Differential Expression of MicroRNAs in Uterine Cervical Cancer and Its Implications in Carcinogenesis; An Integrative Approach.

OBJECTIVES: Cervical cancer is the second most common cancer in women in developing countries, including India. Recently, microRNAs (miRNAs) are gaining importance in cancer biology because of their involvement in various cellular processes. The present study aimed to profile miRNA expression pattern in cervical cancer, identify their target genes, and understand their role in carcinogenesis. METHODS: Human papillomavirus (HPV) infection statuses in samples were assessed by heminested polymerase chain reaction followed by direct DNA sequencing. Next-generation sequencing and miRNA microarray were used for miRNA profiling in cervical cancer cell lines and tissue samples, respectively. MicroRNA signature was validated by quantitative real-time PCR, and biological significance was elucidated using various in silico analyses. RESULTS: Cervical cancer tissues samples were mostly infected by HPV type 16 (93%). MicroRNA profiling showed that the pattern of miRNA expression differed with respect to HPV positivity in cervical cancer cell lines. However, target and pathway analyses indicated identical involvement of these significantly deregulated miRNAs in HPV-positive cervical cancer cell lines irrespective of type of HPV infected. Microarray profiling identified a set of miRNAs that are differentially deregulated in cervical cancer tissue samples which were validated using quantitative real-time PCR. In silico analyses revealed that the signature miRNAs are mainly involved in PI3K-Akt and mTOR pathways. CONCLUSIONS: The study identified that high-risk HPV induces similar carcinogenic mechanism irrespective of HPV type. The miRNA signature of cervical cancer and their target genes were also elucidated, thereby providing a better insight into the molecular mechanism underlying cervical cancer development.

Tumor Marker Decline in Predicting Treatment Outcome among Poor-Risk Testicular Germ Cell Tumors-A Tertiary Cancer Center Data.

Lakshmi Haridas K.Introduction Testicular germ cell tumors are rare in India. Despite the advances in chemotherapy, poor-risk testicular nonseminomatous germ cell tumors (NSGCT) remain as a clinical challenge. Various prognostic factors have been described in this rare disease. The Indian data in this regard is scarce. Our study is the first attempt to assess the tumor marker decline with respect to treatment outcome in poor-risk NSGCT in Indian patients. Materials and Methods This retrospective study was done among newly diagnosed poor-risk NSGCT, treated at genitourinary clinic, at our tertiary cancer center during the period 2017 to 2019. The prognostic significance of tumor marker decline in them was correlated with 2-year progression-free survival (PFS) and 2-year overall survival (OS). Statistical Methods The association between two variables were assessed using chi-squared/Fischer's exact test. The PFS and OS were estimated using Kaplan-Meier method and the significance difference between survival curves was tested using log rank test. The risk for survival was estimated using cox regression analysis. A p -value of <0.05 was considered as significant. Results Out of 11 eligible patients, four (36%) had favorable tumor marker decline and seven (64%) had unfavorable decline. The 2-year PFS among favorable and unfavorable decline group were 66.7 and 42.9%, respectively ( p -0.358), and the 2-year OS was 66.7 and 71.4%, respectively ( p -0.974). Teratoma was not found to be a significant factor in our study. Tumors with only beta human chorionic gonadotropin (ßHCG) elevation were observed to have good outcome. Postchemotherapy unresectable residual disease showed a significant trend toward inferior survival, the 2-year PFS was 38 versus 100% ( p -0.188) and the 2-year OS was 62.5 versus 100% ( p -0.334) in patients with and without unresectable residual disease, respectively. Conclusion Majority of our poor-risk NSGCT patients had unfavorable tumor marker decline and progressive events. However, the survival difference was not significant, given the small sample size. Tumors with only ßHCG elevation were observed to have good outcome. Postchemotherapy unresectable residual disease showed a significant trend toward inferior survival.

Erratum to: Prognostic Factors for Survival in Patients with Carcinoma Endometrium.

[This corrects the article DOI: 10.1055/s-0041-1735563.].

Uterine Sarcoma: Retrospective Study From A Single institute.

