Human papillomavirus prevalence in pregnant women living with human immunodeficiency virus infection: a scoping review of the literature.

OBJECTIVES: Studies already pointed out the increased risk of human papillomavirus (HPV) positivity and the implied risk of cervical dysplasia and even cervical carcinoma in pregnant women with human immunodeficiency virus (HIV) infection. Nevertheless, due to less data there is still no standardised and expanded screening for this high-risk group. CONTENT: Two online databases (PubMed, EMBASE) were used to identify eligible studies. Results are shown in percentages. Wherever useful the arithmetic mean was calculated. SUMMARY: Seven studies were included. Pregnant WLWH showed HPV prevalence between 34 and 98.4 %. Different sensitivity and specificity among PCR methods for HPV detection could be a reason for the large range concerning HPV prevalence. Risk factors like Age, Smoking, Sexuality, HIV status and education level should always be taken into account. Association between HPV prevalence and level of CD4 cells or HIV virus load was seen. In which way use of Antiretroviral Therapy (ART) could decries the risk for HPV infections is still discussed. When cytology was performed only few high-grade squamous intraepithelial lesion (HSIL) were found. OUTLOOK: Standardisation and expansion of preventive screening for cervical dysplasia and carcinoma for pregnant WLWH is necessary. Then better comparability of the data will also be achieved.

Prenatal ultrasound screening and pregnancy outcomes in HIV-positive women in Germany: results from a retrospective single-center study at the Charité-Universitätsmedizin Berlin.

OBJECTIVES: The aim of this study was to investigate the rate of Mother-to-child-transmission (MTCT) in women living with HIV (WLWH) in a tertiary care institution. Furthermore, we aimed to assess prenatal ultrasound screening for fetal anomalies and outcomes in high-risk pregnancies due to maternal HIV infection." METHODS: In this single-center study, retrospective data related to pregnancy and childbirth were collected from 420 WLWH. All data were evaluated descriptively. RESULTS: From January 2014 to December 2020, a total number of 420 pregnant WLWH delivered 428 newborns. 415 (98.8%) were receiving antiretroviral therapy (ART) and 88.8% had a viral load of < 50 cop/ml prior delivery. 46 (11%) of the newborns were born prematurely. Low birth weight < 2500 g occurred in 38 (9.1%) of the children. 219 (52.1%) caesarean sections (CS) were performed. The most frequent indication for an elective CS was a previous CS (70.2%). 8 severe malformations were detected using first and second trimester ultrasound. In one child, MTCT was detected postpartum, resulting in an HIV transmission rate of 0.2% in the presented cohort. CONCLUSIONS: The low rate of vertical HIV-transmission in our cohort of 0.2% is the result of interdisciplinary prenatal care and high experience of healthcare providers in treatment of WLWH. Despite high ART coverage and adherence, good maternal immune system and very low vertical HIV transmission rate, maternal HIV infection remains a challenge in obstetric care. First and second ultrasound screening should be a part of prenatal care for HIV-infected women and should also be offered to HIV-negative women. A reduction of the rate of unnecessary elective caesarean deliveries in WLWH is necessary to reduce complications in subsequent pregnancies.

Assessment of high-risk human papillomavirus infections and associated cervical dysplasia in HIV-positive pregnant women in Germany: a prospective cross-sectional two-centre study.

PURPOSE: Invasive cervical cancer (ICC) is associated in nearly 100% with persistent high-risk Human Papillomavirus (HR-HPV) infection. ICC is still one of the leading causes for cancer mortality in women worldwide. The immunosuppressive influence of Human Immunodeficiency Virus (HIV) and the immunocompromised period of pregnancy due to tolerance induction against the hemiallogeneic fetus, are generally risk factors for acquisition and persistence of HR-HPV infections and their progression to precancerous lesions and HPV-associated carcinoma. METHODS: Overall, 81 pregnant women living with HIV (WLWH) were included. A medical history questionnaire was used to record clinical and HIV data. Participants received cervicovaginal cytological smear, colposcopy and HPV testing. HPV test was performed using BSGP5+/6+ PCR with Luminex read-out. The HR-HPV genotypes 16, 18, 31, 33, 45, 52, 58 were additionally grouped together as high-high-risk HPV (HHR-HPV) for the purpose of risk-adapted analysis. RESULTS: HR-HPV prevalence was 45.7%. Multiple HPV infections were detected in 27.2% of participants, of whom all had at least one HR-HPV genotype included. HR-HPV16 and HR-HPV52 were the most prevalent genotypes and found when high squamous intraepithelial lesion (HSIL) was detected by cytology. HIV viral load of ≥ 50 copies/ml was associated with higher prevalence of HR-HPV infections. Whereas, CD4 T cells < 350/µl showed association with occurrence of multiple HPV infections. Time since HIV diagnosis seemed to impact HPV prevalence. CONCLUSION: Pregnant WLWH require particularly attentive and extended HPV-, colposcopical- and cytological screening, whereby clinical and HIV-related risk factors should be taken into account.

