BRCA1 expression, its correlation with clinicopathological features, and response to neoadjuvant chemotherapy in high-grade serous ovarian cancer.

AIM: In high-grade serous ovarian cancers (HG-SOC), BRCA1 mutation is one of the predominant mutations reported by various studies. However, the non-mutational mechanisms of BRCA pathway inactivation in HG-SOC are unclear. We evaluated BRCA1 inactivation by estimating its expression with its repressor, ID4, in primary and neoadjuvant chemotherapy (NACT)-treated HG-SOC tumors with known therapeutic responses. METHODS: We evaluated the expression pattern of BRCA1 protein by immunohistochemistry in 119 cases of HG-SOC from a hospital cohort consisting of primary (N = 69) and NACT-treated (N = 50) tumors. Histological patterns (SET), stromal infiltration by lymphocytes (sTILs), and chemotherapy response score (CRS) were estimated by microscopic examination. Gene expression levels of BRCA1, and its repressor ID4, were estimated by qPCR. The association of BRCA1 protein and mRNA with clinicopathological features was studied. The relevance of the BRCA1/ID4 ratio was evaluated in tumors with different CRS. RESULTS: BRCA1 protein expression was observed in 12% of primary and 19% of NACT-treated HG-SOC tumors. We observed moderate concordance between BRCA1 protein and mRNA expression (AUC = 0.677). High BRCA1 mRNA expression was significantly associated with a more frequent SET pattern (p = 0.024), higher sTILs density (p = 0.042), and increased mitosis (p = 0.028). BRCA1-negative tumors showed higher expression of ID4 though not statistically significant. A higher BRCA1/ID4 ratio was associated with high sTILs density in primary (p = 0.042) and NACT-treated tumors (p = 0.040). CONCLUSION: Our findings show the utility of the BRCA1/ID4 ratio in predicting neoadjuvant therapy response, which needs further evaluation in larger cohorts with long-term outcomes.

Phase II Trial on the Feasibility of Single-Dose Intraoperative Intraperitoneal Carboplatin in Advanced Epithelial Ovarian Cancer Following Optimal Cytoreductive Surgery.

To evaluate the feasibility administering single-dose intraoperative intraperitoneal carboplatin (IP) in advanced epithelial ovarian cancer (EOC) after optimal primary or interval debulking surgery. A phase II non-randomized prospective study conducted at a regional cancer institute from January 2015 to December 2019. The advanced high-grade epithelial ovarian cancer FIGO stage IIIB-IVA was included. A total of 86 consented patients with optimal primary and interval cytoreductive surgeries received single-dose intraoperative IP carboplatin. The immediate (< 6 h), early (6-48 h), and late (48 h-21 days) perioperative complications were recorded and analyzed. The severity of adverse events was graded on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). A total of 86 patients received single-dose intra-operative IP carboplatin during the study period. The 12 (14%) patients underwent primary debulking surgery and 74(86%) interval debulking surgery (IDS). The 13 (15.1%) patients underwent laparoscopic/robotic IDS. All the patients tolerated the intraperitoneal carboplatin well with no or minimal adverse events. Three cases (3.5%) needed resuturing for the burst abdomen, three cases (3.5%) had paralytic ileus for 3-4 days, one case (1.2%) underwent re-explorative laparotomy for hemorrhage, and one case (1.2%) mortality due to due late sepsis. The 84 (97.7%) of 86 cases received scheduled IV chemotherapy on time. Single-dose intraoperative IP carboplatin is a feasible procedure with no or minimal manageable morbidity. The procedure is user friendly combining the prognostic benefits of IP chemotherapy with assurance of earliest timely administration of chemotherapy in advanced EOC. Our study is a hypothesis generating for the future clinical trials comparing single-dose NIPEC versus HIPEC in advanced EOC.

Outcomes of Cancer Surgery During the COVID-19 Pandemic: Preparedness to Practising Continuous Cancer Care.

