Overall Survival in Patients with Endometrial Cancer Treated with Dostarlimab plus Carboplatin-Paclitaxel in the Randomized ENGOT-EN6/GOG-3031/RUBY Trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint. RESULTS: A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial.

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274.

Dermatofibrosarcoma protuberans of the vulva.

Dermatofibrosarcoma protuberans of the vulva is an uncommon low-grade sarcoma of dermal origin. Although wide local excision is the treatment of choice, microscopic tumor projections beyond the central tumor nodule explain the tumors' propensity for local recurrence. Frozen sections of margins may be useful to ensure complete resection. The following report contributes two additional patients with this uncommon neoplasm. Notably, one of these two had a fibrosarcomatous area within the dermatofibrosarcoma protuberans. This is the second reported case of a fibrosarcoma arising in a dermatofibrosarcoma protuberans of the vulva.

Placental site trophoblastic tumor in a postmenopausal woman.

Placental site trophoblastic tumor is a rare neoplasm that arises in the trophoblastic tissue of the placental bed. This case report is unusual because of the patient's advanced age at the time of diagnosis and the favorable response of the disease to chemotherapy. Although the clinical course is benign for most patients with placental site trophoblastic tumor, the malignant variant of the disease is characterized by recurrence, relative insensitivity to radiation and chemotherapy, and death. To the authors' knowledge, the 53-year-old woman reported is the oldest patient with histologically confirmed placental site trophoblastic tumor. Initially, surgery, radiation, and multiagent chemotherapy failed to control vaginal and pulmonary metastatic disease. After administration of four treatment cycles of a "second-line" chemotherapeutic regimen consisting of cyclophosphamide and cisplatin, complete clinical and radiologic remission was achieved. The patient's serum level of human chorionic gonadotropin has remained undetectable, and she has been without measurable evidence of disease for 16 months.

Investigation of ovarian neoplasia of low malignant potential for human papillomavirus.

Recent in situ hybridization studies have suggested the presence of human papillomavirus type 6 (HPV-6) DNA in ovarian cancer cells. An association between HPV and ovarian neoplasia of low malignant potential (LMP) has not been previously identified. Paraffin-embedded tissue blocks from 24 patients with LMP ovarian tumors were screened for human papillomavirus DNA. The patients ranged in age from 18 to 73 years. Corresponding microscopic slides from each tissue block were reviewed to confirm the histopathologic diagnosis. For identification of HPV genome, deparaffinized sections were subjected to the polymerase chain reaction to achieve amplification of DNAs of HPV types 6, 11, 16, and 18. For each HPV type, a 120-base-pair region of the E6 gene was targeted for amplification. Human papillomaviral DNA was not detected in the tissue specimens subjected to polymerase chain reaction. These results suggest that HPV types 6, 11, 16, and 18 are not likely to play a role in LMP ovarian tumors. These results do not totally exclude possible contributions of other HPV types.

Vulvar congenital dysplastic angiopathy.

Congenital dysplastic angiopathy is a syndrome consisting of vascular angiomata, congenital varicosities, and trophic changes of the soft tissue and the skeleton. Frequently referred to as Klippel-Trenaunay or Klippel-Trenaunay-Weber syndrome, it rarely affects the female genitalia. An 18-year-old woman underwent evaluation and treatment for Klippel-Trenaunay syndrome with vulvar involvement. Preoperative evaluation included consultation with pediatric surgeons, gynecologic surgeons, and an interventional radiologist as well as individual and family psychological counseling. Attention to intraoperative detail resulted in minimal operative blood loss and preservation of normal anatomy. A postoperative hematoma was treated aggressively with surgical evacuation and drainage. Six-month follow-up revealed functionally and cosmetically normal vulvar anatomy.

The predominance of human papillomavirus type 16 in vulvar neoplasia.

Southern transfer analysis for human papillomavirus genomic sequences was conducted on 152 vulvar and vaginal tissue specimens obtained from 86 patients. Histopathologic diagnoses included condyloma acuminatum, intraepithelial neoplasia, and invasive cancer. In six patients, lesions of more than one pathologic type were identified. Vaginal lesions constituted less than 5% of tissues examined. Distribution of lesions was as follows: condyloma, 93 lesions from 57 patients; intraepithelial neoplasia, 47 lesions from 29 patients; and invasive carcinoma, 12 lesions from six patients. Seventy-five percent of the patients were white. The mean age of the patients increased from 25 years for condyloma to 38 years for vulvar intraepithelial neoplasia III to 56 years for invasive cancer. A viral diagnosis was made in 81% of condylomas, 84% of vulvar intraepithelial neoplasia III, and 58% of invasive carcinomas. Distribution of viral types differed markedly for the various histopathologies. Types 6/11 accounted for 77% of condylomas and 0% of vulvar intraepithelial neoplasia III. Type 16 was recovered from 12% of condylomas and 81% of vulvar intraepithelial neoplasia III. Type 18 was identified in a small proportion in both categories; type 31 was seen in a few vulvar intraepithelial neoplasia III lesions. In invasive carcinomas, type 16 was the predominantly identified virus. Papillomavirus type 16 emerges as the dominant oncogenic virus in vulvar neoplasms. Its presence in a large percentage of condylomas raises the issue of an "atypical condyloma" as a precursor of neoplasia.

Genital warts, papillomaviruses, and genital malignancies.

Human papillomavirus (HPV) infections of the genital tract are widespread and often subclinical. Of about a dozen genital tract HPVs, types 16 and 18 are strongly associated with squamous cell carcinoma of the cervix and of other sites in the lower genital tract. In invasive cervical cancers, the viral genomes are often integrated into the cellular DNA and are transcriptionally active. These viruses, with additional cofactors, play a role in genital tract malignancies.

