Publications by authors named "Shirley Sundersingh"

63 Publications

Identification and validation of plasma biomarkers for diagnosis of breast cancer in South Asian women.

Sci Rep 2022 Jan 7;12(1):100. Epub 2022 Jan 7.

Department of Epidemiology and Biostatistics, Cancer Institute (WIA), 38, Sardar Patel Road, Chennai, 600036, India.

Breast cancer is the most common malignancy among women globally. Development of a reliable plasma biomarker panel might serve as a non-invasive and cost-effective means for population-based screening of the disease. Transcriptomic profiling of breast tumour, paired normal and apparently normal tissues, followed by validation of the shortlisted genes using TaqMan Low density arrays and Quantitative real-time PCR was performed in South Asian women. Fifteen candidate protein markers and 3 candidate epigenetic markers were validated first in primary breast tumours and then in plasma samples of cases [N = 202 invasive, 16 DCIS] and controls [N = 203 healthy, 37 benign] using antibody array and methylation specific PCR. Diagnostic efficiency of single and combined markers was assessed. Combination of 6 protein markers (Adipsin, Leptin, Syndecan-1, Basic fibroblast growth factor, Interleukin 17B and Dickopff-3) resulted in 65% sensitivity and 80% specificity in detecting breast cancer. Multivariate diagnostic analysis of methylation status of SOSTDC1, DACT2, WIF1 showed 100% sensitivity and up to 91% specificity in discriminating BC from benign and controls. Hence, combination of SOSTDC1, DACT2 and WIF1 was effective in differentiating breast cancer [non-invasive and invasive] from benign diseases of the breast and healthy individuals and could help as a complementary diagnostic tool for breast cancer.
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http://dx.doi.org/10.1038/s41598-021-04176-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742108PMC
January 2022

Immunophenotypic expression and immunomodulation in minimal residual disease analysis of pediatric B acute lymphoblastic leukemia by high sensitive flow cytometry.

Leuk Lymphoma 2021 Nov 2:1-9. Epub 2021 Nov 2.

Departments of Oncopathology, Cancer Institute (Women's India Association), Chennai, India.

The major challenge in minimal residual disease MRD) detection is the antigen modulation in post treated samples restraining the use of diagnostic immunophenotypic (IP) signature of leukemic blasts for MRD detection. The IP expression of 10 antigens in 167 children diagnosed as B-acute lymphoblastic leukemia B-ALL) in comparison to hematogones and the extent of immunomodulation in 60 post treated MRD positive cases were studied. Upregulation was the predictable shift noted in antigens like CD73, CD86, CD19, CD20 and CD45 which was statistically significant for all except CD45. Downregulation was the predictable shift noted in antigens like CD10, CD38, CD58 and CD34 and was statistically significant in all. CD123 showed no significant trend. This immunomodulation in B-ALL results in aberrant expression of antigens during follow-up compared to the diagnostic phenotypic pattern. Hence it is necessary to be aware of the immunomodulations of antigens used in primary diagnosis to avoid being misled during MRD analysis.
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http://dx.doi.org/10.1080/10428194.2021.1992755DOI Listing
November 2021

SERMs suppresses the growth of ERα positive cervical cancer xenografts through predominant inhibition of extra-nuclear ERα expression.

Am J Cancer Res 2021 15;11(6):3335-3353. Epub 2021 Jun 15.

Department of Oncopathology, Cancer Institute (W.I.A) No. 38, Sardar Patel Road, Adyar, Chennai 600 036, India.

The role of estrogens and estrogen receptors (ER) in cervical cancer (CC) is not well established. However, epidemiological studies and abundant evidence from genetically engineered mouse models support such hypothesis. In this study, we have addressed estrogen responsiveness in a human CC cell line xenograft mouse model. We assessed the sensitivity of Ethynyl Estradiol (EE), SERMs (fulvestrant, MPP) and a non-SERM (EGCG) to competitively modulate the growth of ERα+ MS751 CC xenografts. We also checked the agonistic-antagonistic propensity of the above treatments to alter the histology of ovariectomised mouse uterine cervix. Chronic EE treatment encouraged the growth of ERα+ MS751 CC xenografts, while SERMs and EGCG significantly decreased tumor formation. SERMs were found to inhibit ERα expression, localized within cytoplasmic and membrane compartments. Conversely, ERα was not inducible and EE administration suppressed the growth of ERα- HeLa CC xenografts. SERMs competitively induced atrophic features to uterine cervix, with MPP giving rise to mucinous metaplasia in the ectocervix. We have demonstrated that, estrogen sensitivity mediated through ERα has promoted CC tumorigenesis. This in turn was modulated by SERMs, predominantly through inhibition of extra-nuclear ERα expression. Though, induction of hyper-estrogenic status in the ectocervix, might underrate the utility of SERMs in ERα+ CC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263693PMC
June 2021

Association between RAD51, XRCC2 and XRCC3 gene polymorphisms and risk of ovarian cancer: a case control and an in silico study.

Mol Biol Rep 2021 May 7;48(5):4209-4220. Epub 2021 Jun 7.

Department of Human Genetics, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research (DU), Porur, Chennai, 600116, Tamilnadu, India.

