 | Issue 7  
    Online since October 6, 2016

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Adoptive immunotherapy with interleukin-2 & induced killer cells in non-small cell lung cancer: A systematic review & meta-analysis
Denghai Mi, Weiwei Ren, Kehu Yang
May 2016, 143(7):1-10
DOI:10.4103/0971-5916.191738  PMID:27748271
Background & objectives: The effectiveness of interleukin-2 (IL-2) and induced killer cells for non-small cell lung cancer (NSCLC) is controversial. This study evaluates the efficacy and safety of interleukin-2 and induced killer cells on NSCLC, so as to provide references for further clinical practice and research. Methods: Relevant randomized controlled trials (RCTs) were searched in Cochrane library (Issue 2, 2013), Web of Science (1980-March 2013), PubMed (1966-March 2013), China Knowledge Resource Integrated database (CNKI) (1994-March 2013), China Biology Medicine database (CBM) (1978-March 2013), VIP (1989-March 2013), and Wan Fang databases (1997-March 2013). There were no language restrictions. After independent quality assessment and data extraction by two authors, meta-analysis was conducted by RevMan 5.1 software. Results: Ten RCTs were included. Odds ratio (OR), 95% confidence intervals (CI), P value expressed as test group (interleukin-2 or induced killer cells combined chemotherapy) versus control group (chemotherapy alone), was 2.02 (1.24, 3.29; P=0.004) for disease control rate. Hazard ratios (HR) (95% CI; P value), expressed as test group (interleukin-2 or induced killer cells) versus control group, were 0.60 (0.46, 0.79; P=0.0003) for overall survival of postoperative treatment, and 0.77 (0.60, 0.99; P =0.04) for overall survival of combination with chemotherapy. Mean differences (MD) (95% CI; P value), expressed as test group (interleukin-2 or induced killer cells) versus control group (after treatment), were 11.32 (6.32, 16.33; P=0.00001) for NK cells, 11.79 (2.71, 20.86; P=0.01) for CD3+ cells, 14.63 (2.62, 26.64; P=0.02) for CD4+ cells, and -4.49 (-7.80, 1.18; P=0.008) for CD8+ cells. Interpretation & conclusions: The meta-analysis showed that IL-2 or induced killer cells combination therapy was efficacious in treating NSCLC and improved overall survival. Further analysis of trials having adequate information and data need to be done to confirm these findings.
  1,704 1,611 2
Diagnostic utility of Wilms' tumour-1 protein (WT-1) immunostaining in paediatric renal tumours
Surbhi Goyal, Kiran Mishra, Urvee Sarkar, Satendra Sharma, Anita Kumari
May 2016, 143(7):59-67
DOI:10.4103/0971-5916.191776  PMID:27748279
Background & objectives: Renal tumours constitute about 7 per cent of all neoplasms in children. It is important to differentiate Wilms' tumour (commonest tumour) from non-Wilms' tumours. The aim of this study was to evaluate the immunoexpression and diagnostic role of Wilms' tumour-1 protein (WT1) in paediatric renal tumours. Methods: A total of 53 cases of renal tumours in children (below 18 yr) who underwent total nephrectomy were included in this retrospective study. WT1 immunostaining was done using mouse monoclonal WT1 antibody (clone: 6F-H2). Results: Of the 53 cases, 38 (72%) were of Wilms' tumour. Non-Wilms' group (15) included six cases of mesoblastic nephroma (MN), two each of clear cell sarcoma (CCSK), renal cell carcinoma (RCC) and peripheral neuroectodermal tumour (PNET) and one each of angiomyolipoma (AML), rhabdomyosarcoma (RMS) and malignant rhabdoid tumour (MRT). Proportion of WT1 positivity in Wilms' tumour was 100 per cent in contrast to 26.7 per cent in non-Wilms' tumours ( P<0.001). Epithelial and blastemal components of Wilms' tumour showed moderate (2+) nuclear and cytoplasmic staining in 80 (24/30) and 75 per cent (24/32) cases, respectively. MN, PNET, CCSK and AML were negative for WT1. RMS, RCC and MRT showed cytoplasmic staining, strongest in RMS. No significant association was seen between WT1 expression and NWTSG (National Wilms' Tumor Study Group) stage. Interpretation & conclusions: WT1 helps to differentiate Wilms' tumour from other paediatric renal tumours. It may help in differentiating the two subgroups of Wilms' tumour which have distinct molecular pathogenesis and biological behaviour, however, further prospective studies are required for validation of this hypothesis.