Genotype-specific high-risk human papillomavirus infections and risk factors for cervical dysplasia in women with human immunodeficiency virus in Germany: results from a single-center cross-sectional study.

OBJECTIVE: Women living with HIV have an increased risk of human papillomavirus (HPV) infection and cervical cancer. Little is known about genotype-specific HPV prevalence, the impact of antiretroviral therapy, immunological status, and additional risk factors in women living with HIV in Germany. The goal of this study was to characterize the risk profile for cervical dysplasia in these women. METHODS: Patients with HIV infection presenting at Charité-Universitätsmedizin Berlin from October 2017 to September 2020 were included and underwent gynecological examination, colposcopy, cervical cytology and HPV genotype testing. HPV genotypes were stratified by carcinogenicity. Atypical squamous cells of undetermined significance or higher were considered abnormal cytology. Data were analyzed by SPSS software (version 26, 2019). A two-tailed p-value ≤0.05 was considered statistically significant. RESULTS: A total of 84 women were evaluated. The majority (95.2%) received antiretroviral therapy. Median CD4 cell count was 564 cells/µl (range 20-1969). 95.2% were previously screened for cervical cancer. High-risk HPV prevalence was 44%. High-high-risk HPV subtypes (16, 18, 31, 33, 45, 52, 58) were significantly associated with abnormal cytology (p<0.001). HPV16 was the most common genotype (23%), was significantly associated with abnormal cytology (p=0.002) and was the main risk factor for abnormal cytology (OR 8.55, 95% CI 2.15 to 34.13, p=0.002), followed by age <35 years (OR 4.96, 95% CI 1.23 to 19.61, p=0.033) and cigarette smoking (OR 3.944, 95% CI 0.98 to 15.88, p=0.053). CONCLUSIONS: Antiretroviral therapy and adherence to cervical cancer screening was high. High-high-risk HPV, especially HPV16, coincided with high incidence of cytological abnormalities. Women living with HIV in Germany have adequate immune status and are often pre-screened for cervical cancer, and therefore have a different risk profile for cervical dysplasia than in low-income or medium-income countries. Adapted screening programs should be defined.

Expectations and preferences of patients with primary and relapsed ovarian cancer to maintenance therapy: A NOGGO/ENGOT-ov22 and GCIG survey (Expression IV).

BACKGROUND: Maintenance therapy induces remission and prolongs disease free interval in primary and recurrent ovarian disease. For the treatment decision making process, aspects of quality of life and patients' preferences are crucial, despite the fact that scientific data are lacking. Therefore, we conducted this European-wide study in patients with ovarian cancer. METHODS: A 25 item questionnaire was provided to ovarian cancer patients via the internet or as a paper version in 10 European countries (Austria, Belgium, France, Germany, Italy, Romania, Slovenia, Finland, Turkey, and Spain). Data recorded were demographics, tumor stage, therapy after firstline and recurrent disease, preferences for administration, and expectations concerning maintenance therapy. RESULTS: Overall, 1954 patients participated from September 2013 to March 2016; 42% had recurrent disease. Most patients (98%) with primary epithelial ovarian cancer underwent surgery followed by chemotherapy (91%). Almost one-third of participants (29%) were receiving maintenance therapy whereas 45% had only heard of it. For 70% of patients with primary epithelial ovarian cancer, they heard about maintenance therapy from their doctor, 10% heard about maintenance therapy from other patients, and 8% from the internet. The main source of information about maintenance therapy in patients with epithelial ovarian cancer relapse was from the treating physician (72%), from other patients (8%), and from the internet (7%). For patients undergoing maintenance therapy, the four most disturbing adverse effects were polyneuropathy (37%), nausea (36%), hair loss (34%), and vomiting (34%). The main objective of maintenance treatment, as perceived by patients, was to increase the chances of cure (73%), improvement in quality of life (47%), and delay in tumor growth (37%). Many patients were willing to undergo maintenance therapy until tumor progression (38%) and 39% would prefer oral administration. No significant differences were detected in the cross country subanalysis regarding expectations of maintenance therapy and patients with primary or relapsed ovarian cancer. CONCLUSION: Patients with ovarian cancer were willing to accept maintenance therapy of prolonged duration and preferred oral administration. There is still a gap between the efficacy of maintenance therapy and patient expectations. Patients need more information on the adverse effects and treatment goals of maintenance therapy to avoid misunderstandings.