Homologous recombination (HR) is one of the important mechanisms in repairing double-strand breaks to maintain genomic integrity and DNA stability from the cytotoxic effects and mutations. Various studies have reported that single nucleotide polymorphisms (SNPs) in the HR-associated genes may have a significant association with ovarian cancer (OCa) risk but the results were inconclusive. In the present study, five polymorphisms of HR-associated genes (RAD51, XRCC2 and XRCC3) were genotyped by allelic discrimination assay in 200 OCa cases and 200 healthy individuals. The association with OCa risk was evaluated by unconditional logistic regression analyses. The results revealed that the mutant allele in both rs1801320 (CC) and rs1801321 (TT) of RAD51 gene was associated with increased risk of OCa (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.21-11.78, p = 0.014 and OR 1.61, 95% CI 1.06-2.45, p = 0.025, respectively). Moreover, a significant association of TT allele (OR 4.68, 95% CI 1.27-17.15, p = 0.011) of rs3218536 of XRCC2 gene with OCa was observed. Stratified analysis results showed that patients with early menarche and stages 3 and 4 were found to be associated with rs1801321 of RAD51 gene and rs1799794 of XRCC3 gene. In silico analysis predicted that the two missense SNPs (rs3218536 and rs1799794) were found to have an impact on the protein structure, stability and function. The present study suggested that RAD51 and XRCC2 gene polymorphisms might have an impact on the OCa risk in the South Indian population. However, studies with a larger sample and on different populations are needed to support the conclusions.
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http://dx.doi.org/10.1007/s11033-021-06434-6DOI Listing
May 2021

Cytogenetics and FISH negative cryptic acute promyelocytic leukemia with CD56 expression.

Indian J Pathol Microbiol 2021 Apr-Jun;64(2):406-409

Department of Oncopathology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu, India.

Acute promyelocytic leukemia (APL) is characterized by reciprocal translocation t(15;17)(q22;q21) and has a favorable prognosis upon immediate recognition and treatment. However, rare cases of APL show a cryptic insertion of retinoic acid receptor alpha (RARA) gene into promyelocytic leukemia (PML) gene which is negative both by fluorescence in situ hybridization (FISH) and conventional cytogenetics (CC). Morphology, cytochemistry and flow cytometry play a key role in early identification of such cases. Polymerase chain reaction (PCR) remains the most efficient diagnostic modality for detection of cryptic APL and other variants. It is important to identify these cases as they show beneficial response to retinoids and favourable prognosis. We herein present a rare case of cryptic APL negative by FISH and conventional cytogenetics but positive for PML-RARA by PCR.
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http://dx.doi.org/10.4103/IJPM.IJPM_409_20DOI Listing
October 2021

Identification of novel dysregulated circular RNAs in early-stage breast cancer.

J Cell Mol Med 2021 04 5;25(8):3912-3921. Epub 2021 Feb 5.

Department of Molecular Oncology, Cancer Institute (WIA), Chennai, India.

Breast cancer is a major cause of cancer-related death in women worldwide. Non-coding RNAs are a potential resource to be used as an early diagnostic biomarker for breast cancer. Circular RNAs are a recently identified group of non-coding RNA with a significant role in disease development with potential utility in diagnosis/prognosis in cancer. In this study, we identified 26 differentially expressed circular RNAs associated with early-stage breast cancer. RNA sequencing and two circRNA detection tools (find_circ and DCC) were used to understand the circRNA expression signature in breast cancer. We identified hsa_circ_0006743 (circJMJD1C) and hsa_circ_0002496 (circAPPBP1) to be significantly up-regulated in early-stage breast cancer tissues. Co-expression analysis identified four pairs of circRNA-miRNA (hsa_circ_0023990 : hsa-miR-548b-3p, hsa_circ_0016601 : hsa_miR-1246, hsa_circ_0001946 : hsa-miR-1299 and hsa_circ_0000117:hsa-miR-502-5p) having potential interaction. The miRNA target prediction and network analysis revealed mRNA possibly regulated by circRNAs. We have thus identified circRNAs of diagnostic implications in breast cancer and also observed circRNA-miRNA interaction which could be involved in breast cancer development.
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http://dx.doi.org/10.1111/jcmm.16324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051735PMC
April 2021

Precursor B-lineage acute lymphoblastic leukemia patients with aberrant natural killer cell and T cell - lineage antigen expression: experience from a tertiary cancer care center.

Hematol Transfus Cell Ther 2020 Oct 7. Epub 2020 Oct 7.

Cancer Institute (W.I.A.), Adyar, Chennai, India.

Introduction: Flow cytometric immunophenotyping (FCI) plays a major role in diagnosing hematologic malignancies. In patients diagnosed with precursor B-lineage acute lymphoblastic leukemia (B-ALL), expression of certain non-lineage/cross lineage antigens is of prognostic and cytogenetic relevance. There is a paucity of studies that have comprehensively analyzed the clinical and laboratory profiles of B-ALL patients showing aberrant T/natural killer (NK) cell antigen expression.

Materials And Methods: This is a prospective study where 152 consecutive B-ALL patients were analyzed for aberrant expression of T/NK cell antigens (CD1a, CD5, CD4, CD7, CD8 and CD56) by FCI. The clinical and laboratory profile of these T/NK-cell antigen-expressing B-ALL patients was statistically analyzed against conventional B-ALL patients.