  1,466 319 2
Side scatter versus CD45 flow cytometric plot can distinguish acute leukaemia subtypes
Annapurna Saksena, Parul Gautam, Parth Desai, Naresh Gupta, AP Dubey, Tejinder Singh
May 2016, 143(7):17-22
DOI:10.4103/0971-5916.191743  PMID:27748273
Background & objectives: Flow cytometry is an important tool to diagnose acute leukaemia. Attempts are being made to find the minimal number of antibodies for correctly diagnosing acute leukaemia subtypes. The present study was designed to evaluate the analysis of side scatter (SSC) versus CD45 flow dot plot to distinguish acute myeloid leukaemia (AML) from acute lymphoblastic leukaemia (ALL), with minimal immunological markers. Methods: One hundred consecutive cases of acute leukaemia were evaluated for blast cluster on SSC versus CD45 plots. The parameters studied included visual shape, CD45 and side scatter expression, continuity with residual granulocytes/lymphocytes/monocytes and ratio of maximum width to maximum height (w/h). The final diagnosis of ALL and AML and their subtypes was made by morphology, cytochemistry and immunophenotyping. Two sample Wilcoxon rank-sum (Mann Whitney) test and Kruskal-Wallis equality-of-populations rank tests were applied to elucidate the significance of the above ratios of blast cluster for diagnosis of ALL, AML and their subtypes. Receiver operating characteristic (ROC) curves were generated and the optimal cut-offs of the w/h ratio to distinguish between ALL and AML determined. Results: Of the 100 cases, 57 of ALL and 43 cases of AML were diagnosed. The median w/h ratio of blast population was 3.8 for ALL and 1 for AML (P<0.001). ROC had area under curve of 0.9772.The optimal cut-off of the w/h ratio for distinction of ALL from AML was found to be 1.6. Interpretation & conclusions: Our findings suggest that if w/h ratio on SSC versus CD45 plot is less than 1.6, AML may be considered, and if it is more than 1.6, ALL may be diagnosed. Using morphometric analysis of the blast cluster on SSC versus CD45, it was possible to distinguish between ALL and AML, and their subtypes.
  1,391 382 -
Level of PAX5 in differential diagnosis of non-Hodgkin's lymphoma
Brij Bharti, Sachin Shukla, Ratnakar Tripathi, Suman Mishra, Mohan Kumar, Manoj Pandey, Rajnikant Mishra
May 2016, 143(7):23-31
DOI:10.4103/0971-5916.191747  PMID:27748274
Background & objectives: The PAX5, a paired box transcription factor and B-cell activator protein (BSAP), activates B-cell commitment genes and represses non-B-cell lineage genes. About 14 transcript variants of PAX5 have been observed in human. Any alteration in its expression pattern leads to lymphogenesis or associated diseases and carcinogenesis in non-lymphoid tissues. Its mechanisms of function in pathophysiology of non-Hodgkin's lymphoma (NHL) are unclear. This study was intended to explore influence of PAX5 in cascade of NHL pathogenesis and diagnosis. Methods: Samples of 65 patients were evaluated by immunohistochemical staining for cellular localization of PAX5, CD19, CD3, cABL, p53, Ras and Raf and by TUNEL assay, RNA-isolation and reverse transcriptase (RT)-PCR, w0 estern blot analysis, and lactate dehydrogenase (LDH) specific staining. Results: B-cell type NHL patients were positive for PAX5, p53, Ras, CD19, Raf and CD3. All of them showed TUNEL-positive cells. The differential expression pattern of PAX5, CD19, p53, CD3, Zap700 , HIF 1α, Ras, Raf and MAPK (mitogen-activated protein kinase) at the levels of transcripts and proteins was observed. The LDH assay showed modulation of LDH4 and LDH5 isoforms in the lymph nodes of NHL patients. Interpretation & conclusions: The histological observations suggested that the patients represent diverse cases of NHL like mature B-cell type, mature T-cell type and high grade diffuse B-cell type NHL. The findings indicate that patients with NHL may also be analyzed for status of PAX5, CD19 and ZAP70, and their transcriptional and post-translational variants for the differential diagnosis of NHL and therapy.