Abstract: Uterine sarcomas are heterogeneous group of tumours comprising 1% of gynaecological malignancies. There is lack of concences on optimal treatment of uterine sarcomas. This is because of lack of randomised controlled trials due to rarity of these tumours. Surgical management without spill remains the standard primary treatment. Most of the times uterine sarcomas are diagnosed postoperatively from histopathology report of either myomectomy or hysterectomy. This retrospective study analysed the clinico pathological characteristics, prognostic factors, treatment details and survival outcome of different types of uterine sarcomas. Materials and methods: This is a retrospective analysis of 59 patients of uterine sarcomas. All patients underwent surgery. Adjuvant chemotherapy or radiation treatment were given according to histopathological report and FIGO stage. Patients were followed up every three months for first two years and then every six months. Disease free survival (DFS) and Overall survival (OS) were calculated. Statistical analysis: The data were summarized using descriptive statistics as mean, percent and range. Survival probabilities were estimated using Kaplan-Meier method and the significance of difference between the survival curves were calculate using log-rank test. Results: Uterine sarcomas are rare and aggressive tumours of uterus. Majority of these tumours present in early stage. Surgery remains the main treatment modality. Role of adjuvant radiation treatment remains controversial. Tumour stage is the most important prognostic factor.

Prognostic Factors for Survival in Patients with Carcinoma Endometrium.

Francis. V. JamesObjective The study aimed to see the clinical outcome and to identify prognostic factors for survival in patients with carcinoma endometrium. Methods Patients registered at Regional Cancer Centre, Thiruvananthapuram, Kerala, India, with carcinoma endometrium from January 2009 to December 2013 were identified from hospital registry. Data regarding patient demographics, tumor characteristics, treatment schedules, and follow-up were collected using a structured proforma. Survival estimates were generated using the Kaplan-Meier method. Univariate analysis was done using chi-square and Fisher's exact tests. Multivariate analysis using the Cox regression model was performed to determine the impact of prognostic factors on outcome. The statistical analysis was done using SPSS software version 11. Results The median follow-up of the 686 patients was 95 months (range 3-178 months).There were 432 stage 1 (63%), 100 stage II (14.6%), 108 stage III (15.7%), and 46 stage IV patients (6.7%). The 5-year overall survival was 89.2%. Prognostic factors for survival on univariate analysis were age 60 years or older, nonendometrioid histology, high-grade tumor, cervical stromal involvement, para-aortic node involvement, negative progesterone receptor expression, deep myometrial invasion advanced stage, surgery versus no surgery, serosal involvement, and ovarian and fallopian tube involvement. However, on multivariate analysis, age over 60 years, higher histological grade, advanced stage, and deep myometrial and parametrial invasion were associated with significantly poorer survival. Conclusion We found that age over 60 years at presentation, higher grade, advanced stage, deep myometrial invasion, and parametrial invasion were associated with poorer survival.

Transition of cancer in populations in India.

BACKGROUND & OBJECTIVES: An assessment of transition of cancer in India during the past 30 years, according to changes in demographic and epidemiologic risk factors was undertaken. MATERIALS & METHODS: Cancer registry data (http://www.ncdirindia.org), (population coverage <10%), was compared with transition in life-expectancy and prevalence on smoking, alcohol and obesity. We fitted linear regression to the natural logarithm of the estimated incidence rates of various cancer registries in India. RESULTS: Burden of cancer in India increased from 0.6 million in 1991 to 1.4 million in 2015. Among males, common cancers are lung (12.0%), mouth (11.4%), prostate (7.0%), and tongue (7.0%) and among females, they are breast (21.0%), cervix-uteri (12.1%), ovary (6.9%), and lung (4.9%) in 2012. Increased life-expectancy and population growth as well as increased use of alcohol and increased prevalence of overweight/obesity reflected an increase in all cancers in both genders except a reduction in infection-related cancers such as cervix-uteri and tobacco-related cancers such as pharynx (excludes nasopharynx) and oesophagus. INTERPRETATION & CONCLUSION: Transition in demographics and epidemiologic risk factors, reflected an increase in all cancers in both genders except a reduction in a few cancers. The increasing incidence of cancer and its associated factors demands a planned approach to reduce its burden. The burden assessment needs to be strengthened by increasing the population coverage of cancer registries. Continued effort for tobacco prevention and public health efforts for reducing obesity and alcohol consumption are needed to reduce the cancer burden.

Malignant melanoma metastasizing to tonsil: A rare presentation.

Malignant melanoma (MM) has a high potential of lymphatic and hematogeneous spread, and metastatic disease is always incurable with a high mortality. We present a rare phenomenon of MM metastasizing to the palatine tonsil.

Dosimetric comparison of bladder, rectal, and vaginal surface doses between ovoids and cylinder-based vaginal brachytherapy in carcinoma of the endometrium.