The COVID-19 pandemic has placed unprecedented pressure on healthcare services. Deprioritisation of nonemergency clinical services and growing concerns of adverse outcomes of COVID-19 in cancer patients is having a deleterious impact across oncologic practice. We report cancer surgery outcomes taking into account the acuity of the COVID-19 situation. A prospectively maintained database of the Department of Surgical Oncology was analysed from 1st May to 30th June, 2020, to evaluate the perioperative outcomes, morbidity and mortality following major surgical procedures. A total of 359, preoperatively, tested negative for COVID-19 underwent surgery. Median age was 52 years with 26.7% (n = 96) above the age of 60 years. Sixty-one percent (n = 219) patients were American Society of Anaesthesiology grades II-III. As per surgical complexity grading, 36.8% (n = 132) cases were lower grades (I-III) and 63.2% (n = 227) were complex surgeries (IV-VI). 5.3% (n = 19) had ≥ grade III Clavien-Dindo complication, and the postoperative mortality rate was 0.27% (n = 1). Major complication rates in patients > 60 years were 9.3% in comparison to 4.1% in < 60 years (p = 0·63). The median hospital stay was 1-10 days across subspecialties. Postoperatively, repeat COVID 19 testing in 2 suspected patients were negative. Our study showed that after screening, triaging and prioritisation, asymptomatic cases may undergo cancer surgeries without increased morbidity during COVID-19 pandemic.

Impact of Optimal Therapy and Prognostic Factors in Malignant Germ Cell Tumors of Ovary: 20 Years' Institutional Experience.

The objective of this study is to analyze the impact of clinicopathological and treatment-related factors on survival in patients with malignant ovarian germ cell tumor. A total of 253 patients of ovarian germ cell malignancy were retrospectively reviewed during 2000-2019. Out of these, 111 had primary treatment at our institute, which is a dedicated regional cancer center. The remaining 142 were operated elsewhere and were referred to us for adjuvant chemotherapy or with recurrent disease. The clinicopathological and treatment-related characteristics were analyzed for association with tumor persistence/recurrence or death. Among them, 107 were dysgerminomas; 60 had endodermal sinus tumor, 53 mixed germ cell tumors, and 31 immature teratoma; and one each had embryoma and primitive germ cell tumor. The median follow-up period was 19 months (range 0-214). Median time to recurrence or progression was 5 months. Forty-nine patients (19.4%) had a recurrence and there were 16 (6.3%) deaths. Five-year disease-free-survival was 71.3% and 5-year overall survival rate was 88.1%, for the entire cohort. Disease-free-survival was 90.4% and overall survival was 92.1% for patients entirely treated at the reporting institute. Sub-group analysis based on treatment adequacy showed that survival rate was 91.0% in patients who had timely and complete initial treatment versus 78.3% in patients where treatment was incomplete or delayed (p = 0.032). Factors affecting relapse were tumor histology, absence of surgical staging, presence of residual disease, inadequate response to chemotherapy, treatment outside reporting institute, and incomplete/delayed chemotherapy. Significant factors adversely affecting survival were presence of post-operative residual disease, tumor histology, incomplete response to chemotherapy, and inadequate/delayed treatment at primary setting. There was no statistically significant difference based on disease stage and whether fertility-sparing surgery or non-fertility-sparing surgery was performed. Prognosis of ovarian germ cell malignancies is excellent with timely, optimal treatment. The outcome improves significantly if managed adequately in the primary setting, involving dedicated gynecologic oncologists.

Metabolic Reprogramming and Lipophagy Mediates Survival of Ascites Derived Metastatic Ovarian Cancer Cells.

OBJECTIVE: The study was aimed at understanding the survival of metastatic ovarian cancer spheroids in the malignant ascites microenvironment. METHODS: All the assays were performed using aseptically collected patient samples. The cells were characterized for the expression of ovarian and cancer stem cell markers using immunocytochemistry. The presence of lipid in the primary metastatic cancer spheroids were confirmed by neutral fat staining using Oil Red-O and transmission electron microscopy. The mRNA expression of autophagy and lipid metabolism genes was analyzed using RT-PCR. The lipid content was analyzed using lipidomics analysis. Etomoxir and chloroquine were used to study the effect of inhibition of autophagy in the metastatic cells. The data were analyzed using appropriate statistical tools and a p-value <0.05 was considered to be statistically significant. RESULTS: Metastatic ovarian cancer spheroids exhibit cancer stem like properties and undergo a metabolic reprogramming when they disseminate from the primary tumor. We report here the accumulation of numerous cytoplasmic lipid droplets and lipophagic vesicles in the metastatic cells in contrast to their primary tumors. In addition we also report that these cells depend on lipophagy for the utilization of lipids rather than the conventional lipolytic pathway. The lipidomics analysis data reveals that the metastatic cells possess high levels of unsaturated fatty acids. We have also reported the occurrence of distinct accumulation of multiple nuclei in the patient derived metastatic cells. Inhibition of beta-oxidation and autophagic machinery using etomoxir and chloroquine resulted in cell death suggesting a potential mode to suppress metastatic cancer cells. CONCLUSION: Metabolic reprogramming is a characteristic feature of the metastatic ovarian cancer cells that are persisting in the malignant ascites. Targeting of the metastatic by gaining an insight into the various metabolic and molecular changes that occur in the metastatic niche provides a promising therapeutic approach in management of the disease.