  1,481 289 -
Determinants of lymph node status in women with breast cancer: A hospital based study from eastern India
Abhijit Chakraborty, Chinmoy Kumar Bose, Jayasri Basak, Aditya Narayan Sen, Raghwendra Mishra, Ashis Mukhopadhyay
May 2016, 143(7):45-51
DOI:10.4103/0971-5916.191761  PMID:27748277
Background & objectives: Number of metastatic lymph nodes has a strong prognostic value in the course of breast cancer treatment, morbidity and mortality. This study was undertaken to determine the association between axillary lymph node metastasis and several variables such as age, tumour size, grade, lymphovascular invasion, oestrogen and progesterone receptor expression and HER2/neu status in patients with breast cancer. Methods: In this study 426 (with complete information on study variables) patients with breast cancer on treatment during March 2010 to December 2013, were analyzed. TNM (tumour node matastasis) staging was evaluated. The histological grading of tumours was done according to modified Bloom-Richardson Grading System. The immunophenotype of the tumour was determined as the expression of oestrogen (ER) and progesterone (PR) receptors and Her0 2/neu status. Univariate and multivariate analyses were carried out to determine the independent predictors of metastatic lymph node. Results: Among the studied patients, 44.36 per cent (189 of 426) of the patients had nodal metastases. t0 umour histology, tumour grade, size and lympho-vascular invasion were related with node positivity. On univariate analysis, age, menopause, hormone receptor status did not relate with the node metastasis. Age, tumour grade, tumour size, lympho-vascular invasion and HER2/neu expression was likely to be associated with the number of lymph node metastasis. Interpretation & conclusions: The lymph node status was associated with clinical stage, tumour grade, tumour histology and HER2/neu status. t0 hese factors may be used for better management of such patients.
  1,478 289 1
PI3K/Akt/mTOR signaling & its regulator tumour suppressor genes PTEN & LKB1 in human uterine leiomyomas
Annu Makker, Madhu Mati Goel, Abbas Ali Mahdi, Vikram Bhatia, Vinita Das, Anjoo Agarwal, Amita Pandey
May 2016, 143(7):112-119
DOI:10.4103/0971-5916.191808  PMID:27748285
Background & objectives: Despite their high occurrence and associated significant level of morbidity manifesting as spectrum of clinical symptoms, the pathogenesis of uterine leiomyomas (ULs) remains unclear. We investigated expression profile of tumour suppressor genes PTEN (phosphatase and tensin homolog deleted on chromosome ten) and LKB1 (liver kinase B1), and key signaling components of P13K (phosphatidylinositol 3-kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in leiomyomas and adjacent normal myometrium in women of reproductive age, to explore the possibility of targeting this pathway for future therapeutic implications. Methods: Real time PCR (qPCR) was used to quantify relative gene expression levels of PTEN, Akt1, Akt2, mTOR, LKB1 and VEGFA (vascular endothelial growth factor A) in leiomyoma as compared to adjacent normal myometrium. Immunohistochemistry was subsequently performed to analyze expression of PTEN, phospho-Akt, phospho-mTOR, phospho-S6, LKB1 and VEGFA in leiomyoma and adjacent normal myometrium. Results: Significant upregulation of PTEN (2.52 fold; P=0.03) and LKB1 (3.93 fold; P0.01), and downregulation of VEGFA (2.95 fold; P=0.01) genes were observed in leiomyoma as compared to normal myometrium. Transcript levels of Akt1, Akt2 and mTOR did not vary significantly between leiomyoma and myometrium. An increased immunoexpression of PTEN (P=0.015) and LKB1 (P<0.001) and decreased expression of VEGFA (P=0.01) was observed in leiomyoma as compared to myometrium. Immunostaining for activated (phosphorylated) Akt, mTOR and S6 was absent or low in majority of leiomyoma and myometrium. Interpretation & conclusions: Upregulation of PTEN and LKB1 in concert with negative or low levels of activated Akt, mTOR and S6 indicates that PI3K/Akt/mTOR pathway may not play a significant role in pathogenesis of leiomyoma.