Y-box protein-1/p18 as novel serum marker for ovarian cancer diagnosis: A study by the Tumor Bank Ovarian Cancer (TOC).

INTRODUCTION: The cold shock Y-box binding protein-1 (YB-1) fulfills important roles in regulating cell proliferation and differentiation. Overexpression occurs in various tumor cells. Given the existence of extracellular YB-1 we set out to determine the diagnostic, predictive and prognostic role of serum YB-1/p18 for patients with primary epithelial ovarian cancer (EOC). METHODS: The protein fragment YB-1/p18 was quantified by sandwich ELISA in serum samples from 132 healthy female volunteers and 206 patients with histological diagnosis of primary EOC. The ELISA sensitivity and specificity to detect EOC were calculated using receiver operating curves. Survival data were calculated using Kaplan Maier curves. RESULTS: Median age at the time of diagnosis was 60years and follow-up ended with a mean of 44.8month. 188 (91%) patients were diagnosed at advanced stages (FIGO III/IV) and 188 patients (91%) suffered from high-grade serous ovarian carcinoma. YB-1/p18 levels were significantly decreased in older patients (p=0.021). Significantly lower serum levels of YB-1/p18 were detected in the EOC cohort when compared to the control group (p<0.0001, AUC=0.827; 95% CI, 0.787-0.867). Using the expression of serum YB-1/p18 in early stages I and II cases these could be differentiated from control cases (p<0.0001, AUC=0.816; 95% CI 0.704-0.929). No other significant associations between clinical prognostic factors and YB-1/p18 serum levels were detected. Immunoblotting results with serum samples suggest that masking of epitopes by the YB-1/p18 fragment in multiprotein-complexes under non reducing conditions leads to the observed reduced ELISA readings in the EOC cohort. CONCLUSIONS: The quantification of fragment YB-1/p18 derived from cold shock protein YB-1 in serum samples could be useful for the early diagnosis of EOC.

The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study.

Patients with epithelial ovarian cancer (EOC) are at high risk of tumor recurrence. Human epididymis protein 4 (HE4) has been shown to be overexpressed in EOC. The primary aim of our study was to evaluate the role of HE4 in predicting recurrence in EOC patients. Furthermore, we assessed the role of HE4 in predicting recurrence after second-line chemotherapy. We retrospectively analyzed data of 92 out of 275 primary EOC patients of the multicenter project "Ovarian Cancer: Diagnosis of a silent killer" (OVCAD). The concentrations of HE4 and CA125 were determined preoperatively and 6 months after the end of platinum-based first-line chemotherapy (FU) using ELISA and Luminex technique, respectively. The role of HE4 and CA125 for prediction of recurrence was determined using receiver operating characteristics (ROC) curves. Out of 92 patients included, 70 (76 %) were responders and 22 (23 %) non-responders in terms of response to platinum-based first-line chemotherapy. Median HE4 concentrations at follow-up (FU) differed between responders and non-responders (60.5 vs. 237.25 pM, p = 0.0001), respectively. The combined use of HE4 and CA125 at FU with cut-off values of 49.5 pM and 25 U/ml for HE4 and CA125, respectively, for predicting recurrence within 12 months after first-line chemotherapy performed better than HE4 or CA125 alone (area under the curve (AUC) 0.928, 95 % confidence intervals (CI) 0.838-1, p < 0.001). HE4 at FU could predict recurrence within 6 months after second-line chemotherapy (AUC 0.719, 95 % CI 0.553-0.885, p = 0.024). The combination of both elevated biomarkers revealed significantly worse estimated median progression-free survival (PFS; hazard ratio (HR) 8.14, 95 % CI 3.75-17.68, p < 0.001) and slightly worse PFS in those in whom only one biomarker was elevated (HR 1.46, 95 % CI 0.72-2.96, p = 0.292) compared to those patients in whom no biomarker was elevated. For the estimated median overall survival (OS), our analysis revealed similar results. HE4 in combination with CA125 performed better than CA125 and HE4 alone in predicting recurrence within 12 months after first-line chemotherapy.

Peritoneal and upper genital tract tuberculosis.