Role of Salvage Surgery in Gestational Trophoblastic Neoplasia: a Regional Cancer Centre Experience.

Gestational trophoblastic neoplasia (GTN) is a curable cancer with chemotherapy. However, some develop chemoresistance to standard chemotherapy and surgery can be a useful option in them. Our study aimed to assess the role of salvage surgery in GTN with chemoresistance. It is a retrospective hospital-based study from 2000 to 2021. Case sheets of women who underwent salvage surgery for chemoresistance were reviewed and clinical parameters like preoperative hCG, antecedent pregnancy, WHO risk score, multiple chemotherapy regimens prior surgery, presence of > 1 disease site, and presence of residual choriocarcinoma that predicted the effect of surgery on serological response were assessed using Fisher's exact test. A total of 19 patients with high-risk GTN developed chemoresistance and underwent salvage surgery. Eight underwent hysterectomy, 3 underwent hysterectomy plus adnexal tumour resection, six received fertility-sparing surgery, and two underwent segmental resection of the lung. Histopathological examination revealed viable tumour in 7/19 patients, but significant fall in median hCG level from 161.5 mIU/ml (preoperatively) to 15.5 mIU/ml (postoperatively) was noted. Preoperative hCG < 100 mIU/ml (p = 0.019) was the most important determinant of complete response to surgery. All the patients who had disease confined to the uterus and/or lungs at the time of surgery achieved remission after completion of treatment. Our study concludes that in the case of chemoresistant high-risk GTN, carefully selected cases with low hCG levels and disease confined to the uterus and/or lungs get the most benefit of surgery. The use of postoperative chemotherapy after complete response is essential to maintain remission and prevent relapse.

Growing Teratoma Syndrome a Rare Clinical Entity: Two Decades Management Experience from the Regional Cancer Institute.

To study the clinical, biochemical, radiological, pathological characteristics, surgical treatment details, and follow-up of growing teratoma syndrome (GTS) patients. This is a retrospective study of GTS treated in the Department of Gynaecological Oncology at a regional cancer institute from March 2000 to March 2020. A total of 303 cases of germ cell ovarian cancers were treated, and 8 (2.6%) of 303 cases recurred as GTS during this period. The patients presenting with recurrent GTS were studied for clinical, radiological, tumor markers, surgical management, histopathology, and post-operative follow-up details that were analyzed retrospectively. The Kaplan-Meier curve was used for the survival analysis. The 8 out of 303 cases of germ cell ovarian cancers recurred as GTS and the incidence rate is 2.6% during this period. In the six (75%) of eight cases, the histopathology report was immature teratoma ovaries. The five cases (62.5%) were in advanced stage. All the eight recurrent GTS cases received optimal surgical cytoreduction. The overall disease-free survival is 85.7% and one patient has recurrence after the surgery for GTS at 23rd month of follow-up visit. All the patients are alive till date. The GTS represents a rare clinical and pathological phenomenon. Nevertheless, GTS should be considered as one of the differential diagnosis in young patients having normal tumor markers with recurrent carcinomatosis following the primary treatment germ cell tumors of ovaries. The optimal cytoreduction of recurrent GTS leads to prolonged survival and possible cure in young patients.

A Prospective Study on Metronomic Scheduling of Non-chemotherapeutic Drugs in Advanced Epithelial Ovarian Cancers.

