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.

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.

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.

Carcinoma in situ of the vulva.

Of 106 patients with carcinoma in situ (CIS) of the vulva, 102 have been followed from 1 to 15 years. The average age of the patient was 47 years; however, 40% were under the age of 41. Twenty-seven percent had associated cervical malignancy. Only 4 patients developed invasive cancer. Of these, 2 were postmenopausal and the 2 younger patients had been immunosuppressed because of systemic disease; thus the subsequent invasive cancer. The incidence of recurrence was essentially the same whether the patient was treated by vulvectomy or wide local excision. In view of the uncertainties about the invasive potential of CIS of the vulva in young patients and the absence of a proved need for an extensive procedure, it is suggested that this entity be treated only by local excision.

Spontaneous rupture of benign cystic teratomas.

Spontaneous preoperative rupture and/or perforation of an adjacent organ by a benign cystic teratoma is rare. Between 1952 and 1979 there were 4 documented cases at The Johns Hopkins Hospital. The incidence, etiology, and pathology of this complication are discussed.

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.

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.

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 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.

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.

Progressive histobiologic alterations in the development of vulvar cancer.

Identification of the patient at risk for the development of cancer and the precursory histopathologic changes has led to improvement in 5-year survivals among patients with cancer of the cervix and endometrium. In conrast, there has been controversy as to these factors in discussions of vulvar neoplasia. This report of five cases of patients who developed invasive cancer after treatment for in situ disease attempts to define some of the at-risk factors, including the specific area at which three of the five malignancies subsequently developed.

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.

The significance of the histologic alterations adjacent to invasive vulvar carcinoma.

It has been superficially recognized, but not appreciated, that carcinoma of the vulva differs in many respects from carcinoma of the uterine cervix. Past studies have suggested that "leukoplakia and leukoplakia-like lesions" are probably premalignant conditions since they are commonly associated with invasive cancer. Conversely, studies of the dystrophies during the past 15 years have indicated that the latter uncommonly progress to invasive cancer if treated adequately. In an attempt to review the histopathologic changes associated with invasive cancer, the last 98 cases of invasive disease were studied and the histopathologic characteristics of the adjacent tissue were divided into categories. It was noted that less than 20% of the invasive cancers demonstrated classic in situ neoplasia in the adjacent area, whereas more than 50% showed patterns suggestive of the dystrophies. Thus, although the dystrophies were not necessarily the precursory lesions, they did demonstrate probable long-term irritation, which is of major importance in the genesis of vulvar cancer. Furthermore, in situ cancer, as seen in the young patient, rarely seems to progress to invasive disease.

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.

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.