  1,316 309 3
Evaluation of HER2/neu oncoprotein in serum & tissue samples of women with breast cancer
Shailaja Shukla, Bhawana Komal Singh, Om Prakash Pathania, Manjula Jain
May 2016, 143(7):52-58
DOI:10.4103/0971-5916.191769  PMID:27748278
Background & objectives: The proto-oncogene HER2/neu has been extensively studied in breast cancer patients. Serum levels of HER2/neu by ELISA in breast cancer patients were compared with tissue HER2/neu expression and with other clinicopathological parameters with the aim to investigate whether the serum assay could replace the established tests (IHC/FISH) for HER-2 status. Methods: Blood and Tru-cut biopsy samples were collected for determining HER2/neu status in 64 breast cancer patients. The tissue specimens were processed routinely and immunohistochemistry (IHC) for HER2/ER/PR (oestrogen/progesterone receptors) performed. Fluorescence in-situ hybridization (FISH) was performed on all HER2/neu 2 positive cases. Sixty age matched healthy females and females with benign breast disease were taken as controls for ELISA. Results: Of the 64 breast cancer cases, 25 (39.1%) had elevated serum HER2/neu levels accompanied with increased tissue expression of HER2/neu receptors. On IHC, HER2/neu score was 3+ in 24 (37.5%) cases, 2+ in three (4.6%), 1+ in 18 (28.1%); while 19 cases (29.7%) showed no HER2/neu expression. o0 f the three 2+ cases on IHC, two showed amplification on FISH. Twenty one (32.8%) patients were ER positive and 17 (26.6%) were PR positive. There was a significant correlation (P<0.001) of serum HER2 concentration with tumour size, lymph node involvement, stage of disease and histological grade. Serum HER2/neu levels showed a negative correlation with ER status (P=0.047) but no correlation with PR status. Interpretation & conclusions: The results suggest that elevated serum HER2 level was associated with a clinicopathological aggressive phenotype of breast carcinoma and was related to tissue HER2 overexpression. Therefore, serum HER2 may be useful for monitoring the course of the disease and response to treatment.
  1,142 350 5
Does awareness of diagnosis influence health related quality of life in north Indian patients with lung cancer ?
Ashutosh Nath Aggarwal, Navneet Singh, Dheeraj Gupta, Digambar Behera
May 2016, 143(7):38-44
DOI:10.4103/0971-5916.191757  PMID:27748276
Background & objectives: Several patients with cancer in India are not aware of their diagnosis. We evaluated the impact of awareness of cancer diagnosis on health-related quality of life (HRQL) in newly diagnosed patients with lung cancer. Methods: A total of 391 treatment-naïve patients with lung cancer, seen at the Lung Cancer Clinic of a tertiary care hospital in north India, were categorized into those aware of their diagnosis (group A) and those not aware (group B). All patients answered Hindi versions of abbreviated World Health Organization Quality of Life questionnaire (WHOQOL-Bref) and European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30), and its lung cancer module, EORTC QLQ-LC13. Various domain scores were computed and compared between the two groups. Analysis of covariance was used to determine significance of differences after adjustment for potential confounding factors. Results: Only 117 (29.9%) patients were aware of their diagnosis. Of all, 302 (77.2%) patients had non-small cell lung cancer, and 301 (77.0%) had advanced disease. All HRQL domain scores were similar between the two groups, except that group B patients had significantly poorer median (interquartile range) Physical [39.3 (28.6-50.0) vs 46.4 (28.6-57.1)] and Environment [46.9 (40.6-56.3) vs 53.1 (0.6-65.6)] domain scores of WHOQOL-Bref, and p0 hysical function [60.0 (40.0-73.3) vs 66.7 (46.7-80.0)] and Fatigue [66.7 (55.6-77.8) vs 66.7 (44.4-66.7)] scores of QLQ-C30. After adjusting for gender, age, education, family income, and tumour extent, these differences were not significant. Interpretation & conclusions: Disclosure of cancer diagnosis, or lack of it, had no significant impact on HRQL in patients with lung cancer after adjustment of potential confounders.
  1,140 290 3
Potential diagnostic implications of miR-144 overexpression in human oesophageal cancer
Priyanka Sharma, Anoop Saraya, Rinu Sharma
May 2016, 143(7):91-103
DOI:10.4103/0971-5916.191796  PMID:27748283
Background & objectives: Insidious symptomatology, late clinical presentation and poor prognosis of oesophageal cancer (EC) highlight the pressing need for novel non-invasive biomarkers for early tumour diagnosis and better prognosis. The present study was carried out to evaluate the clinical significance of circulating and tissue miR-144 expression in oesophageal cancer. Methods: Clinical significance of miR-144 expression was evaluated in preneoplastic (12) and neoplastic (35) oesophageal cancer tissues as well as matched distant non-malignant tissues using real-time PCR (qPCR). Circulating levels of miR-144 were also analyzed in serum samples of EC patients as well as normal individuals to determine the diagnostic potential of miR-144. Further, targets of miR-144 were predicted using bioinformatic tools and their gene ontology (GO) terms were assigned. Results: Real-time PCR analysis revealed significant upregulation of miR-144 in 29 of 35 (83%) EC tissues as compared to matched distant non-malignant tissues (P=0.010). a0 ll the dysplastic tissues showed upregulation of miR-144 as compared to their matched distant non-malignant tissues. Relative levels of circulating miR-144 in serum significantly distinguished EC patients from normal controls (P=0.015; AUC = 0.731) with high sensitivity of 94.7 per cent. Bioinformatically predicted target, PUR-aplha (PURA) was found to be significantly (P=0.018) downregulated in 81 per cent (26/32) EC patients and its expression was found to be significantly and negatively correlated with miR-144 expression at mRNA level. Interpretation & conclusions: Our findings showed significant upregulation of miR-144 in serum samples of EC patients indicating its potential as minimally invasive marker. Further studies need to be done to understand the role of miR-144 in the pathogenesis of EC.