The objectives of this study are to assess the role of non-chemotherapeutic combination of drugs as maintenance therapy, after standard treatment, for advanced epithelial ovarian cancers (EOC) and to determine the recurrence-free survival (RFS) and cancer-specific survival (CSS). One hundred women with advanced high-grade EOC who had completed standard treatment by primary/interval debulking surgery followed by adjuvant chemotherapy were randomised to either receive (study group) or not to receive (control group) the non-chemotherapeutic maintenance therapy (oral metformin, anastrozole, aspirin, atorvastatin, vitamin D, injection zoledronic acid). Both groups were followed up, and trends of RFS and CSS were analysed. One hundred patients were analysed. Median RFS was 18 months (95% CI: 13-24) in study group versus 16 (95% CI: 14-20) in the control group (P value = 0.57). Median CSS in the study group was lesser than that in the control group (47 months (95% CI: 31-68) versus 51 (95% CI: 32-66), P value = 0.76). Five-year CSS was not significantly different between the groups (47% study vs 40% control, P value = 0.51). The use of combination of non-chemotherapeutic drugs as maintenance therapy was found to have no significant impact on the survival or reduction of recurrences in patients with advanced epithelial ovarian cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13193-020-01261-w.

Aberrant Promoter Hypermethylation of RASSF1a and BRCA1 in Circulating Cell-Free Tumor DNA Serves as a Biomarker of Ovarian Carcinoma.

OBJECTIVE: Ovarian cancer is one of the leading causes of cancer deaths in women. Ovarian cancer is diagnosed at the late stages and generally relapses within 12-14 months of cytoreductive surgery. This is attributed to lack of precise molecular detection methodologies to detect and track the disease. Epigenetic alteration such as aberrant promoter hypermethylation is an important early event that occurs during cancer development and progression. This study focuses on development of a minimally invasive methylation marker that could be used for detection and prognosis of ovarian cancer patients. METHODS: Aberrant promoter hypermethylation of RASSF1a and BRCA1 was assessed in circulating DNA of 72 EOC patients using methylation-specific PCR. The findings were correlated with various clinicopathological parameters. Statistical analysis was done using the Fisher exact test and chi-square test. RESULTS: The aberrant methylation patterns of RASSF1a and BRCA1 was identified to be present in the cancerous samples. A total of 31.9 % and 56.9% methylation was observed for RASSF1a and BRCA1 respectively. A striking 50% methylation of BRCA1 was identified in the benign sample cohort, which marks the significance of assessing the hypermethylation pattern to detect cancer at its early stages. Methylation of the two tumor suppressor genes was evident across various stages and grades of ovarian tumors suggesting that this could also help as a prognostic marker. CONCLUSION: The results of the current study hold significance since the hypermethylation patterns can be identified in the cell-free circulating tumor DNA from a small volume of blood plasma and is a simple and minimally-invasive method. Assessment of hypermethylation patterns of a panel of TSG along with the existing screening markers could aid in better diagnosis and management of the disease. It could also aid in designing specifically tailored treatment strategies to fight the disease.

Role of salvage therapy in chemo resistant or recurrent high-risk gestational trophoblastic neoplasm.

OBJECTIVES: To assess the importance of salvage therapy in the management of high-risk gestational trophoblastic neoplasia (HR GTN) after failure of first line multiagent chemotherapy. METHODS: This retrospective study involving women with HR GTN treated at Kidwai cancer institute from 2000 to 2015. Initial chemotherapy consisted of etoposide, methotrexate with folinic acid, actinomycin D, cyclophosphamide and vincristine (EMA-CO). Thirty one patients who had incomplete response or relapsed were treated with various drug combinations employing etoposide and platinum agents. Adjuvant surgery and radiation were used in selected patients. Clinical response, survival and factors affecting outcomes were analysed. RESULTS: Thirty one (37.8%) of the 82 patients developed resistance or relapsed after EMA-CO.Of these 25 (80.6%) had lasting complete response to salvage therapy. Salvage chemotherapy included, EMA EP alone in-15, EMA EP followed with BIP in-1, EMAEP followed with VAC in-2, EMA EP followed by TC and VAC in-1, EMA EP followed by TC in-6, TC followed by IA in-1 patient. Irradiation was given to 6 patients for brain metastasis, 1 for spine metastasis, 1 for pelvic tumor, and 1 for mediastinal mass. Operative procedures were hysterectomy in 9, conservative uterine tumour resection in 4 and excision of resistant lung lesion in one. Median follow up 25 (80.6%) patients was 2 years. Complete response to salvage therapy was seen in 25 (80.6%) patients. Overall survival after salvage therapy was 87.1% with median follow up of 2 years. Remission and survival was significantly influenced by ßhCG level at the start of salvage therapy (p<0.001 and 0.006) but not with the stage or with WHO score. CONCLUSIONS: Salvage therapy with platinum/etoposide based drug regimens in conjunction with surgery and radiation, was successful in achieving significant cure and survival in HR-GTN patients.

