BCOR Internal Tandem Duplication Associated Uterine Sarcoma: Expanding the Clinicopathologic Spectrum.

The diagnosis of high-grade endometrial stromal sarcoma has become more refined following molecular characterization of these tumors. Recently BCOR internal tandem duplications (ITD) have been identified in a small number of high-grade endometrial stromal sarcoma. Here we present an additional case of this rare entity in a young woman in her late teens. She presented with menorrhagia and underwent resection of 2 uterine lesions. The tumor was a spindle cell neoplasm composed of long fascicles with low to moderate cellularity, mild to moderate cytologic atypia, and up to 2 mitotic figures per 10 high power fields. Necrosis was not identified. Immunohistochemical stains showed the tumor to be positive for cyclin D1 in >50% of tumor cells, focally positive for CD10, and negative for SMA, desmin, h-caldesmon, and ALK1. BCOR ITD was confirmed by polymerase chain reaction with subsequent Sanger sequencing. Clues to the diagnosis of BCOR ITD uterine sarcoma include young patient age, uniform nuclear features, and diffuse positivity for cyclin D1. These features should prompt further molecular interrogation for definitive diagnosis, which is important for prognostication.

Direct Genetics Referral Pathway for High-Grade Serous Ovarian Cancer Patients: The "Opt-Out" Process.

PURPOSE: In order to meet a clinical need for better pathways to access genetic testing for ovarian cancer patients, we implemented and reviewed an opt-out referral process for genetic consultation whereby a referral is automatically sent to genetics following a pathological diagnosis of HGSC. METHODS: Following implementation of the opt-out referral process, each month a list of new cases of HGSC was generated from the synoptic pathology report and forwarded directly to the Cancer Genetics clinic. Using an advanced directive, patients were automatically referred for genetic counselling two months after surgery. If the patient declined genetic counselling (opted-out) after discussion with their surgeon within the two months after surgery, the Genetic Counsellor was informed and the patient was removed from the referral process. RESULTS: Between January 1, 2015, and December 31, 2017, 168 women were diagnosed with HGSC, of whom 167 received a referral for genetic consultation. In only one case the referral was cancelled by the surgeon, resulting in a referral rate of 99.4%. By the end of the study period, 133 women attended a genetics consultation appointment and 125 (94%) agreed to proceed with genetic testing. Among those who completed genetic testing, 15% tested positive for a BRCA1 or BRCA2 gene mutation. Of the women who tested positive for a BRCA1/2 mutation, 56% had no family history of breast or ovarian cancer. CONCLUSIONS: The opt-out referral process described in this study is s a feasible, effective, and patient-centred approach to increase access to BRCA1/2 testing for patients with ovarian cancer.

When Pap Testing Fails to Prevent Cervix Cancer: A Qualitative Study of the Experience of Screened Women Under 50 with Advanced Cervix Cancer in Canada.

INTRODUCTION: While Papanicolaou (Pap) smears have resulted in a significant decline in cervical cancer incidence and mortality, our clinical experience indicates some women still present with locally advanced cervical cancer (LACC) despite having received Pap smear screening. Recent guidelines have decreased the recommended frequency of Pap smears to every three years. Our study sought to investigate the experiences of young women compliant with cervical screening who presented with LACC. METHODS: Women under 50 with LACC, FIGO (International Federation of Gynecology and Obstetrics) stage IB1 to IVA who underwent a Pap smear within two years of diagnosis and received curative intent chemoradiotherapy between September 2010 and December 2012 were included. Participants were treated at a tertiary academic cancer centre and invited for a semi-structured, in-person interview, which was analysed qualitatively using thematic analysis. RESULTS: Thirteen out of 38 women had Pap screening two or less years before diagnosis. Ten consented to participate in an interview. Several key themes emerged: I) Belief that LACC does not occur in those who undergo screening; II) Lack of understanding about LACC symptoms/diagnosis of cervix cancer; III) Reluctance from health care providers to perform a detailed pelvic examination in the presence of symptoms; IV) Negative emotions including anger, shame, regret, mistrust; V) Changes in quality of life from treatment; VI) Advice for other women. CONCLUSIONS: One-third of women presenting with LACC had appropriate Pap screening prior to diagnosis. Patients believe delays in their diagnosis resulted in detrimental quality of life. There is a need to educate physicians and the public about the symptoms of cervix cancer and to consider this diagnosis even when Pap screening has occurred.