  1,104 248 5
Preliminary evaluation of indigenous 90 Y-labelled microspheres for therapy of hepatocellular carcinoma
Suresh Subramanian, Usha Pandey, Pradip Chaudhari, Monica Tyagi, Sanjay Gupta, Geetanjali Singh, Ashutosh Dash, Grace Samuel, Meera Venkatesh
May 2016, 143(7):74-81
DOI:10.4103/0971-5916.191786  PMID:27748281
Background & objectives: Yttrium-90 ( 90 Y)-based radioembolization has been employed to treat hepatocellular carcinoma (HCC) as commercial radioactive glass and polymeric resin microspheres. However, in India and other Asian countries, these preparations must be imported and are expensive, validating the need for development of indigenous alternatives. This work was aimed to develop an economically and logistically favourable indigenous alternative to imported radioembolizing agents for HCC therapy. Methods: The preparation of 90 Y-labelled Biorex 70 microspheres was optimized and in vitro stability was assessed. Hepatic tumour model was generated in Sprague-Dawley rats by orthotopic implantation of N1S1 rat HCC cell line. In vivo localization and retention of the 90 Y-labelled Biorex 70 microspheres was assessed for seven days, and impact on N1S1 tumour growth was studied by histological examination and biochemical assays. Results: Under optimal conditions, >95% 90 Y-labelling yield of Biorex70 resin microspheres was obtained, and these showed excellent in vitro stability of labelling (>95%) at seven days. In animal studies, 90 Y-labelled Biorex 70 microspheres were retained (87.72±1.56% retained in liver at 7 days). Rats administered with 90 Y-labelled Biorex 70 microspheres exhibited lower tumour to liver weight ratio, reduced serum alpha-foetoprotein level and greater damage to tumour tissue as compared to controls. Interpretation & conclusions: 90 Y-labelled Biorex 70 microspheres showed stable retention in the liver and therapeutic effect on tumour tissue, indicating the potential for further study towards clinical use.
  1,056 255 2
Spectrum of AIDS defining & non-AIDS defining malignancies in north India
Ravinder Kaur Sachdeva, Aman Sharma, Surjit Singh, Subhash Varma
May 2016, 143(7):129-135
DOI:10.4103/0971-5916.191813  PMID:27748287
Background & objectives: There is scarcity of data on the frequency of malignancies in HIV infected individuals from India. The objective of this study was to determine the type and frequency of malignancies in HIV infected individuals attending a tertiary care hospital in north India. Methods: The study design included retrospective analysis of data of all HIV infected individuals registered in the Immunodeficiency clinic from December 2009 to December 2011 and a prospective analysis of HIV infected individuals registered from January 2012 to April 2013. The clinical details and treatment outcomes of all individuals diagnosed to have AIDS defining and non-AIDS defining malignancies were recorded. Results: Records of 2880 HIV infected individuals were reviewed. Thirty one (19 males, 12 females) individuals were diagnosed to have malignancy. AIDS defining malignancy was found in the form of non-Hodgkin's lymphoma in 12 individuals and cervical cancer in six women. Non-AIDS defining malignancies included Hodgkin's lymphoma (n=2); and chronic myelogenous leukaemia, carcinoma base of tongue, carcinoma larynx, carcinoma bronchus, sinonasal carcinoma, ovarian carcinoma, anal carcinoma, carcinoma urinary bladder, pleomorphic sarcoma, parathyroid adenoma, and renal cell carcinoma in one individual each. Mean CD4+cell count prior to ART initiation was 250 ± 195.6 (median: 187; range, 22-805) cells/μl and at the time of diagnosis of malignancy was 272 ± 202 (median: 202; range, 15-959) cells/μl. The mean CD4+ count of individuals with AIDS defining malignancy was significantly lower when compared with non-AIDS defining malignancy (P<0.001). Fourteen individuals were alive and on regular follow up, 15 had died and two cases were lost to follow up. Interpretation & conclusions: The frequency of malignancies in HIV infected patients at our centre was 1 per cent, with non-Hodgkin's lymphoma being the commonest. Further studies need to be done to document similar data from different parts of the country.