Gastrointestinal Stromal Tumor Mimicking as Ovarian Tumor in Gynaecologic Oncology.

To report the clinical presentation and outcomes of a series of patients who presented with abdominal/pelvic mass or pelvic pain and were diagnosed with a gastrointestinal stromal tumor (GIST). Retrospective data were collected of all patients who presented with an abdominal/pelvic mass or pelvic pain between January 2010 and July 2015 and who were ultimately diagnosed with a GIST. The patients' medical records were reviewed. A literature review was also conducted. The event free survival and overall survival was calculated for all patients using Kaplan Meier curve (SPSS19-SPSS Inc. USA). A total ten patients were identified with GIST during the study period. Eight of ten patients had a tumor in the small intestine, one in sigmoid colon and one in base of small bowel mesentry. The mean tumor size was 13.9 cm (range, 3.9 to 24 cm). A complete resection was achieved in all 10 patients. No patient had distance metastasis. There were no intraoperative complications. One patient developed postoperative intestinal fistula and was managed conservatively. All patients were treated with imatinib after surgery. The mean follow-up time was 18 months (range, 2 to 47 months). The seven of the 10 patients (70 %) with no evidence of disease, two (20 %) lost follow up and one patient developed recurrence during follow up period and was started on sunitinib and patient died during follow up period because of disease. Gastrointestinal stromal tumors should be considered in the differential diagnosis of patients presenting with an abdominal/pelvic mass or pelvic pain in Gynaecologic oncology department. In such unusual circumstances the complete resection and appropriate adjuvant treatment results in complete durable remission.

Vascular endothelial growth factor polymorphisms and a synchronized examination of plasma and tissue expression in epithelial ovarian cancers.

In this study, we have analyzed six genetic polymorphisms of the VEGF-A gene and correlated the genetic data with plasma and tissue expression of VEGF-A in epithelial ovarian carcinomas. A total of 130 cases including 95 malignant carcinomas, 17 low malignant potential and 18 benign tumours were studied. rs699947, rs833061, rs1570360, rs2010963, rs1413711 and rs3025039 were studied by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma levels of VEGF-A were estimated by enzyme-linked immunosorbent assay (ELISA) and tissue expression of VEGF-A by immunohistochemistry (IHC). Four polymorphisms of the above excluding rs699947 and rs3025039 showed significant association with malignancy, and we observed the presence of positive correlation between haplotype CCGGCC and increased expression of VEGF-A in both plasma and tissues which also correlated with poor prognosis and recurrence suggesting a probable increase in resistance to treatment in such carriers. Highly upregulated tissue expression of VEGF-A was seen in all epithelial ovarian carcinomas with intensity of expression increasing from benign to malignant cases. ELISA data from our study showed an increase in circulating levels of VEGF-A in malignancies. VEGF-A plasma levels can be employed as a biomarker for high-grade malignancy in epithelial ovarian cancers alongside tissue expression and CA-125 levels. This study is unique due to the fact that a simultaneous analysis of plasma and tissue expression has been demonstrated and is a first such study in epithelial ovarian cancers and representing the Indian population (South-east Asian) synchronized with genetic polymorphism data as well.

A review of squamous cell carcinoma arising in mature cystic teratoma of the ovary.

INTRODUCTION: Germ cell tumors account for 20-25% of ovarian neoplasms. Mature cystic teratoma (MCT) is the most common ovarian germ cell tumor. Malignancy in MCT is seen in 1-2% of the cases. Squamous cell carcinoma (SCC) accounts for 80% of the cases and carries a poor prognosis. AIM: To study the clinicopathological factors, management protocols and its outcome. MATERIALS AND METHODS: Case records reviewed from August 2006 to August 2011 at our institute identified 10 women with SCC in ovarian MCT. Staging was done according to FIGO 2009 guidelines. Primary surgery followed by adjuvant treatment with platinum based chemotherapy was given. RESULTS: Median age was 53.5 years. Six out of 10 patients were postmenopausal and aged above 50 years. Abdominal pain and abdominal mass were the most common presenting symptoms. According to FIGO: Two in stage 1, five in stage 2, two in stage 3 and one in stage 4. Among six optimally cytoreduced patients, five (83%) had no evidence of disease with a median follow up of 10 months. Whereas all four (100%) suboptimally cytoreduced patients had progressive disease within 3 to 4 months of primary surgery despite chemotherapy. CONCLUSION: Squamous cell carcinoma in MCT of ovary is a rarity. It carries a poor prognosis, especially in advanced stages and suboptimally cytoreduced patients. Platinum with or without taxane based chemotherapy may be useful as adjuvant treatment. However, further studies and standardization of treatment protocols are required for any recommendations.