Results: In our B-ALL cohort, CD5, CD7 and CD56 expression were observed in one, six and nine patients, respectively. CD56-expressing B-ALL patients were predominantly children (89%) and presented as standard clinical risk (p=0.010) disease with frequent ETV6-RUNX1 fusion (p=0.021) positivity. On the contrary, CD7-expressing B-ALL patients were adolescent-young adult/adult-age skewed (83%) and had an adverse cytogenetic profile (p=0.001), especially for the frequent presence of BCR-ABL1 fusion (p=0.004) and KMT2A rearrangement (p=0.045). CD7-expressing B-ALL patients had inferior event-free survival (p=0.040) than their CD56-expressing counterparts, but there was no significant difference in the overall survival (p=0.317).

Conclusion: In comparison to conventional B-ALL patients, there are significant differences in the age, cytogenetic profile and event-free survival of T/NK-cell antigen-expressing B-ALL patients.
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http://dx.doi.org/10.1016/j.htct.2020.08.012DOI Listing
October 2020

Blast size-specific flowcytometric ploidy assessment using FxCycle Violet dye and its correlation with conventional cytogenetic ploidy in pediatric precursor B-lineage acute lymphoblastic leukemia patients.

Int J Lab Hematol 2021 Aug 20;43(4):760-770. Epub 2020 Dec 20.

Department of Oncopathology, Cancer Institute (W.I.A.), Chennai, India.

Introduction: Numerical chromosomal abnormalities (aneuploidies), present in approximately 30%-50% of pediatric precursor B-lineage acute lymphoblastic leukemia (B-ALL) patients, are commonly identified through a laborious conventional cytogenetic (CG) technique. Flow cytometry (FCM) can identify both physical and fluorescent properties of cells together, and by using fluorescent nucleic-acid-binding dyes, FCM can identify variations in total nucleic-acid content of cells. FxCycle Violet dye (FxCV) is a selective DNA-binding dye which permits simultaneous multiparametric immunophenotyping and cell-cycle/ploidy assessment in a single assay. To date, only two studies have demonstrated the feasibility of FxCV-aided FCM-ploidy analysis in B-ALL patients and only one of these studies have compared their results with CG-ploidy.

Methodology: Blast size-specific FCM-ploidy was prospectively analyzed using FxCV-dye in 109 pediatric B-ALL patients, and the results were compared with concurrent CG-ploidy status.

Results: FCM-ploidy categorization was feasible in 98% of samples tested and the results were 82% concordant with CG-ploidy status. We observed significant correlation between DNA content and blast size (r = .823, P < .001) and could demonstrate size differences between diploid vs low-hyperdiploid (P = .025), diploid vs high-hyperdiploid (P < .001) and low- vs high-hyperdiploid blasts (P = .007).

Conclusion: FCM-ploidy assessment using FxCV dye is a reliable assay and the results closely concur with CG-based ploidy stratification and risk assessment. Using blast size-assisted DNA content analysis, the results of FCM-ploidy analysis can be further fine-tuned.
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http://dx.doi.org/10.1111/ijlh.13436DOI Listing
August 2021

Lymph Node Harvest After Neoadjuvant Treatment for Rectal Cancer and Its Impact on Oncological Outcomes.

Indian J Surg Oncol 2020 Dec 24;11(4):692-698. Epub 2020 Jul 24.

Department of Onco-Pathology, Cancer Institute (WIA), Chennai, 600036 India.

The aim of this study was to analyze the influence of neoadjuvant treatment on nodal harvest after rectal cancer surgery and its impact on long-term oncological outcomes. A retrospective analysis of patients with rectal cancer who received curative intent treatment from 2002 to 2012 in our institution was performed. Data on various clinic-pathological and treatment details were recovered from the records. The number of nodes harvested after surgery was analyzed. The influence of number of nodes harvested on overall survival and disease free survival was analyzed. Among the 459 patients included in this study, 326 underwent surgery after neoadjuvant treatment (NAT). The mean number of nodes harvested was significantly lower in patients who received NAT compared with those who did not (8.9 ± 5.77 vs 14 ± 9.84,  < 0.001). However, the mean number of pathologically positive nodes was not significantly different. A minimum of 12 nodes were harvested in only 27.9% of patients who received NAT. No lymph nodes were identified in the specimen in 15 patients (4.6%) who underwent surgery after NAT. The only independent factors influencing harvest of a minimum of 12 nodes were patient age and NAT. The 5-year overall survival was not significantly different in patients in whom < 12 or ≥ 12 nodes were harvested (64% vs 69% respectively,  = 0.5). Neoadjuvant chemoradiation significantly reduces nodal harvest in patients undergoing treatment for rectal cancer. However, this reduced nodal harvest did not adversely impact survival in patients. However, every effort must be made by the surgeon and the pathologist to maximize the nodal harvest.
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http://dx.doi.org/10.1007/s13193-020-01162-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714796PMC
December 2020

Pioglitazone modulates doxorubicin resistance in a in vivo model of drug resistant osteosarcoma xenograft.

Naunyn Schmiedebergs Arch Pharmacol 2021 02 5;394(2):361-371. Epub 2020 Oct 5.

Department of Molecular Oncology, Cancer Institute (WIA), Chennai, 600036, India.