  1,009 289 1
High fms-like tyrosine kinase-3 (FLT3) receptor surface expression predicts poor outcome in FLT3 internal tandem duplication (ITD) negative patients in adult acute myeloid leukaemia: A prospective pilot study from India
Surender Kumar Sharawat, Vinod Raina, Lalit Kumar, Atul Sharma, Radhika Bakhshi, Sreenivas Vishnubhatla, Ritu Gupta, Sameer Bakhshi
May 2016, 143(7):11-16
DOI:10.4103/0971-5916.191740  PMID:27748272
Background & objectives: Mutations in fms-like tyrosine kinase 3 (FLT3) receptor have significant role in assessing outcome in patients with acute myeloid leukaemia (AML). Data for FLT3 surface expression in relation to FLT3 internal tandem duplication (ITD) status and outcome are not available from India. The objective of the current study was to investigate adult patients with AML for FLT3 expression and FLT3 ITD mutation, and their association with long-term outcome. Methods: Total 51 consecutive de novo AML patients aged 18-60 yr were enrolled in the study. FLT3 ITD was detected by polymerase chain reaction (PCR); flowcytometry and qPCR (Taqman probe chemistry) were used for assessment of FLT3 protein and transcript, respectively. Kaplan Meier curves were obtained for survival analysis followed by log rank test. Results: FLT3 ITD was present in eight (16%) patients. Complete remission was achieved in 33 (64.6%) patients. At 57.3 months, event free survival (EFS) was 26.9±6.3 per cent, disease free survival (DFS) 52.0±9.2 per cent, and overall survival event (OS) 34.5±7.4 per cent. FLT3 surface expression was positive (>20%) by flow-cytometry in 38 (88%) of the 51 patients. FLT3 surface expression and transcripts were not associated with FLT3 ITD status. FLT3 expression was significantly associated with inferior EFS (P=0.026) and OS (P=0.018) in those who were negative for FLT3 ITD. Interpretation & conclusions: This study evaluated FLT3 ITD mutation along with FLT3 expression in AML patients, and associated with survival. Negative impact of FLT3 surface expression on survival was observed in AML patients who were FLT3 ITD negative.
  1,026 271 1
Microsatellite instability & survival in patients with stage II/III colorectal carcinoma
Markovic Srdjan, Antic Jadranka, Dimitrijevic Ivan, Zogovic Branimir, Bojic Daniela, Svorcan Petar, Markovic Velimir, Krivokapic Zoran
May 2016, 143(7):104-111
DOI:10.4103/0971-5916.191801  PMID:27748284
Background & objectives: The two key aspects associated with the microsatellite instability (MSI) as genetic phenomenon in colorectal cancer (CRC) are better survival prognosis, and the varying response to 5-fluorouracil (5-FU)-based chemotherapy. This study was undertaken to measure the survival of surgically treated patients with stages II and III CRC based on the MSI status, the postoperative 5-FU treatment as well as clinical and histological data. Methods: A total of 125 consecutive patients with stages II and III (American Joint Committee on Cancer, AJCC staging) primary CRCs, were followed prospectively for a median time of 31 months (January 2006 to December 2009). All patients were assessed, operated and clinically followed. Tumour samples were obtained for cytopathological verification and MSI grading. Results: Of the 125 patients, 21 (20%) had high MSI (MSI-H), and 101 patients (80%) had MSI-L or MSS (low frequency MSI or stable MSI). Patients with MSS CRC were more likely to have recurrent disease (P=0.03; OR=3.2; CI 95% 1-10.2) compared to those with MSI-H CRC. Multi- and univariate Cox regression analysis failed to show a difference between MSI-H and MSS groups with respect to disease-free, disease-specific and overall survival. However, the disease-free survival was significantly lower in patients with MSI-H CRC treated by adjuvant 5-FU therapy (P=0.03). Interpretation & conclusions: MSI-H CRCs had a lower recurrence rate, but the prognosis was worse following adjuvant 5-FU therapy.
