ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer.

BACKGROUND: Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. METHODS: We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. RESULTS: A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. CONCLUSIONS: Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. RESEARCH SUPPORT: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Primary mucinous carcinoma of the vulva with signet ring cells deriving from the cloaca.

Vulvar neoplasias are rarely encountered lesions at female genital tract, regardless if they are primary or metastatic. Presence of signet ring cells in a tumour at female genito-urinary tract is highly suggestive of a metastatic lesion particularly from a gastrointestinal tumour. Here the authors present a case of vulvar carcinoma with signet ring cells with an undetermined primary site possibly originating from embryonic cloaca.

Diagnostic performance of p16 staining in atypical squamous cells 'cannot exclude high-grade squamous epithelial lesion' in predicting high-grade cervical pathology.

Atypical squamous cells 'cannot exclude high-grade squamous epithelial lesion' (ASC-H) cytology represents clear risk and has been a controversial issue in clinical practice. The objective of this study is to investigate the diagnostic performance of p16(INK4A) immunohistochemistry (IHC) among ASC-H Pap smears in predicting high-grade cervical intraepithelial lesions. Decolourisation and staining process with p16(INK4A) is applied to 27 ASC-H diagnosed conventional Pap smears, which were all managed with colposcopy-directed cervical biopsy priorly. Staining characteristics of ASC-H Pap smears were compared with histopathological data and sensitivity-specificity values of p16 triage to detect CIN2 + histopathology were determined. The sensitivity and specificity of positive p16(INK4A) immune staining to detect CIN2 + histopathology were as 87.5% and 68%, respectively. The positive predictive value of p16 triage is found as 53.8% and negative predictive value was as 92.8%. p16(INK4A) IHC seems applicable for conventional Pap smears and may provide an alternative triage option in ASC-H category.

Comparison of laparoscopy and laparotomy in surgical staging of clinical early stage endometrial cancer: a report of early experiences from Turkey.

The objective of this study was to assess the feasibility of laparoscopy (LS) in endometrial carcinoma staging. Clinical early stage endometrial cancer patients (n = 153) staged by LS or laparotomy (LT) were compared. A total of 40 (26.1%) patients were treated by LS and 113 (73.9%) by LT. All patients underwent pelvic lymphadenectomy. Lymphadenectomy has been extended to para-aortic space in 55% of the LS group and 70% of the LT group. The majority of patients had stage I-II disease. The median numbers of removed pelvic and para- aortic lymph nodes were similar in two groups (p values 0.213 and 0.199, respectively). Body mass index (BMI) (kg/m(2)) was higher in the LT group (31.2 vs 27.4, p < 0.05). Operation time, age, tumour histology, para-aortic lymphadenectomy and complication rates were similar in the two groups. Four (10%) patients in the LS group and 12 (10.6%) in the LT group had recurrence of disease (p = 1.0). There was no statistical difference for overall survival between the two groups. In conclusion, these findings showed that in endometrial carcinoma cases, laparoscopy has provided adequate staging and similar survival rates with laparotomy.

High-risk human papilloma virus prevalence and its relation with abnormal cervical cytology among Turkish women.

In this study we aimed to investigate high-risk human papilloma virus (hrHPV) prevalence among Turkish women. Cervical samples were collected from 501 women for cytological screening and hrHPV testing by Digene Hybrid Capture 2. hrHPV prevalence and its relation with cytological results and epidemiologic data were analysed by SPSS. The prevalence of hrHPV was 4.2% (21 of the 501 women). Women with abnormal cytological screening results have significantly higher risk of hrHPV positivity compared with women with normal cytological results (19% vs 3.5%) (p ≤ 0.01). The incidence of HPV infection was only associated with the number of sexual partners, but there was no association with age, contraception methods or age at the first sexual intercourse. The prevalence of hrHPV among histological-confirmed cervical intraepithelial neoplasia (CIN) 1, CIN 2 and normal cases were found as 37.5%, 25% and 25%, respectively. The prevalence of cervical hrHPV infection is 4.2% in our population and this rate seems lower than reported rates from other regions. According to further studies with a larger sample size, reflex cytology based on hrHPV positivity should be considered for our national cervical cancer screening programme.