Osteosarcoma has been reported with treatment failure in up to 40% of cases. Our laboratory had identified genes involved in the PPARγ pathway to be associated with doxorubicin (DOX) resistance. We hence used PPARγ agonist pioglitazone (PIO) to modulate DOX resistance. DOX-resistant cell line (143B-DOX) was developed by gradient exposure to DOX. The cytotoxicity to PIO and in combination with DOX was assayed in vitro, followed by HPLC to estimate the metabolites of PIO in the presence of microsomes (HLMs). Gene expression studies revealed the mechanism behind the cytotoxicity of PIO. Further, the effects were evaluated in mice bearing 143B-DOX tumors treated either with PIO (20 mg/kg/p.o or 40 mg/kg/p.o Q1D) alone or in combination with DOX (0.5 mg/kg/i.p Q2W). 143B-DOX was 50-fold resistant over parental cells. While PIO did not show any activity on its own, the addition of HLMs to the cells in culture showed over 80% cell kill within 24 h, possibly due to the metabolites of PIO as determined by HPLC. In combination with DOX, PIO had shown synergistic activity. Additionally, cytotoxicity assay in the presence of HLMs revealed that PIO on its own showed promising activity compared to its metabolites-hydroxy pioglitazone and keto pioglitazone. In vivo studies demonstrated that treatment with 40 mg/kg/p.o PIO alone showed significant activity, followed by a combination with DOX. Gene expression studies revealed that PIO could modulate drug resistance by downregulating MDR1 and IL8. Our study suggests that PIO can modulate DOX resistance in osteosarcoma cells.
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http://dx.doi.org/10.1007/s00210-020-01982-3DOI Listing
February 2021

Gastrointestinal Stromal Tumours (GIST): Indian Experience of Rare Malignancy.

Indian J Surg Oncol 2020 Sep 22;11(3):348-354. Epub 2020 May 22.

Department of Medical Oncology, Cancer Institute (WIA), Chennai, 600020 India.

GISTs are rare tumours of the GI tract arising from the intestinal cells of Cajal. Though various risk stratification systems have been proposed, none has been universally accepted. We audited the survival and recurrence patterns in our patients and evaluated clinicopathological features to identify prognostic factors affecting survival. We conducted a retrospective analysis of patients treated at our hospital from 1999 to 2012. Patient variables, clinicopathological factors and treatment variables were collected. Sixty-three patients were evaluated and treated at our institute of which 38 were non-metastatic. The most common site of origin was the stomach. On univariate analysis, presence of metastasis, male gender, high mitotic rate, non-gastric primary and epithelioid histology were significantly associated with poor overall survival. Tumour size > 10 cm, mitotic rate > 10/50 hpf and presence of necrosis significantly affected disease-free survival for non-metastatic patients. Multivariate analysis showed higher mitotic rate and non-gastric primary to correlate with worse outcome. In our experience, a high mitotic rate and non-gastric primary independently predicted a poor prognosis in GIST.
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http://dx.doi.org/10.1007/s13193-020-01095-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501329PMC
September 2020

Study of pathological complete response rate with neoadjuvant concurrent chemoradiation with paclitaxel in locally advanced breast cancer.

Indian J Cancer 2020 Oct-Dec;57(4):428-434

Department of Radiotherapy, Cancer Institute (W.I.A), Chennai, Tamil Nadu, India.

Background: Neoadjuvant concurrent chemoradiation (CTRT) is not widely practiced in breast cancers. The current study presents our experience with the use of neoadjuvant CTRT in patients with locally advanced breast cancers (LABC) treated at our center.

Methods: The study included all consecutive female patients with inoperable stage III LABC treated at Cancer Institute (W.I.A), Chennai, India, from December 2015 to September 2016. Data were collected retrospectively from the patients' case records. The impact of neoadjuvant CTRT on the pathological complete response (pCR) and survival was analyzed. Neoadjuvant chemotherapy consisted of 4 cycles of adriamycin and cyclophosphamide given either before or after 4 cycles of paclitaxel. All chemotherapy cycles were given once in 3 weeks. Concurrent radiotherapy was incorporated with 2 cycles of paclitaxel.

Results: The study included 100 patients with a median age of 49 years, among whom 9 (9%) had IIIA disease, 73 (73%) IIIB, and 18 (18%) had IIIC disease. The hormone receptor-positive disease was observed in 36 (36%) patients, triple-negative in 24 (24%), and Her2/neu positive disease in 40 (40%) patients. All patients were operable after completing the planned neoadjuvant treatments. Ninety-one out of 100 (91%) patients underwent modified radical mastectomy whereas 9 (9%) did not consent for surgery. Among the patients who underwent MRM, 34/91 (37.7%) patients had a pCR. Moreover, pCR was observed in 12/22 (54.5%) patients with triple-negative disease, 10/34 (29.4%) patients with hormone receptor-positive disease, and 12/35 (34.2%) patients with Her2/neu positive disease (P = 0.19). Most common morbidity observed was grade 3 skin reactions. The 2-year event-free survival and overall survival for the entire cohort was 73.1% and 88%, respectively.

Conclusion: Neoadjuvant CTRT is associated with a higher pCR rate than what has been reported with neoadjuvant chemotherapy alone. Further prospective studies are required to confirm our findings.
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http://dx.doi.org/10.4103/ijc.IJC_524_19DOI Listing
June 2021

"Hairy Cell Leukemia (HCL): 'Real World' Outcome".

Indian J Hematol Blood Transfus 2020 Apr 28;36(2):267-270. Epub 2019 Sep 28.

1Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu 600036 India.

HCL is an uncommon B cell lympho-proliferative disorder with high remission rates. There is paucity of data on the long-term outcome of HCL from India. We retrospectively collected data from individual case records of patients with HCL who were treated in Cancer Institute, Chennai from January 2001 until January 2018. Sixteen patients were diagnosed with HCL and were treated with cladribine (81%), interferon (13%) and one patient received only best supportive care (6%). All the treated patients achieved complete response. More than half of the patients developed febrile neutropenia but there were no treatment related mortality. The 5-year DFS was 77% and 5-year OS was 80%. Relapse of disease was seen in 27%. HCL is a curable malignancy with high remission rates and survival comparable to patient treated in west.
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http://dx.doi.org/10.1007/s12288-019-01199-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229049PMC
April 2020

The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary.

Cell Oncol (Dordr) 2020 Aug 8;43(4):601-616. Epub 2020 May 8.

Laboratory for Cancer Biology, Departments of Medical Oncology and Clinical Research, Cancer Institute (WIA), 38, Sardar Patel Road, Guindy, Chennai, Tamil Nadu, 600036, India.

Purpose: Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC).

Methods And Results: We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers.

Conclusions: Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target.
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http://dx.doi.org/10.1007/s13402-020-00504-wDOI Listing
August 2020

Expression of cancer stem cell markers CD24, EPHA1 and CD9 and their correlation with clinical outcome in epithelial ovarian tumours.

Cancer Biomark 2020 ;28(3):397-408

Laboratory for Cancer Biology, Department of Medical Oncology and Clinical research, Cancer Institute (WIA), Chennai, Tamilnadu, India.

Background: There has been variability between laboratories in the identification of cancer stem cells (CSCs) markers for epithelial ovarian cancer (EOC). We have evaluated three new surface markers for EOC to identify CSCs precisely.

Methods: Three new putative CSCs specific surface markers CD9, CD24 and EPHA1 identified by a bioinformatics approach were evaluated in normal ovary, fallopian tube and ovarian tumours.

Results: The expression of CD9 alone was observed in normal ovarian surface epithelium and fallopian tube whereas CD24 and EPHA1 were not expressed (n= 5). CD24 was expressed in all tumours (N= 101) while CD9 and EPHA1 were expressed in 89 and 71 tumours, respectively. The statistical analysis showed significant correlation of the stage of the disease (p< 0.0001), type of surgery (p< 0.0001) and residual disease (p< 0.0001) with overall survival. Although expression of CD9, CD24 and EPHA1 was observed in the majority of tumours there was no significant correlation with outcome. In patients who underwent primary surgery, increased expression of CD24 significantly correlated with poor survival. The expression of CD24 was significantly reduced (p< 0.002) upon analysis of paired sections from patients prior to surgery and at interval debulking surgery (n= 16).

Conclusion: These findings suggest that overexpression of these new markers may be useful in identifying and targeting ovarian CSCs and CD24 may be a putative CSCs marker in ovarian cancer.
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http://dx.doi.org/10.3233/CBM-201463DOI Listing
January 2021

Isolated regional nodal metastasis in giant cell tumor of the bone: Case report and review of literature.

South Asian J Cancer 2020 Jan-Mar;9(1):58

Department of Pathology, Cancer Institute (WIA), Chennai, Tamil Nadu, India.

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http://dx.doi.org/10.4103/sajc.sajc_244_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956574PMC
January 2020

CD19 negative and dim precursor B-lineage acute lymphoblastic leukemias: real-world challenges in a targeted-immunotherapy era.

Leuk Lymphoma 2019 12 11;60(13):3154-3160. Epub 2019 Jun 11.

Department of Medical Oncology, Cancer Institute (W.I.A.), Chennai, India.

Flow cytometric diagnosis and minimal residual disease (MRD) assessment of precursor B-lineage acute lymphoblastic leukemia (B-ALL) are heavily dependent on CD19 based gating strategies. However, this approach is not optimal in the diagnosis and follow-up of CD19 negative or dim B-ALLs. Though CD19 negative B-ALLs are rare, in the current era of CD19 targeted immuno-therapy, CD19 negative B-ALL relapses are frequent. We have presented our cohort of 14 CD19 negative and dim B-ALLs and have highlighted the difficulties faced during diagnosis and MRD assessment of these patients. We have also discussed the need to identify alternative B-lineage gating markers and strategies to deal with such scenarios.
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http://dx.doi.org/10.1080/10428194.2019.1625043DOI Listing
December 2019

Cancer stem cells contribute to angiogenesis and lymphangiogenesis in serous adenocarcinoma of the ovary.

Angiogenesis 2019 08 3;22(3):441-455. Epub 2019 Jun 3.

Laboratory for Cancer Biology, Departments of Medical Oncology and Clinical Research, Cancer Institute (WIA), 38, Sardar Patel Road, Guindy, Chennai, 600036, India.