PURPOSE: The study aims to estimate the differences in vaginal surface, bladder, and rectal doses when adjuvant intracavitary brachytherapy is carried out with ovoids or with vaginal cylinders, in postoperative carcinoma endometrium and to assess the difference in variability in organs at risk (OAR) doses and thereby the reproducibility of application in subsequent sittings. MATERIALS AND METHODS: Fifteen patients each received vaginal brachytherapy with ovoid and cylindrical applicators. The dose received by 0.1 cc, 1.0 cc, 2.0 cc, 5.0 cc, and 10.0 cc volumes of the OAR, namely, bladder, and rectum were analyzed using independent t-test. Interfractional variation in dose to OAR was evaluated using a two-way repeated ANOVA test. The dose received by the upper 2 cm of vagina was assessed using volume receiving 100% (V100) and dose received by 100% (D100) for documenting dose distribution to the target volume. RESULTS: The mean dose to rectum and bladder were significantly lesser with ovoids (P < 0.0001). This difference was seen in all volumes analyzed. V100 (99.05% vs. 67.7%, P < 0.0001) and D100 (95.70% vs. 53.08%, P < 0.0001) were significantly better with cylinders compared to ovoids. There was no statistically significant interfractional variation between sittings with either applicator. CONCLUSION: The two applicators studied have different dosimetric properties conferring specific advantages and disadvantages as far as dose to OARs and target is concerned. Both applicators provide good reproducibility. The choice of applicator would ultimately depend on the clinical outcomes of these dosimetric differences which need to be prospectively analyzed.

Ifosfamide-Induced Malignancy of Ureter and Bladder.

Cyclophosphamide-induced bladder malignancy is a well-known entity mediated by its metabolic product, acrolein. There is a significant association between the incidence of hemorrhagic cystitis during treatment and the later development of malignancies. We report a case of multifocal urothelial carcinoma occurring in a patient treated with ifosfamide 19 years ago. No case report of ifosfamide-induced malignancy could be identified in the literature. A brief review of the literature on the relative risks of ifosfamide therapy, the mechanism of bladder toxicity, and suggestions to minimize the deleterious effects of the drug have been done. Ifosfamide should be used in the lowest possible dose and that patients receiving more than 20 grams of the drug should undergo a routine urinalysis for microscopic hematuria. Prophylactic measures such as high fluid intake, frequent voiding, day time administration of the drug, and concomitant use of mesna may decrease the contact time and the concentrations of toxic metabolites on the bladder urothelium.

The impact of patient positioning and use of belly board on small bowel toxicity in patients receiving pelvic radiotherapy for gynecological malignancies.

AIM: To determine the efficacy of belly board device in patients receiving postoperative radiation for gynecological malignancies in terms of setup error and acute small bowel toxicity. MATERIALS AND METHODS: Patients requiring postoperative radiation for gynecological malignancies were prospectively randomized to either treatment with supine position (supine arm) or prone position using belly board (prone arm). Each patient underwent computed tomography simulation in the assigned treatment position, and a three-dimensional conformal radiation was planned. Weekly two to three treatment sessions were verified using portal imaging and setup errors were noted. All patients were reviewed weekly to assess for symptoms and toxicity using a structured format. The systematic and random errors were calculated along the three axes. RESULTS: Twenty-four patients were randomized and 22 patients were available for the final analysis. The systematic error in supine arm versus prone arm was 3.9 versus 3.5 mm, 2.1 versus 4.8 mm and 3.1 versus 3.1 mm along lateral, antero-posterior (AP) and cranio-caudal (CC) direction. The random error in supine arm versus prone arm was 5 versus 3.9 mm, 2.9 mm versus 4.4 mm and 4.3 versus 3.4 mm along lateral, AP and CC direction. The calculated planning target volume margin for supine arm was 1.3, 0.7, and 1.0 cm and margin for prone arm was 1.1, 1.5, and 1.0 cm along lateral, AP, and CC direction, respectively. One patient in supine arm developed Grade 3 toxicity. CONCLUSION: The systematic error and random error is more along AP direction for prone position. The acute small bowel toxicity was less using belly board.

Mixed Germ Cell Tumour in a Case of Pure Gonadal Dysgenesis (Swyer Syndrome) - A Case Report.

Swyer syndrome or pure gonadal dysgenesis 46, XY is a medical condition associated with 46 XY karyotype and primary amenorrhea in a phenotypic female. In this syndrome, there is an abnormality in testicular differentiation. Patients with disorders in sexual differentiation have an increased risk for development of genital malignancies. A 14-year-old female admitted with abdominal pain was diagnosed to have Swyer syndrome and a pelvic tumor after clinical and laboratory investigations. She underwent surgery, and the histology report revealed a mixed germ cell tumor in a dysgenetic gonad. She recurred three months later and was successfully treated with chemotherapy and a second surgery to remove the differentiated teratoma. The early diagnosis of patients with Swyer syndrome is important because of the increased risk for the development of malignancy. Early surgical treatment is required. Recurrent and metastatic disease respond well to chemotherapy.