The role of ultrasound and symptom-based triage for detection of pathological endometrial changes in patients undergoing tamoxifen therapy for breast cancer.

PURPOSE OF INVESTIGATION: To estimate the value of ultrasonographic screening and symptom-based triage for the detection of endometrial pathologies in breast cancer patients using tamoxifen. METHOD(S): A total of 292 breast cancer patients using tamoxifen were analyzed retrospectively. A total of 115 endometrial biopsies were performed on the basis of ultrasonographic examination and symptomatic status of both premenopausal and postmenopausal patients. Endometrial thickness and symptomatic status were then correlated with histopathologic data to figure out the clinical implications of ultrasonographic screening and symptom-based triage. RESULT(S): The cut-off value of endometrial thickness was 8 mm for asymptomatic postmenopausal patients and the positive predictive value of transvaginal ultrasound for endometrial pathologies was 59%. The positive predictive values of symptom-based triage alone for premenopausal and postmenopausal patients were 37.5% and 48.2%, respectively. CONCLUSION: Transvaginal ultrasound may be a useful method for the detection of pathological endometrial changes in asymptomatic postmenopausal breast cancer patients administered adjuvant tamoxifen. In premenopausal patients, symptom-based triage alone does not seem to be an effective diagnostic tool for endometrial pathologies.

Identification of point mutations and large rearrangements in the BRCA1 gene in 667 Turkish unselected ovarian cancer patients.

OBJECTIVE: The aim of this study was to evaluate the prevalence and spectrum of a known founder mutation, 5382insC and large genomic rearrangements (LGRs) in BRCA1 in ovarian cancer patients in Turkey. The additional aim was to determine the genetic testing strategy in Turkish breast/ovarian cancer family. METHODS: Six hundred and sixty-seven ovarian cancer patients from five large geographical regions in Turkey, 61 of which had family history of breast/ovarian cancer, were tested for the mutation 5382insC by mutagenically separated polymerase chain reaction and direct sequencing of the entire coding sequence and the splicing sites. Additionally, multiplex ligation-dependent probe amplification (MLPA) was performed for large mutational scanning of BRCA1 gene in unselected ovarian cancer. RESULTS: In this study, BRCA1 point mutations were observed in 1% of all patients and 9.8% of familial cases: 5382insC, unique novel missense variant-G1748S and unclassified splice site variant IVS20+5A>T. 5382insC was observed in two patients. However, G1748S, previously unreported, was found in four patients and thus led to the conclusion that this mutation may be unique to Turkey. A splice site variant, IVS20+5A>T, was detected in three patients, with two of them including G1748S and IVS20+5A>T, together. Using MLPA, six different distinct LGRs in BRCA1 were observed: the deletion of E1A-1B-2, E11, E17-19, E18 and E18-19 and duplication of E5-9. The prevalence of LGRs in this study was 40.9% among patients with family history. The deletion of E1A-1B-2 was the common mutation, and patients with this deletion were referred to us from four different geographical regions in Turkey. Therefore, it was hypothesized that this deletion covering E1-2 is common in Turkey. CONCLUSION: LGRs in BRCA1 were strongly associated with positive family history among the Turkish population. On the basis of these findings, it can be recommended that a low-cost screening for LGRs in BRCA1 may be the first-line mutation detection method in families with strong breast/ovarian cancer history in Turkey.

The role of telomerase activity in predicting early recurrence of epithelial ovarian cancer after first-line chemotherapy: a prospective clinical study.