  1,013 281 2
Epigenetic regulation of APC in the molecular pathogenesis of gallbladder cancer
Dinesh Singh Tekcham, Satish S Poojary, Shushruta Bhunia, Mustafa Ahmed Barbhuiya, Sanjeev Gupta, Braj Raj Shrivastav, Pramod Kumar Tiwari
May 2016, 143(7):82-90
DOI:10.4103/0971-5916.191792  PMID:27748282
Background & objectives: Loss of function of adenomatous polyposis coli (APC) has been reported in cancer. The two promoters of APC, 1A and 1B also have roles in cancer. But, the epigenetic role of APC promoters is not yet clear in gallbladder cancer (GBC) and gallstone diseases (GSD). We undertook this study to determine the epigenetic role of APC in GBC and GSD. Methods: Methylation-specific (MS)-PCR was used to analyze the methylation of APC gene. The expression of APC gene was studied by semi-quantitative PCR, real-time PCR and immunohistochemistry (IHC) in GBC, GSD and adjacent normal tissues. Results: Of the two promoters, APC 1A promoter was found methylated in 96 per cent GBC ( P=0.0155) and 80 per cent GSD (P=0.015). Exon 1 was downregulated in grade II (P=0.002) and grade III (P=0.0001) of GBC, while exon 2 was normally expressed. Scoring analysis of IHC revealed 0 or negativity in 34.48 per cent (P=0.057) and 1+ in 24.14 per cent (P=0.005) GBC cases suggesting loss of APC expression. Interpretation & conclusions: The present findings indicate epigenetic silencing of APC in advanced GBC. The methylation pattern, followed by expression analysis of APC may be suggested for diagnostic, prognostic and therapeutic purposes in GBC in future.
  975 214 2
Predictors for progression of metastatic prostate cancer to castration-resistant prostate cancer in Indians
Sanjoy Kumar Sureka, Ruchir Maheshwari, Shalini Agnihotri, Nilay Mitash, Shamim Ahmad, Anil Mandhani
May 2016, 143(7):68-73
DOI:10.4103/0971-5916.191783  PMID:27748280
Background & objectives: There is lack of data on natural history and progression of prostate cancer (PC) which have implications in the management of the disease. We undertook this retrospective study to analyze factors predicting progression of metastatic PC to castration-resistant prostate cancer (CRPC) in Indian men. Methods: Complete records of 223 of the 489 patients with metastatic PC were obtained from computerized data based system in a tertiary care hospital in north India between January 2000 to June 2012. Patients with follow up of < 6 months were excluded. Age (≤ and > 65 yr), baseline PSA (< and ≥ 50 ng/ml), bone scan and Gleason score (≤7 and >7) were recorded. Extent of bone disease (EOD) was stratified according to the number of bone lesions i.e., < 5, 5-10, > 10. CRPC was defined as two consecutive PSA rise of > 50 per cent from nadir or an absolute value of > 5 ng/ml. Results: Mean age of patients was 61.5 ± 12.45 yr and their PSA level was 325.6 ± 631.35 ng/dl. Of the 223 patients, 193 (86%) progressed to CRPC at median time of 10.7 (4-124) months. Median follow up was 24 (6-137) months. On univariate and multivariate analyses EOD on bone scan was found to be a significant predictor ( P=0.006) for time to CRPC. Median time to CRPC was 10 months (CI 95%, 7.5-12.48) with >10 lesions or super scan versus 16 months (CI 95%, 10.3-21.6) with <10 bone lesion (P=0.01). Ninety (46.6 %) patients of CRPC died with median time to death from time of CRPC 21 (10-120) months. Interpretation & conclusions: Median time for progression of metastatic PC to CRPC ranged from 10-16 months depending on the extent of the bone involvement. In Indians, the aggressive course of advanced prostate cancer warrants further clinical trials to explore the need for additional treatment along with initial castration.
  942 244 -
Dual transcripts of BCR-ABL & different polymorphisms in chronic myeloid leukaemia patients
S Rajashree Nandagopalan, Nivedita Kuila, Sutapa Biswas, Naresh Chandra Pattnayak, Gyanashyam Biswas, Soumen Chakraborty
May 2016, 143(7):136-141
DOI:10.4103/0971-5916.191816  PMID:27748288
Background & objectives: Chronic myeloid leukaemia is (CML) characterized by the presence of a hallmark chromosomal translocation, the Philadelphia chromosome. Although there are many reports available regarding the different variants of BCR-ABL in CML, we studied the co-expression of e13a2 and e14a2 transcripts and a few polymorphisms in CML patients. Methods: Molecular genetics approach was adapted to screen for polymorphisms, mutation and translocation in BCR, ABL kinase domain and BCR-ABL breakpoint region in 73 CML patients. Results: All eight patients with dual transcripts were found to harbour an exonic polymorphism (c.2700 T>C) and an intronic polymorphism (g.109366A>G) that were earlier reported to be associated with co-expression of both the transcripts. We also observed c.763G>A mutation in ABL kinase domain and two polymorphisms, c.2387 A>G and c.2736A>G in the BCR gene. Interpretation & conclusions: Though our data support the previous findings that co-expression of BCR-ABL transcripts is due to the occurrence of exonic and intronic polymorphisms in the BCR gene, it also shows that the intronic polymorphism can arise without the linked exonic polymorphism. The occurrence of ABL kinase domain mutation is less frequent in Indian population.