Treatment Tolerance and Side Effects of Intraperitoneal Carboplatin and Dose-Dense Intravenous Paclitaxel in Ovarian Cancer.

OBJECTIVE: To describe the frequency of clinically significant side effects associated with adjuvant intraperitoneal (IP) carboplatin and intravenous (IV) dose-dense paclitaxel chemotherapy for epithelial ovarian cancer (EOC). METHODS: Patients with stage II to IV EOC who underwent upfront cytoreductive surgery followed by adjuvant IP carboplatin (AUC 6) every 3 weeks with IV paclitaxel weekly at 80 mg/m2 were included. Side effects and the resulting changes in treatment are presented using univariate analysis and compared to major phase III RCTs. RESULTS: Between March 2013 and October 2015, 49 patients comprising 289 cycles of chemotherapy were included in the analysis; 43 patients (87.8%) completed six cycles of chemotherapy and 38 (77.6%) completed six cycles of IP carboplatin. Treatment was discontinued early due to neuropathy (5/49) and disease progression (1/49). Carboplatin IV was substituted due to port access (3/49) and poor postoperative performance status (3/49). Neutropenia occurred in 16 patients (32.7%). Fourteen patients (28.6%) required red blood cell transfusion. Thrombocytopenia affected nine patients (18.4%). Infection delaying treatment occurred in five patients (10.4%). Gastrointestinal and renal toxicity occurred in four (8.1%) and one patient (2.0%), respectively. Four patients experienced a taxane reaction. No patients experienced ototoxicity, fistula formation, chemotherapy leakage, or severe abdominal pain. CONCLUSION: Carboplatin IP and weekly IV paclitaxel was well-tolerated with a side-effect profile similar to or better than previously published traditional treatment regimens.

High-dose-rate interstitial brachytherapy for the treatment of high-volume locally recurrent endometrial carcinoma.

PURPOSE: Limited therapeutic options are available for the treatment of locally recurrent endometrial carcinoma. Our objective was to report an institutional experience using interstitial brachytherapy (IBT) to treat significant recurrent endometrial carcinoma, including previously irradiated disease. METHODS AND MATERIALS: Between December 2004 and September 2012, 40 patients with high-volume locally recurrent endometrial cancer were treated by high-dose-rate IBT (± external beam radiation therapy EBRT). Sixteen patients had prior radiotherapy: EBRT alone (n = 5), intracavitary brachytherapy alone (n = 3), or EBRT with intracavitary brachytherapy boost (n = 8). Actuarial outcome rates were calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Median followup interval was 18 months. Median disease-free interval was 61 months. Actuarial local control, progression-free survival (PFS), and overall survival were 74% and 60%, 70% and 51%, and 83% and 72% at 12 and 24 months, respectively. p-Values for local control, progression-free survival, and overall survival between patient who had prior RT (n = 16) to no prior RT (n = 24) were p = 0.38, 0.32, and 0.90, respectively. Acute toxicities include Grade 1-2 pain (5%), genitourinary (7%), gastrointestinal (12%), soft tissue (5%), and dermatologic (12%). Four patients observed late Grade 3-4 toxicities, including rectal bleeding/fistula and soft tissue necrosis. CONCLUSIONS: High-dose-rate IBT is an effective treatment for locally recurrent endometrial carcinoma with an acceptable toxicity profile. Outcomes are similar between previously irradiated and nonirradiated patients. In women who have received prior radiotherapy and are often considered for palliative treatment, interstitial brachytherapy is a potentially curative option.

Role of Adjuvant Therapy for Stage IA Serous and Clear Cell Uterine Cancer: Is Observation a Valid Strategy?