The origin of blood and lymphatic vessels in high-grade serous adenocarcinoma of ovary (HGSOC) is uncertain. We evaluated the potential of cancer stem cells (CSCs) in HGSOC to contribute to their formation. Using spheroids as an in vitro model for CSCs, we have evaluated their role in primary malignant cells (PMCs) in ascites from previously untreated patients with HGSOC and cell lines. Spheroids from PMCs grown under specific conditions showed significantly higher expression of endothelial, pericyte and lymphatic endothelial markers. These endothelial and lymphatic cells formed tube-like structures, showed uptake of Dil-ac-LDL and expressed endothelial nitric oxide synthase confirming their endothelial phenotype. Electron microscopy demonstrated classical Weibel-Palade bodies in differentiated cells. Genetically, CSCs and the differentiated cells had a similar identity. Lineage tracking using green fluorescent protein transfected cancer cells in nude mice confirmed that spheroids grown in stem cell conditions can give rise to all three cells. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor inhibited the differentiation of spheroids to endothelial cells in vitro. These results suggest that CSCs contribute to angiogenesis and lymphangiogenesis in serous adenocarcinoma of the ovary, which can be inhibited.
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http://dx.doi.org/10.1007/s10456-019-09669-xDOI Listing
August 2019

Microvessel Density (MVD) in Locally Advanced Breast Cancer

Asian Pac J Cancer Prev 2019 May 25;20(5):1537-1545. Epub 2019 May 25.

Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), 38, Sardar Patel Road, Guindy, Chennai, India. Email:

Background: The aim of this study was to evaluate microvessel density (MVD) by expression of CD31 and CLEC14A in core biopsies from previously untreated patients with locally advanced breast cancer (LABC) and assess its prognostic significance. Methods: MVD was evaluated in core needle biopsies (n = 92), collected prior to any treatment, from patients who were diagnosed with locally advanced breast cancer (LABC). Immunohistochemistry for expression of CD31 and CLEC14A were performed on these tumours. The median duration of follow-up was 9.3 years. The effect of prognostic factors on disease free survival (DFS) and overall survival (OS) was assessed using a Log rank test and Cox regression model. Results: The clinical factors such as age, clinical nodal stage, stage and pathological nodal status were found to be significant in predicting overall survival by multivariate analysis (P<0.05). Out of 92, 52 tumours had blood vessels expressing CD31, whereas in the remainder, there was no expression. The mean and median MVD of CD31 in 92 tumours was 38 and 5.5 respectively, and it was not a significant factor for predicting disease free survival or overall survival. When we considered the tumours (n=52) which expressed CD31, patients who had very high MVD (>100), had inferior progression free survival and overall survival (P=0.5). There was no expression of CLEC14A in any of the core needle biopsies whereas it was expressed in specimens from mastectomy from the same patient. Conclusion: This is the first report of MVD in LABC prior to any treatment. The results suggest angiogenesis could be a prognostic factor in LABC.
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http://dx.doi.org/10.31557/APJCP.2019.20.5.1537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857865PMC
May 2019

Identification of lncRNAs associated with early-stage breast cancer and their prognostic implications.

Mol Oncol 2019 06 8;13(6):1342-1355. Epub 2019 May 8.

Department of Molecular Oncology, Cancer Institute (WIA), Chennai, India.

Breast cancer is the most common malignancy among women, with the highest incidence rate worldwide. Dysregulation of long noncoding RNAs during the preliminary stages of breast carcinogenesis is poorly understood. In this study, we performed RNA sequencing to identify long noncoding RNA expression profiles associated with early-stage breast cancer. RNA sequencing was performed on six invasive ductal carcinoma (IDC) tissues along with paired normal tissue samples, seven ductal carcinoma in situ tissues, and five apparently normal breast tissues. We identified 375 differentially expressed lncRNAs (DElncRNAs) in IDC tissues compared to paired normal tissues. Antisense transcripts (~ 58%) were the largest subtype among DElncRNAs. About 20% of the 375 DElncRNAs were supported by typical split readings leveraging their detection confidence. Validation was performed in n = 52 IDC and paired normal tissue by qRT-PCR for the identified targets (ADAMTS9-AS2, EPB41L4A-AS1, WDFY3-AS2, RP11-295M3.4, RP11-161M6.2, RP11-490M8.1, CTB-92J24.3, and FAM83H-AS1). We evaluated the prognostic significance of DElncRNAs based on TCGA datasets and report that overexpression of FAM83H-AS1 was associated with patient poor survival. We confirmed that the downregulation of ADAMTS9-AS2 in breast cancer was due to promoter hypermethylation through in vitro silencing experiments and pyrosequencing.
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http://dx.doi.org/10.1002/1878-0261.12489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547626PMC
June 2019

Gastrointestinal mucormycosis in a child with acute lymphoblastic leukemia: An uncommon but ominous complication.

Indian J Cancer 2018 Jul-Sep;55(3):304-305

Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India.

Invasive fungal infections constitute a major cause of morbidity and mortality in children undergoing therapy for hematological malignancies. We report a 1-year-old boy who was receiving chemotherapy for acute lymphoblastic leukemia. His clinical course was complicated by a clinical syndrome consistent with neutropenic enterocolitis to which he succumbed. Histopathology of the surgically resected bowel revealed evidence of mucormycosis. Gastrointestinal mucormycosis is an unusual presentation which requires high degree of clinical suspicion and aggressive management.
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http://dx.doi.org/10.4103/ijc.IJC_260_18DOI Listing
June 2019

Prognostic Utility of the IPS 3 Score for Predicting Outcomes in Advanced Hodgkin Lymphoma.

Clin Lymphoma Myeloma Leuk 2019 02 13;19(2):116-122. Epub 2018 Nov 13.