Refractory Gestational Trophoblastic Neoplasia: A Novel Drug Combination With Paclitaxel and Carboplatin Produces Durable Complete Remission.

OBJECTIVE: The aim of this study was to evaluate the results with novel drug combination consisting of paclitaxel and carboplatin (PC) for salvage of refractory high-risk gestational trophoblastic neoplasia (GTN) previously treated with EMA-CO (etoposide, methotrexate, actinomycin, cyclophosphamide, and vincristine) and EMA-EP (etoposide, methotrexate, actinomycin, and cisplatin) regimens. STUDY DESIGN: This was a prospective study conducted at a regional cancer institute from 2008 to 2012. The study group received the combination of paclitaxel (175 mg/m) and carboplatin (area under the curve, 6) intravenously every 3 weeks. After undetectable ß-subunit of human chorionic gonadotropin values are achieved, 2 courses of additional chemotherapy were administered to reduce the risk of relapse. They were followed up and assessed by clinical examination, monthly ß-subunit of human chorionic gonadotropin for a minimum of 24 months. The event-free survival and overall survival were calculated for all patients using Kaplan-Meier curve (SPSS version 19; SPSS Inc). RESULTS: A total of 65 persistent GTN patients were treated during the study period. Eight (12.3%) of 65 patients having refractory GTN were treated with PC regimen. The initial International Federation of Gynecology and Obstetrics staging in the study group was stage I disease in 1 (12.5%), stage III in 4 (50%), and stage IV in 3 (37.5%) patients. According to the World Health Organization prognostic risk scores, 1 patient was in the low-risk group (12.5%), and 7 patients were in the high-risk group (87.5%). The study group received a total 35 courses of the combination PC. The median number of courses for each patient was 4.4. The complications include mucositis in 3 patients and thrombocytopenia, febrile neutropenia, and transient hepatic dysfunction in other patients. Six (75%) of 8 patients had good response, whereas 2 patients had progression. Five patients (62.5%) are in remission at median 30 months' follow-up, and 3 (37.5%) of 8 patients have died. CONCLUSION: The combination of paclitaxel and carboplatin (PC) regimen produces durable complete remission and manageable side effect profile in patients with refractory GTN previously treated extensively with frontline chemotherapies.

Primary peritoneal carcinoma: regional cancer institute experience.

Primary peritoneal serous carcinoma (PPSC) is a rare malignancy that arises primarily from peritoneal surface epithelium. However there are limited studies on these tumors even in world literature. To study the clinical, pathologic profile, outcome and prognostic features of PPSC. A 5 year retrospective study of PPSC diagnosed and treated at our centre was conducted. The pathological specimen of PPSC diagnosed from January 2008 to December 2012 were reviewed by gynaeconcopathologists. The diagnosis was based on GOG criteria, complemented with IHC. Majority of the patients underwent upfront de-bulking surgery. Postoperatively, six cycles of combination chemotherapy with paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) was administered every 3 weekly. These patients were analysed for progression free survival (PFS), this was correlated with stage and surgical adequacy. The median age of presentation was 56 years. The total number of ovarian cancers treated during study period was 374. The 30 cases were clinically suspected to have primary peritoneal carcinoma (PPC) on pre- and intra-operatve gross findings, but further evaluation with histopathological examination, IHC and GOG criteria revealed only 10 cases were genuine PPSC. The remaing 20 cases; 13 were found to poorly differentiated ovarian carcinomas, six were primary fallopian tube carcinoma and one was appendicular carcinoma. The 10 (2.7 %) cases of the 374 were eligible for the PPSC analysis. The two (20 %) of the 10 cases had family history of breast and ovarian cancers, two (20 %) cases were diagnosed as abdominal tuberculosis (TB) prior referral to our centre. Radiological presentation includes gross ascites, with omental caking and normal adenexa. The eight (80 %) of 10 cases presented with stage IIIC and other two cases (20 %) with stage IV disease. The eight (80 %) of 10 cases underwent upfront surgery; six (75 %) of these eight cases had optimal cytoreduction, i.e. residual disease (RD) <1 cm or no visible disease (R0) and other two (25 %) suboptimal cytoreduction. The two (20 %) of 10 cases with stage IV disease received neoadjuvant chemotherapy (NACT) followed by interval cytoreduction. After debulking surgery the most useful IHC marker include CK7+, CK20-, CA125+, WT-1+, and GCDFP- . At median follow up of 24 months (range 3-60 months), the median progression free survival (PFS) was 22 months, while the estimated 5 year PFS was 18 %. Stage IV disease and suboptimal surgery had poor outcome. The PPSC presents with advanced stage disease and are observed to be misdiagnosed abdominal TB in tropical countries. The GOG criteria and IHC complement the diagnosis. These have poor outcome despite optimal care, highlighting need for larger studies on this disease.