Targeted agents in epithelial ovarian cancer: review on emerging therapies and future developments.

Epithelial ovarian cancer (EOC) remains a clinical challenge and there is a need to optimise the currently available treatment and to urgently develop new therapeutic strategies. Recently, there has been improved understanding of the molecular characteristics and tumour microenvironment of ovarian cancers. This has facilitated the development of various targeted agents used concurrently with chemotherapy or as maintenance. Most of the studies have explored the tumour angiogenesis pathways. In phase-III trials, bevacizumab showed a statistically significant improvement in progression-free survival, although there was no improvement in overall survival in selected high-risk cases. Although several multi-targeted tyrosine kinase inhibitors were found to be useful, the toxicity and survival benefit has to be weighed. Poly ADP ribose polymerase (PARP) inhibitors have been another marvellous molecule found to be effective in breast cancer 1, early onset (BRCA)-positive ovarian cancers. Several newer molecules targeting Her 2, Wee tyrsine kinases, PIP3/AKT/mTR-signalling pathways, folate receptors are under development and may provide additional opportunities in the future. This article focuses on the targeted agents that have successfully paved the way in the management of epithelial ovarian cancer and the newer molecules that may offer therapeutic opportunities in the future.

Metachronous bilateral testicular germ cell tumors: report of two cases.

Metachronous bilateral testicular germ cell tumors is a rare known problem. However, no report of metachronus bilateralism was identified in the PubMed database published from India so far, where testicular cancer is relatively rare. We report the cases of two gentlemen. One had stage 1 nonseminomatous germ cell tumor (NSGCT) at the age of 32 in 1990 and developed marker relapse on surveillance and had chemotherapy using cisplatin and etoposide for four cycles. He developed contralateral seminoma in the testis 13 years later. Another patient had left orchidectomy in 2003 for NSGCT, had adjuvant BEP for two cycles, and developed a contralateral testicular tumor 5 years later, which was also seminoma. As more patients with germ cell tumors are cured with chemotherapy, long-term problems become important. Contralateral testicular tumor is one of them. As it can be very late, many years of continued follow-up examination and patients' awareness are necessary.

Germline genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes in Indian cervical cancer: associations with tumor progression, age and human papillomavirus infection.

OBJECTIVES: Host genetic factors may play a role in human papillomavirus (HPV)-associated tumorigenesis, although the issue continues to be a focus of much debate. Biotransformation is critical in carcinogenic activity of numerous environmental carcinogens. It is therefore possible that polymorphisms of genes producing functional changes in xenobiotic metabolizing enzymes may be susceptible factors in cervical carcinogenesis. This study looked into possible relationships among these factors. METHODS: In this case-control study, we analyzed leukocyte DNA from a total of 312 subjects for germline polymorphisms of CYP1A1 (m1 and m2), GSTM1 and GSTT1 at various stages of the cervical tumor progression spectrum, using PCR and RFLP. RESULTS: Both m1 and m2 polymorphisms of the CYP1A1 gene were more frequent among cases (36.1% for m1 and 38.1% for m2) compared to control subjects (18.2% and 17.6% respectively). The odds ratio of a subject with homozygous CYP1A1 m1 and m2 variant being a case was highest (m1 OR = 4.77 [95% CI = 1.28-17.77]; P = 0.02 and m2 OR = 5.48 [95% CI = 1.49-20.19]; P = 0.011) respectively. The distribution of m1 and m2 CYP1A1 genotypes was also studied as a function of age and in relation to the presence of HPV 16 infection. The risk due to CYP1A1 m1 genotype, when adjusted for HPV status, showed a significantly increased risk (OR = 3.58, 95% CI = 1.88-6.81; P = 0.0001). Similar results were observed in the case of CYP1A1 m2 variant and HPV 16. There was a significant over-representation of both m1 (25.9% vs. 13.9%) and m2 (27.9% vs. 13.3%) polymorphisms in older women (46 years or more). GSTM1 and GSTT1 deletions were also prominent among cases (53.7% and 16.3% respectively) compared to controls (32.7% and 9.7% respectively). A higher proportion of both GSTT1 and GSTM1 deletions were also detected in HPV-16-positive subjects. CONCLUSIONS: These results suggest that polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes may render women more susceptible to the development of cervical cancer. The association between this susceptibility and the presence of human papillomavirus infection further emphasizes the significance of the genetic polymorphisms.