Department of Medical Oncology, Cancer Institute, Chennai, India.

Background: The International Prognostic Scoring System (IPSS) consisting of 7 parameters (IPS7) has been the standard prognostic model used in advanced Hodgkin lymphoma (aHL). However, recent studies have questioned its discriminatory power. For retrospective analyses, its utility might be limited by missing parameters. A recent study has shown that the IPSS consisting of only 3 high-risk features (IPS3; stage IV, age 45 years or older, and hemoglobin <105 g/L) is a simple predictor of survival in aHL. However, there are limited data validating the IPS3.

Patients And Methods: Outcomes of adults with aHL treated between 2001 and 2015 at a single center were retrospectively analyzed with data from medical records. The prognostic validity of various baseline parameters was assessed individually as well as in combination (IPS7 and IPS3 scores). The Kaplan-Meier method was used to describe the event-free survival (EFS) and overall survival (OS) and univariate (log rank) and multivariate (Cox regression) tests were performed to identify prognostic factors.

Results: We identified 314 patients (median age, 32 [range, 18-60] years; male sex [n = 215; 68%]) treated during this period. IPS7 was available in 231 of 314 (73%) and IPS3 in all (100%) patients. Most (71%) were treated with 6 to 8 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and others received hybrid or cyclophosphamide, vincristine, procarbazine, prednisolone regimens, and 72 (23%) underwent interim positron emission tomography imaging with escalation to bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisolone in 8 patients. After a median follow-up of 57 months (range, 1.3-167), the 5-year EFS and OS were 72% and 82%, respectively. IPS3 produced a wider separation of survival curves than IPS7 in univariate analysis. In multivariate analysis for EFS, IPS3 (scores of 2 or 3 vs. scores of 0 and 1; hazard ratio, 2.1; P = .004) was the only significant predictor. For OS, no factor emerged as significant.

Conclusion: The IPS3 is a simple 3-point system that is very useful for prediction of outcomes in aHL and might be particularly suited for retrospective data analysis where all components of the IPS7 might not be available.
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http://dx.doi.org/10.1016/j.clml.2018.11.009DOI Listing
February 2019

DA-EPOCH-R in Aggressive CD 20 Positive B Cell Lymphomas: Real-World Experience.

Indian J Hematol Blood Transfus 2018 Jul 4;34(3):454-459. Epub 2017 Nov 4.

1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.

Recent reports have shown that excellent survival outcomes can be achieved in adult Burkitt's lymphoma with the use of DA-EPOCH-R regimen. When compared to earlier intense pediatric-type protocols, this regimen is less toxic. There are limited reports available on the use of this regimen outside the context of clinical trials. We analyzed the outcomes of patients who were treated with the DA-EPOCH-R regimen [Burkitt's lymphoma (BL), primary mediastinal B cell lymphoma (PMBCL) and HIV-positive patients with diffuse large B cell lymphoma (DLBCL)] at our center over a 3 year period. Baseline characters, responses, and toxicity data was captured from records. Event-free survival (EFS-from therapy initiation till occurrence of event (non-achievement of complete response or relapse) and overall survival (OS-from therapy initiation till death due to any cause) were estimated using Kaplan-Meier method. Among 41 patients [median age 40 years (18-76)], the following diagnoses were included-HIV negative patients (N = 29): BL (N = 24), PMBCL (N = 5); HIV positive patients (N = 12): BL (N = 8), and DLBCL (N = 4). Among those with BL, majority had stage III/IV disease (N = 21/32, 65%). At the completion of planned therapy, 33 had achieved CR (81%). One patient died due to toxicity. The actuarial EFS and OS at 2 years were 80 and 77% respectively for all patients. The OS at 2 years was 100% for PMBCL, 80% for BL and 50% for HIV-positive DLBCL. Majority of the failures in BL were in patients with advanced disease. DA-EPOCH-R can be used in real-world setting and allows treatment of older patients with BL.
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http://dx.doi.org/10.1007/s12288-017-0901-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081344PMC
July 2018

Acute Lymphoblastic Leukemia in Young Adults Treated with Intensive "Pediatric" Type Protocol.

Indian J Hematol Blood Transfus 2018 Jul 17;34(3):422-429. Epub 2017 Oct 17.

1Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamilnadu India.

Young adults with acute lymphoblastic leukemia do better when treated on "pediatric" protocols. Young adults (18-30 years) with Ph-negative ALL treated between 2000 and 2014 were retrospectively analyzed. Two-hundred and thirty-two patients were included [median age 21 years (18-30); 176 (76%) males; median WBC 16,000/cmm]. Protocols used were: BFM 95 (N = 147, 63%), MCP-841 (N = 51, 22%), GMALL (N = 21, 9%), INCTR (N = 9, 4%) and UKALL (N = 4, 2%). Complete remission was achieved in 194/232 (84%). Twenty patients (9%) died due to toxicity which was higher with BFM versus others (18/147 vs. 2/85;  = 0.031). After a median follow-up of 48 months, median RFS and OS were 35.5 months (25-46), and 25 months (18-31) and actuarial RFS and OS (5-years) were 45% (37-53) and 39% (32-46). BFM protocol improved RFS (51 vs. 35%,  = 0.027) but not OS (43 vs. 33%,  = 0.2). The survival outcomes reported are 15-20% lower than those reported from West. Better supportive care and risk-adapted therapy may improve outcomes.
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http://dx.doi.org/10.1007/s12288-017-0892-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081315PMC
July 2018

Refractory ALK-Positive Anaplastic Large Cell Lymphoma: Long Term Survival with Crizotinib.