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Carbon ions of different linear energy transfer (LET) values induce apoptosis & G2 cell cycle arrest in radio-resistant melanoma cells
Žakula Jelena, Korićanac Lela, Keta Otilija, Todorović Danijela, AP Cirrone Giuseppe, Romano Francesco, Cuttone Giacomo, Petrović Ivan, Ristić-Fira Aleksandra
May 2016, 143(7):120-128
DOI:10.4103/0971-5916.191811  PMID:27748286
Background & objectives: The main goal when treating malignancies with radiation is to deprive tumour cells of their reproductive potential. One approach is to induce tumour cell apoptosis. This study was conducted to evaluate the ability of carbon ions ( [12] C) to induce apoptosis and cell cycle arrest in human HTB140 melanoma cells. Methods: In this in vitro study, human melanoma HTB140 cells were irradiated with the 62 MeV/n carbon ( [12] C) ion beam, having two different linear energy transfer (LET) values: 197 and 382 keV/μm. The dose range was 2 to 16 Gy. Cell viability was estimated by the sulforhodamine B assay seven days after irradiation. The cell cycle and apoptosis were evaluated 48 h after irradiation using flow cytometry. At the same time point, protein and gene expression of apoptotic regulators were estimated using the Western blot and q-PCR methods, respectively. Results: Cell viability experiments indicated strong anti-tumour effects of [12] C ions. The analysis of cell cycle showed that [12] C ions blocked HTB140 cells in G2 phase and induced the dose dependent increase of apoptosis. The maximum value of 21.8 per cent was attained after irradiation with LET of 197 keV/μm at the dose level of 16 Gy. Pro-apoptotic effects of [12] C ions were confirmed by changes of key apoptotic molecules: the p53, Bax, Bcl-2, poly ADP ribose polymerase (PARP) as well as nuclear factor kappa B (NFκB). At the level of protein expression, the results indicated significant increases of p53, NFκB and Bax/Bcl-2 ratio and PARP cleavage. The Bax/Bcl-2 mRNA ratio was also increased, while no change was detected in the level of NFκB mRNA. Interpretation & conclusions: The present results indicated that anti-tumour effects of [12] C ions in human melanoma HTB140 cells were accomplished through induction of the mitochondrial apoptotic pathway as well as G2 arrest.
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Association of education & lifestyle factors with the perception of genetic knowledge on the development of lung cancer
Liang Wang, Kesheng Wang, Xuefeng Liu, Yi He
May 2016, 143(7):32-37
DOI:10.4103/0971-5916.191751  PMID:27748275
Background & objectives: The perception of genetic knowledge is useful for improving the heath behaviour change against developing cancers. However, no studies have investigated the perception of genetic knowledge on the development of lung cancer. The aim of this study was to examine demographic and lifestyle factors of the perception of genetic knowledge on the development of lung cancer. Methods: Data on 2,295 US adults (739 had the perception of genetic knowledge) were taken from the 2003 Health Information National Trends Survey. Multiple logistic regression models were used to evaluate potential factors of the perception of genetic knowledge of lung cancer. Results: Participants aged ≥65 yr were more likely to have the perception of genetic knowledge than those aged 18-44 yr (OR=1.77, 95% CI=1.27-2.46). Higher education was associated with a greater perception of genetic knowledge (OR=1.47, 95% CI=1.16-1.87). Subjects with correct smoking attitude were more than three times more likely to have the perception of genetic knowledge (OR=3.15, 95% CI=2.10-4.72). Subjects with exercise were at an increased likelihood of having the perception of genetic knowledge than those without exercise (OR=1.63, 95% CI=1.24-2.13). Interpretation & conclusions: Positive associations were observed between education and lifestyle factors and the perception of genetic knowledge on the development of lung cancer among US adults. Strategies developed to improve the perception of genetic knowledge of lung cancer may target on individuals who are young, less educated, and lack correct smoking attitude or exercise.
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