OBJECTIVES: The adjuvant treatment of early stage IA serous and clear cell carcinomas of the uterus is controversial. The aims of the study were to report on a single institution experience treating these high-risk early uterine cancers and to identify women who may be suitable for observation alone. METHODS AND MATERIALS: A retrospective review of patients presenting from 2003 to 2013 with pathologic stage IA (International Federation of Gynecology and Obstetrics 2009) serous or clear cell uterine carcinoma was performed. Patient and disease characteristics, surgical staging, treatment details, and recurrence data were collected. Recurrence rates and 5-year actuarial estimates of recurrence free survival (RFS) were the primary outcomes of interest. RESULTS: A total of 77 patients with stage IA were identified. Median (range) follow-up was 34 (1-108) months. Staging lymphadenectomy was performed in 83%. Adjuvant treatment was given to 27 patients, whereas 50 underwent observation. There were 12 recurrences total, with the 5-year RFS 79% for the cohort, with no statistically significant difference between observation and adjuvant treatment. Only 4 patients received adjuvant chemotherapy and none recurred. In the observation cohort, the presence versus absence of myometrial invasion showed a trend to poorer 5-year RFS (75% vs 93%, P = 0.06). CONCLUSIONS: Observation seems to be a valid strategy in those patients with stage IA serous and clear cell carcinoma without myometrial invasion. The presence of any myometrial invasion may confer a higher risk of recurrence, although further studies are needed to determine the optimal adjuvant treatment regimen.

TGFß signaling regulates epithelial-mesenchymal plasticity in ovarian cancer ascites-derived spheroids.

Epithelial-mesenchymal transition (EMT) serves as a key mechanism driving tumor cell migration, invasion, and metastasis in many carcinomas. Transforming growth factor-beta (TGFß) signaling is implicated in several steps during cancer pathogenesis and acts as a classical inducer of EMT. Since epithelial ovarian cancer (EOC) cells have the potential to switch between epithelial and mesenchymal states during metastasis, we predicted that modulation of TGFß signaling would significantly impact EMT and the malignant potential of EOC spheroid cells. Ovarian cancer patient ascites-derived cells naturally underwent an EMT response when aggregating into spheroids, and this was reversed upon spheroid re-attachment to a substratum. CDH1/E-cadherin expression was markedly reduced in spheroids compared with adherent cells, in concert with an up-regulation of several transcriptional repressors, i.e., SNAI1/Snail, TWIST1/2, and ZEB2. Treatment of EOC spheroids with the TGFß type I receptor inhibitor, SB-431542, potently blocked the endogenous activation of EMT in spheroids. Furthermore, treatment of spheroids with SB-431542 upon re-attachment enhanced the epithelial phenotype of dispersing cells and significantly decreased cell motility and Transwell migration. Spheroid formation was significantly compromised by exposure to SB-431542 that correlated with a reduction in cell viability particularly in combination with carboplatin treatment. Thus, our findings are the first to demonstrate that intact TGFß signaling is required to control EMT in EOC ascites-derived cell spheroids, and it promotes the malignant characteristics of these structures. As such, we show the therapeutic potential for targeted inhibition of this pathway in ovarian cancer patients with late-stage disease.

Intact LKB1 activity is required for survival of dormant ovarian cancer spheroids.

Metastatic epithelial ovarian cancer (EOC) cells can form multicellular spheroids while in suspension and disperse directly throughout the peritoneum to seed secondary lesions. There is growing evidence that EOC spheroids are key mediators of metastasis, and they use specific intracellular signalling pathways to control cancer cell growth and metabolism for increased survival. Our laboratory discovered that AKT signalling is reduced during spheroid formation leading to cellular quiescence and autophagy, and these may be defining features of tumour cell dormancy. To further define the phenotype of EOC spheroids, we have initiated studies of the Liver kinase B1 (LKB1)-5'-AMP-activated protein kinase (AMPK) pathway as a master controller of the metabolic stress response. We demonstrate that activity of AMPK and its upstream kinase LKB1 are increased in quiescent EOC spheroids as compared with proliferating adherent EOC cells. We also show elevated AMPK activity in spheroids isolated directly from patient ascites. Functional studies reveal that treatment with the AMP mimetic AICAR or allosteric AMPK activator A-769662 led to a cytostatic response in proliferative adherent ovarian cancer cells, but they fail to elicit an effect in spheroids. Targeted knockdown of STK11 by RNAi to reduce LKB1 expression led to reduced viability and increased sensitivity to carboplatin treatment in spheroids only, a phenomenon which was AMPK-independent. Thus, our results demonstrate a direct impact of altered LKB1-AMPK signalling function in EOC. In addition, this is the first evidence in cancer cells demonstrating a pro-survival function for LKB1, a kinase traditionally thought to act as a tumour suppressor.