The risk and pattern of pelvic and para aortic lymph nodal metastasis in patients with intermediate and high risk endometrial cancer.

There is a continuous debate about the extent and prognostic value of retroperitoneal lymphadenectomy in endometrial cancer. Systematic pelvic and para-aortic lymphadenectomy in endometrial cancer provides a more accurate assessment of neoplastic spread and may help in better individualization of patients for adjuvant therapy. To evaluate the risk and pattern of retroperitoneal lymph nodes metastasis in patients with endometrial cancers having intermediate and high risk factors for nodal metastasis and recurrence. We conducted a prospective nonrandomized study of 62 cases of high risk endometrial cancers examined and treated at our regional cancer institute between the years 2008 and 2012. The inclusion criteria: The intermediate risk; all patients having grade 3 or undifferentiated adenocarcinomas with less than half MI and the grade 1, 2 tumors having more than half MI with tumor size >2 cm. The high risk group; all the patients having grade 3 or undifferentiated adenocarcinomas with more than half MI, the grade 1, 2 tumors with lymph vascular space invasion (LVSI) or cervical stromal invasion as depicted by pre-operative MRI. The type 2 histology uterine papillary serous, clear cell and squamous cell carcinomas. The patients staging was carried out according to the classification established by the FIGO for endometrial cancer in 2009. The Chi-square test was used to analyze the correlation between tumor grade, myometrial invasion, size of the lesion and lymph nodes metastasis and Fisher's correction done whenever the frequency distribution was less than five. The patients mean age was 58.3 (range 31 to 76 years). A total of 118 endometrial cancer patients were treated during the study period. The 56 (47.5 %) patients belonged to low risk and 62 (52.5 %) patients belonged to high risk endometrial cancers. The 52 of 62 cases were eligible for the analysis. The 10 patients' were excluded from further analysis as the post operative specimens final histopathologic examinations in nine cases revealed carcinosarcoma uterus and one case with yolk sac tumor of endometrium. The total 17(32.7 %) of 52 cases had retroperitoneal nodes metastasis; nine of 17 (52.9 %) in this group had both pelvic and para-aortic lymph nodal metastasis and one of 17 (5.9 %) had isolated para-aortic lymph nodal metastasis. The high grade tumors (grade 3) revealed 41.4 % pelvic and 20.7 % para-aortic lymph nodes metastasis and there was statistically significant higher nodal metastasis in both pelvic and para-aortic lymph nodes with increasing depth of myometrial invasion (P = 0.0119 and P = 0.0001) and increasing size of the lesion. (P = 0.04 and P = 0.0501). The intermediate and high risk endometrial cancer is associated with greater degree of lymph node metastasis. A complete surgical staging which involves extrafascial hysterectomy or a type 3 radical hysterectomy when there is a cervical involvement, along with bilateral salphingo-oophorectomy, pelvic, para-aortic lymphadenectomy and an omentectomy when indicated as in the present study, is a valuable modality of treatment in intermediate and high risk cases of endometrial cancers for determining the prognosis and appropriate categorization of these women for adjuvant therapy. It is also possible to achieve a complete surgical staging in these groups of women with acceptable morbidity when performed by a trained gynaecologic oncologist.

BRCA1 promoter hypermethylation and protein expression in ovarian carcinoma--an Indian study.