Characterization of human papillomavirus type 45, a new type 18-related virus of the genital tract.

DNA of human papillomavirus (HPV) type 45, a new HPV type 18-related papillomavirus of the genital tract, was cloned from a recurrent cervical lesion displaying mild to moderate dysplasia with koilocytosis. HPV-45 DNA was identified in paraffin sections of biopsies of both the initial and recurrent lesions of the patient, taken 7 months apart. HPV-45 DNA hybridized efficiently to that of many different HPV types under low and moderate stringency conditions (Tm - 37 degrees C to Tm - 25 degrees C) but with only HPV-18 DNA under high stringency conditions (Tm - 17 degrees C). HPV-45 DNA was distinguished from HPV-18 DNA by (i) differences in restriction enzyme digest patterns, (ii) lack of hybridization at Tm - 17 degrees C between HPV-18 and some fragments of HPV-45, (iii) a value of 25% in liquid reassociation kinetics between HPV-18 and HPV-45 and (iv) differences in intensities of hybridization with selected tissue DNAs. The prevalence of HPV-45 infection in the genital tract was low. In tests of over 600 tissue DNAs from female genital tract lesions, HPV-45 sequences were detected in three additional tissues, one each of invasive cervical carcinoma, condyloma, and normal cervical epithelium. HPV-45 is a newly recognized papillomavirus which rarely infects the genital tract and is associated with lesions across a wide histological spectrum.

Condylomata acuminata arising in a neovagina.

A case is reported in which condylomata acuminata arose in a McIndoe neovagina. Histopathologic and virologic evidence are provided to support the characterization of these lesions as benign warty processes secondary to human papillomavirus-6. Factors influencing viral site specificity are discussed.

Uterine hemangiopericytoma.

In a clinicopathologic analysis of previously unreported uterine hemangiopericytomas, malignant behavior was observed in four of 21 followed patients. Recurrent disease occurred in the pelvis, abdomen, and lungs. The role of chemotherapy in the treatment of recurrences was not substantiated. No specific histologic features could be identified that correlated with malignant potential.

Genital tract papillomavirus infection in children.

Genital tract papillomas in five children were examined for the presence of human papillomavirus (HPV) DNA by molecular hybridization. Papillomavirus DNA was detected in each sample and was identified as HPV-6 (three cases), HPV-6 or HPV-11 (one case), or HPV-16 (one case). These viruses are the same as are responsible for genital papillomas (condylomata) of adults. The transmission of adult genital tract viruses to children occurs primarily by a venereal route but may occur by a nonvenereal route.

Ovarian cancer metastatic to the breast.

The breast is an uncommon site for metastasis from epithelial ovarian cancer. Such lesions are purportedly secondary to blood-borne metastases. The accurate classification of ovarian epithelial neoplasms is the cornerstone of decisions regarding therapy and prognosis. Taylor, in 1929, reported a hyperplastic variety of papillary cystadenoma which, on occasion, produced multiple implants on the peritoneum but usually behaved in a benign fashion. The International Federation of Gynecologists and Obstetricians adopted a classification of benign cystadenomas, cystadenocarcinomas of low malignant potential (LMP), and cystadenocarcinomas. The serous tumors of LMP rarely metastasize outside of the abdominopelvic cavity. This case, of a serous tumor of LMP with breast metastasis, permits an analysis of metastatic breast lesions secondary to epithelial ovarian cancer.

Epithelioid leiomyosarcoma of the uterus.

Uterine epithelioid leiomyosarcoma is an unusual smooth muscle neoplasm. It is distinguished on cytoarchitectural grounds from the majority of leiomyosarcomas that arise in the uterus. Three cases of this atypical lesion are presented and the pathologic features are discussed. One patient is alive with no evidence of disease at 3.5 years, one patient has persistent disease at 4 years, and the third patient died of disease at 8 months. Fundamental differences in biologic behavior of this subset of uterine smooth muscle tumors cannot be discerned.

Primary breast cancer of the vulva.

Adenocarcinoma originating in a focus of mammary tissue in the vulva is an extremely rare occurrence. Only three such cases have been reported in the literature. Herein, the fourth example of a primary cancer developing in vulvar mammary tissue is described. Extension to regional lymph nodes is documented, as well as the presence of estrogen receptors in this tumor. Immunohistochemical evidence is rendered supporting an origin from mammary anlage.

Vaginal hemangiopericytoma: a histopathologic and ultrastructural evaluation.

The hemangiopericytoma is an uncommon stromovascular neoplasm that arises from the pericyte of Zimmerman. Since their original description in the female genital tract in 1954, the majority of these lesions have been of uterine origin. Presented is a clinicopathologic description of a hemangiopericytoma arising in the vagina and occupying the rectovaginal septum. Light and electron microscopic characterization is rendered. Current understanding of these lesions is reviewed and therapeutic options are discussed.

Rectal serosal hematoma: an unusual complication of culdocentesis.

Culdocentesis is currently a widely used diagnostic technique in gynecology. Although associated with numerous theoretical risks, few complications have been documented in anecdotal reports. Rectal serosal hematoma, an unusual complication of culdocentesis, is described.

Significance of neoplastic atypicalities in endocervical epithelium.

Currently, adenocarcinoma in situ and early invasive adenocarcinoma of the cervix are poorly defined entities. The dangers inherent in such diagnoses are identified in this case report of "early adenoepidermoid" cervical cancer in which deepest glands were not involved; however, pelvic recurrence was recognized 5-years posthysterectomy and the patient died of widespread disease 1 1/2 years later. The danger of correlating the knowledge of cervical cancer with gland involvement to "apparently" similar changes in adenocarcinoma are emphasized. It is suggested that, at least at the present, "early adenocarcinoma" must be considered as invasive and treated as such.