PURPOSE OF INVESTIGATION: To investigate the value of telomerase activity (TA) in the detection of early recurrence in primary epithelial ovarian cancer (EOC). METHOD(S): In this study, TA was studied in 30 patients with Stage III EOC and 50 control patients with benign gynecological disease. All enrolled EOC patients had had primary cytoreductive surgery and six cycles of platinum-based first-line chemotherapy previously. Semi-quantative TA measurements were done by TRAP assay in ascites, taken at second-look surgery, of cancer patients and in peritoneal washings, taken during planned surgery, of the control group. RESULT(S): Early recurrence was diagnosed in ten EOC patients (33.3%). Mean TA was statistically higher in EOC patients than in patients with benign disease. However, the mean TA was insignificantly lower in early recurrent EOC patients than in disease-free EOC patients. CONCLUSION(S): The value of TA is limited in the detection of early recurrence in primary EOC.

The role of p53, Bcl-2 and Ki-67 in premalignant cervical lesions and cervical cancer.

PURPOSE: The aim of this study was to determine the role of p53, Bcl-2 and Ki-67 expression in the carcinogenesis of cervical carcinoma and aggressiveness of cervical intraepithelial neoplasia (CIN). METHODS: The pathology specimens of 63 patients with a diagnosis of normal squamous epithelium (22 cases), CIN I (14), CIN II (5), CIN III (8) and squamous cell carcinoma (14) were evaluated immunohistochemically for the expression of p53, Bcl-2 and Ki-67 in paraffin sections. RESULTS: The expression of p53 and Ki-67 increased proportionally to the grade of CIN and cervical cancer, but only the increase of p53 expression was statistically significant (p = 0.002). There was no significant correlation between Bcl-2 expression and premalignant and malignant cervical lesions. CONCLUSION: p53 expression may have a role in the carcinogenesis of squamous cell cervical carcinoma whereas Bcl-2 expression has no role. Ki-67 expression can not be used in determining the aggressiveness of CIN lesions.

Prognostic significance of tumor angiogenesis in epithelial ovarian cancer: in association with transforming growth factor beta and vascular endothelial growth factor.

We aimed to evaluate the prognostic significance of microvessel density (MVD), vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGFbeta), as well as to find out the relationship between MVD, and VEGF and TGFbeta in epithelial ovarian cancer (EOC). Surgical specimens of 47 patients with stage I-IV primary EOC, who underwent extended surgical staging according to FIGO, were investigated. Five- micro m thick tissue sections were immunostained with antibody to factor VIII-related antigen, and MVD was assessed at three separate areas of x200 magnification. Expressions for VEGF and TGFbeta were evaluated by immunohistochemical staining using related monoclonal antibodies. Results were correlated with clinicopathologic factors and survival. We did not find any correlation between MVD and clinicopathologic factors, or patient survival. Similarly, there was no association between the degree of VEGF staining and survival or clinicopathologic factors, except preoperative ascites volume, which was higher in patients showing moderate and intense VEGF staining than those with weak VEGF staining (P = 0.052). The expression of TGFbeta was inversely correlated with preoperative CA-125 levels (P < 0.05). Furthermore, there was no correlation between MVD and the staining intensity of VEGF or TGFbeta. In conclusion, angiogenesis does not appear as a prognostic factor in EOC. We suggest that VEGF is an important mediator of ascites formation, and that TGFbeta, which is supposed to have tissue-specific actions in tumorigenesis, may have growth-inhibitory functions in EOC.

Primary carcinoma of the fallopian tube in a 88 years old woman: review of the literature.

A woman of 88 years old with primary carcinoma of the fallopian tube, the oldest patient reported in the English literature according to the best of our knowledge, was presented. After debulking surgery four courses of chemotherapy including paclitaxel and carboplatin was performed. The patient was free of disease during two years follow-up.

Choriocarcinoma metastasis in the thyroid gland.

We report a 34-year-old woman with intrathyroid metastasis of choriocarcinoma associated with pulmonary and brain metastasis. The patient presented with a solitary thyroid nodule. Needle biopsy showed anaplastic malignant cells. Pathologic evaluation after thyroidectomy showed choriocarcinoma in the thyroid gland and the patient subsequently underwent combined chemotherapy and radiotherapy with satisfactory response. This is only the third reported case of metastatic choriocarcinoma in the thyroid gland and emphasizes this rare clinical presentation of choriocarcinoma.