Indian J Hematol Blood Transfus 2018 Apr 4;34(2):353-354. Epub 2017 Nov 4.

1Department of Medical Oncology, Cancer Institute (WIA), Sardar Patel Road, Adyar, Chennai, Tamil Nadu 600020 India.

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http://dx.doi.org/10.1007/s12288-017-0889-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884998PMC
April 2018

Extramedullary sarcomatoid variant of plasmablastic plasmacytoma.

J Cancer Res Ther 2017 Oct-Dec;13(6):1078-1079

Department of Oncopathology, Cancer Institute (W.I.A), Chennai, Tamil Nadu, India.

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http://dx.doi.org/10.4103/0973-1482.183196DOI Listing
December 2018

Pediatric Hodgkin Lymphoma Treated at Cancer Institute, Chennai, India: Long-Term Outcome.

J Glob Oncol 2017 Oct 9;3(5):545-554. Epub 2016 Nov 9.

All authors: Cancer Institute (WIA), Adyar, Chennai, India.

Purpose: Pediatric Hodgkin lymphoma (HL) is a highly curable malignancy. Outcomes for pediatric HL may vary between developed and developing countries for multiple reasons. This study was conducted to ascertain the outcomes of children with HL at our center and to identify risk factors for recurrent disease.

Methods: We analyzed the outcomes of 172 consecutive, previously untreated patients with pediatric HL presenting at our center from 2001 to 2010. Patients were treated with either adriamycin, bleomycin, vinblastine, and dacarbazine or adriamycin, bleomycin, vinblastine, cyclophosphamide, vincristine, prednisone, and procarbazine chemotherapy initially, and radiation to bulky sites or a single site of residual disease when appropriate.

Results: The median duration of follow-up was 77 months. The median age of the patients was 10 years; 127 (74%) of the 172 patients were male. The extent of disease was stage I and II in 59% of the patients. B symptoms were present in 32% of the patients, and 27% had bulky disease. The most common histologic subtype was mixed cellularity (45%). The 5-year overall survival (OS) and progression-free survival (PFS) of the entire cohort were 92.9% and 83.1%, respectively. The 5-year OS rates for patients with stage I, II, III, and IV were 96%, 94.7%, 84%, and 69.8%, respectively. On univariate analysis, advanced stage, response on interim radiologic assessment, and presence of B symptoms significantly predicted inferior PFS and OS. On multivariate analysis, only interim radiologic response significantly predicted PFS ( < .001) and OS ( < .001).

Conclusion: Overall, the outcomes of patients treated at our center are comparable to those observed in other centers in India and globally.
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http://dx.doi.org/10.1200/JGO.2016.005314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646877PMC
October 2017

Outcomes in Lung Cancer: 9-Year Experience From a Tertiary Cancer Center in India.

J Glob Oncol 2017 Oct 11;3(5):459-468. Epub 2017 Jan 11.

All authors: Cancer Institute (WIA), Adyar, Chennai, India.

Purpose: Lung cancer is the most common cause of cancer mortality in the world. There are limited studies on survival outcomes of lung cancer in developing countries such as India. This study analyzed the outcomes of patients with lung cancer who underwent treatment at Cancer Institute (WIA), Chennai, India, between 2006 and 2015 to determine survival outcomes and identify prognostic factors.

Patients And Methods: In all, 678 patients with lung cancer underwent treatment. Median age was 58 years, and 91% of patients had non-small-cell lung cancer (NSCLC). Testing for epidermal growth factor receptor mutation was performed in 132 of 347 patients and 61 (46%) were positive.

Results: Median progression-free survival was 6.9 months and overall survival (OS) was 7.6 months for patients with NSCLC. Median progression-free survival was 6 months and OS was 7.2 months for patients with small-cell lung cancer. On multivariable analysis, the factors found to be significantly associated with inferior OS in NSCLC included nonadenocarcinoma histology, performance status more than 2, and stage. In small-cell lung cancer, younger age and earlier stage at presentation showed significantly better survival.

Conclusion: Our study highlights the challenges faced in treating lung cancer in India. Although median survival in advanced-stage lung cancer is still poor, strategies such as personalized medicine and use of second-line and maintenance chemotherapy may significantly improve the survival in patients with advanced-stage lung cancer in developing countries.
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http://dx.doi.org/10.1200/JGO.2016.006676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646892PMC
October 2017

Acinar Cell Carcinoma of Pancreas: a Case Report and Review of Literature.

J Gastrointest Cancer 2019 Mar;50(1):134-136

Department of Oncopathology, Cancer Institute (WIA), Chennai, India.

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http://dx.doi.org/10.1007/s12029-017-9987-9DOI Listing
March 2019

Lomustine induced acute pulmonary toxicity in a pediatric medulloblastoma survivor.

South Asian J Cancer 2017 Jan-Mar;6(1):38-39

Department of Medical Oncology, Adyar Cancer Institute, Chennai, Tamil Nadu, India.

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http://dx.doi.org/10.4103/2278-330X.202570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379896PMC
April 2017
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