CT-based interstitial brachytherapy in advanced gynecologic malignancies: outcomes from a single institution experience.

PURPOSE: To evaluate the clinical outcomes of women receiving a "short" course of high-dose-rate gynecologic interstitial brachytherapy (HDR-ISBT) boost with CT-based 3D planning. METHODS AND MATERIALS: Forty-seven women with no prior radiation received HDR-ISBT from August 2004 to February 2012. The mean external beam radiotherapy dose was 45 Gy. A mean HDR-ISBT boost dose of 18.4 Gy was delivered over 2-4 fractions. Dose volume histograms (DVHs) were computed for organs at risk and clinical target volume. RESULTS: With a median followup of 34.8 months, the 3-year local control rate was 68%. Sixteen patients were identified to have tumor recurrence (including eight local). The median time to any recurrence was 26.8 months. Relapse-free survival and overall survival at 3 years was 65% and 73%, respectively. Ten patients experienced Grade 3 late toxicity, mainly vaginal (5) and proctitis (3). The mean prescription volume (V100) was 85 cc and the mean D90 to CTV was 98%. The mean cumulative dose to tumor was 69.9 Gy (equivalent dose in 2 Gy). The mean cumulative equivalent dose in 2 Gy to D2cc of bladder and rectum was 60.9 Gy and 63.0 Gy, respectively. CONCLUSION: A "short" course HDR-ISBT is effective, safe, and convenient with acceptable local control and toxicity. Higher dose per fraction is similar to an external beam radiotherapy stereotactic boost with the inherent advantages of brachytherapy. A shorter overall time for HDR-ISBT means less time that patients are immobilized and in hospital, making it less resource intensive than a longer course.

Combination of AKT inhibition with autophagy blockade effectively reduces ascites-derived ovarian cancer cell viability.

Recent genomics analysis of the high-grade serous subtype of epithelial ovarian cancer (EOC) show aberrations in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway that result in upregulated signaling activity. Thus, the PI3K/AKT pathway represents a potential therapeutic target for aggressive high-grade EOC. We previously demonstrated that treatment of malignant ascites-derived primary human EOC cells and ovarian cancer cell lines with the allosteric AKT inhibitor Akti-1/2 induces a dormancy-like cytostatic response but does not reduce cell viability. In this report, we show that allosteric AKT inhibition in these cells induces cytoprotective autophagy. Inhibition of autophagy using chloroquine (CQ) alone or in combination with Akti-1/2 leads to a significant decrease in viable cell number. In fact, Akti-1/2 sensitizes EOC cells to CQ-induced cell death by exhibiting markedly reduced EC50 values in combination-treated cells compared with CQ alone. In addition, we evaluated the effects of the novel specific and potent autophagy inhibitor-1 (Spautin-1) and demonstrate that Spautin-1 inhibits autophagy in a Beclin-1-independent manner in primary EOC cells and cell lines. Multicellular EOC spheroids are highly sensitive to Akti-1/2 and CQ/Spautin-1 cotreatments, but resistant to each agent alone. Indeed, combination index analysis revealed strong synergy between Akti-1/2 and Spautin-1 when both agents were used to affect cell viability; Akti-1/2 and CQ cotreatment also displayed synergy in most samples. Taken together, we propose that combination AKT inhibition and autophagy blockade would prove efficacious to reduce residual EOC cells for supplying ovarian cancer recurrence.

Added-value of SPECT/CT to lymphatic mapping and sentinel lymphadenectomy in gynaecological cancers.

Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been successfully used in pre-treatment nodal staging of gynaecological cancers. We hypothesised the added-value of LM/SL plus SPECT/CT in patients with early stage of cervical cancer and vulvar cancer. A prospective, single-center, diagnostic, open label, active control, non-randomized clinical trial has been conducted in 7 patients with FIGO IA-IB1 cervical cancer and 7 patients with FIGO stage I-II-IIIcN0 vulvar cancer. All patients underwent LM/SL plus SPECT/low-dose CT and complete lymph node dissection (CLND) according to the standard of care. In case of negative hematoxylin-eosin staining, serial sections of the SLNs were analysed by immunohistochemistry and high molecular weight cytokeratin. Primary outcome measures were the detection rate, the sensitivity (SV), the negative predictive value (NPV), the diagnostic accuracy (DA) for anatomic localisation of SLNs, and the impact on management of SPECT/CT guided LM/SL versus CLND. The secondary outcome measure was the patient tolerability and operating time of LM/SL guided SPECT/CT versus CLND. http://clinicaltrials.gov/show/NCT00773071 All 14 patients were enrolled into the 1-day research protocol with dual-tracer LM/SL and SPECT/CT. Additional SLNs were detected on SPECT/CT compared to conventional planar imaging. Hot and cold > 1cm SLNs were detected on SPECT/CT. Detection rate, SV, NPV, DA were 100% in both groups; false negative rate was 0%. Rate of SLN metastases was 28.5% in cervical cancer and 42.9% in vulvar cancer. Impact on treatment was 28.5% and 14.3% in cervical cancer and vulvar cancer patients, respectively. SPECT/CT was well tolerated by all patients and operating time for LM/SL was within 30 min. No adverse events were reported with a time frame of 1-to-3 years. In early stage of gynaecological cancers, SPECT/low-dose CT is technically feasible and of clinical added-value for LM/SL.

Uterine smooth muscle tumors of uncertain malignant potential: diagnostic challenges and therapeutic dilemmas. Report of 2 cases and review of the literature.

Morphologically, there exist variants of uterine smooth muscle tumors that cannot be clearly interpreted and classified as benign or malignant. Because their behavior and clinical prognosis is also uncertain, the World Health Organization has termed these "smooth muscle tumors of uncertain malignant potential" (STUMP). Herein we describe 2 cases, present a review of the literature, and highlight the diagnostic challenges and therapeutic dilemmas associated with uterine STUMP in myomectomy specimens from women who wish to maintain or enhance their fertility. The clinical course of residual STUMP remains speculative.

Choriocarcinoma in an AIDS patient--relapsing but not fatal.

Choriocarcinoma is associated with high mortality in immunocompromised patients, in contrast to a good prognosis in immunocompetent individuals. Respiratory failure due to metatstatic choriocarcinoma is associated with high mortality in any patient. We report a case of a woman with AIDS that survived metastatic choriocarcinoma and respiratory failure. We also observed that in contrast to some in vitro studies, the markedly elevated levels of beta-subunit of human chorionic gonadotropin in this patient did not have any apparent inhibitory effect on viral replication.

Cystic struma ovarii (with macrocystic change).

In this article, a case of cystic struma ovarii with macrocystic change is presented. Cysts derived from struma ovarii may mimic a mucinous or serous cystadenoma. A careful examination for any thyroid microfollicles within fibrous septa or areas of solid stroma is key. In problematic cases, immunohistochemical staining with thyroglobulin and thyroid transcription factor-1 may be required to establish the diagnosis.

Cholelithiasis of the ovary after laparoscopic cholecystectomy: a case report.

BACKGROUND: Laparoscopic cholecystectomy may result in spilled bile and dropped gallstones. Although there are usually no consequences, occasionally this can lead to serious complications, including those requiring surgical procedures. Very few cases have been reported documenting the consequence of spilled biliary contents on or near the female genital tract. CASE: A cholelith became embedded in the ovary of a 53-year-old woman and was detected >7 years after laparoscopic cholecystectomy. CONCLUSION: The complications of cholelithiasis of the ovary may include chronic pelvic pain, dysmenorrhea, infection, adhesions, ectopic pregnancy and infertility. Ovarian choleliths may be an incidental finding or can mimic a primary ovarian tumor.

Vernixuria: another sign of uterine rupture.

Uterine rupture complicates approximately 1% of trials of labor after cesarean. Classic signs and symptoms include loss of station, cessation of labor, vaginal bleeding, fetal distress, and abdominal pain. Other signs are also possible. We report a case of uterine rupture at VBAC trial that includes an unusual clinical sign of uterine rupture: vernix caseosa observed in the urine of the parturient. During labor, a bladder catheter was inserted to evaluate oliguria. Vernix caseosa and blood were found in the tubing. Prompt cesarean delivery followed. A tear extending from the original transverse scar into the bladder dome was found. Vernixuria is an additional sign of uterine rupture.