Mounting evidences suggest that aberrant methylation of CpG islands is a major pathway leading to the inactivation of tumour suppressor genes and the development of cancer. The aim of the current study was to examine the prevalence of the promoter hypermethylation and protein expression of the BRCA1 gene in epithelial ovarian carcinoma (EOC) to understand the role of epigenetic silencing in ovarian carcinogenesis. We studied the promoter methylation of the BRCA1 gene by methylation-specific PCR in a cohort of 88 patients with EOC, 14 low malignant potential (LMP) tumours and 20 patients with benign tumours of the ovary. The expression of the BRCA1 protein by immunohistochemical analysis was carried out in a subset of 64 EOCs, 10 LMP tumours, 10 benign tumours and 5 normal ovarian tissues. The frequencies of methylation in EOCs and LMP tumours were 51.2 and 57%, respectively, significantly higher (p = 0.000 and p = 0.001) in comparison to benign tumours and normal ovarian tissue where no methylation was seen. Expression of BRCA1 was significantly lower in EOCs (p = 0.003). Lack of protein expression correlated with tumour grade and type. The methylation status correlated well with downregulation of BRCA1 expression. Our results clearly demonstrate that hypermethylation of BRCA1 promoter is a frequent event in ovarian cancer. These data support the hypothesis that BRCA1 promoter methylation plays an important role in the functional inactivation of BRCA1. Follow-up clinical data will reveal the impact of BRCA1 methylation on survival.

Relationship between promoter methylation & tissue expression of MGMT gene in ovarian cancer.

BACKGROUND & OBJECTIVES: Epigenetic alterations, in addition to multiple gene abnormalities, are involved in the genesis and progression of human cancers. Aberrant methylation of CpG islands within promoter regions is associated with transcriptional inactivation of various tumour suppressor genes. O 6-methyguanine-DNA methyltransferase (MGMT) is a DNA repair gene that removes mutagenic and cytotoxic adducts from the O 6 -position of guanine induced by alkylating agents. MGMT promoter hypermethylation and reduced expression has been found in some primary human carcinomas. We studied DNA methylation of CpG islands of the MGMT gene and its relation with MGMT protein expression in human epithelial ovarian carcinoma. METHODS: A total of 88 epithelial ovarian cancer (EOC) tissue samples, 14 low malignant potential (LMP) tumours and 20 benign ovarian tissue samples were analysed for MGMT promoter methylation by nested methylation-specific polymerase chain reaction (MSP) after bisulphite modification of DNA. A subset of 64 EOC samples, 10 LMP and benign tumours and five normal ovarian tissue samples were analysed for protein expression by immunohistochemistry. RESULTS: The methylation frequencies of the MGMT gene promoter were found to be 29.5, 28.6 and 20 per cent for EOC samples, LMP tumours and benign cases, respectively. Positive protein expression was observed in 93.8 per cent of EOC and 100 per cent in LMP, benign tumours and normal ovarian tissue samples. Promoter hypermethylation with loss of protein expression was seen only in one case of EOC. INTERPRETATION & CONCLUSIONS: Our results suggest that MGMT promoter hypermethylation does not always reflect gene expression.

Altered expression of ß-catenin, E-cadherin, and E-cadherin promoter methylation in epithelial ovarian carcinoma.

The aim of the study was to evaluate the immunoexpression of E-cadherin, ß-catenin, and Ki-67, as well as the promoter methylation of E-cadherin gene in epithelial ovarian cancer (EOC), as well as to find a possible relationship between the immunoexpression and hypermethylation. Promoter methylation was studied using methylation-specific PCR in 86 malignant cases, 14 low malignant potential (LMP) tumors and 19 benign cystadenomas. Immunohistochemical expression was carried out in 64 malignant cases, 8 LMP tumors, and 11 benign cystadenomas. Immunoexpression of E-cadherin was reduced in EOC, while 100 % expression was seen in LMP tumors and benign cystadenomas. An interesting observation was the nuclear expression of E-cadherin in a high percentage of cancers, which showed a positive correlation with Ki-67. Β-Catenin expression showed heterogeneous localization with increased nuclear localization, which was significantly higher in cases that did not express E-cadherin. Promoter methylation of E-cadherin was 36, 14, and 11 % in EOC, LMP tumors, and benign cystadenomas, respectively. Our results suggest that reduced expression of E-cadherin is associated with promoter methylation of E-cadherin gene, in addition to providing evidence for the aberrant nuclear localization of E-cadherin in EOC.