Aim To present diagnostic and therapeutic possibilities for genital and peritoneal tuberculosis, mimicking to other pathological conditions, mainly, ovarian cancer. Methods Transabdominal and transvaginal ultrasound, computerized tomography, Ca125 and HE 4, ROMA- index (Risk of Ovarian Maligancy Algorithm index) and diagnostic laparoscopy were performed in order to diagnose genital tuberculosis in a female patient. Results: A 23-year-old woman from Morocco presented with intermitting abdominal pain, unintentional weight loss and primary infertility. There was no positive family history for breast or ovarian cancer and no history of previous tuberculosis (TB). Elevated CA-125 level, HE 4 normal, ROMA-Index of 13.2 % suggested high risk for epithelial ovarian cancer (EOC). Ultrasound revealed free fluid, dilated fallopian tubes and a cystic mass near the right ovary. Suspecting fallopian tube or ovarian cancer, we performed exploratory laparoscopy, revealing adhesions, multiple miliary nodes and dilated fallopian tubes. Histological investigation revealed granulomatous abscessing salpingitis with suspicion of genital TB, so antituberculous therapy was administered with success. Conclusion Female genital tuberculosis is very rare but important in differential diagnosis and should be kept in mind regarding suspected fallopian tube or ovarian carcinoma to prevent women from extensive surgery. An algorithm for possible differentiation between peritoneal/female genital TB and EOC may be helpful in clinical setting.

Role of IGF-I in Primary Ovarian Cancer - A Study of the OVCAD European Consortium.

BACKGROUND/AIM: IGF-I (insulin growth factor 1) is crucially involved in cellular proliferation. Moreover, deregulation of IGF-I has been shown to be relevant in the carcinogenesis of various tumor entities. However, the impact of IGF-I in epithelial ovarian cancer (EOC) is unclear. In the present study, we investigated the predictive and prognostic role of circulatory IGF-I in primary EOC patients. PATIENTS AND METHODS: In the FP6 European Project "OVCAD", 275 consecutive primary EOC patients were enrolled. Patients were eligible if radical cytoreductive surgery and platinum-based chemotherapy were performed. Plasma IGF-I was detected using ELISA. RESULTS: Increased plasma IGF-I levels were more frequently found in well-differentiated epithelial ovarian carcinoma (p=0.0047). A weak correlation was observed between IGF-I levels and CA-125 in patients with serous EOC (p=0.04). No association between IGF-I expression and other clinico-pathological parameters was observed. CONCLUSION: IGF-I is overexpressed in patients with well-differentiated EOC. Further studies are warranted to elucidate the role of IGF-I in this sub-group of patients.

Imaging of placental transport mechanisms: a review.

Functional analysis of material transfers requires precise statement of residence times in each tissue compartment. For the placenta, neither extractive biochemistry, isotope partitioning, nor mass-based quantitative assays provide adequate spatial resolution to allow the necessary precision. Dual-perfusion assays of material transfer in isolated placental cotyledons provide time-series data for two compartments, the maternal and fetal blood, but fail to distinguish the two cellular compartments (syncytiotrophoblast, fetal endothelium) which actively regulate rates of transfer in each direction for essentially every important molecule type. At present, no definitive technology exists for functional analysis of placental transfer functions. The challenge in developing such a technology lies in the exquisitely small and delicate structures involved, which are scaled at cellular and subcellular sizes (between 50 nm and 50 microm). The only available technologies attaining this high spatial resolution are imaging technologies, primarily light and electron microscopy. To achieve the high-quality images necessary, confocal laser scanning microscopy (CLSM) is required, to provide a uniform optical sectioning plane. In turn, this requires relatively high fluorescence intensities. Design of an adequate technology therefore bases on CLSM imaging fluorochrome-tagged tracers. The temporal resolution necessary to analyse placental material transfers is expected to be of the order of a few seconds, so that conventional wet-fixation protocols are too slow. For adequately rapid fixation, snap-freezing is required. As part of this review we report results obtained from an appropriately designed experimental protocol, analysed by CLSM and transmission electron microscopy (TEM). The images acquired were tested for uniformity of illumination and fluorescence emission strength. Relevant data was encoded in the green channel of the trichrome images obtained, and this was thresholded by application of strict quantitative criteria. The thresholding procedure is suitable for automation and produces reproducible, objectifiable results. Thresholded images were subjected to image calculation procedures designed to highlight image elements (pixels) containing (green) fluorescence associated with the tracer protein; all other sources of fluorescence were visualised in the final images only if no green fluorescence was detectable in that pixel. The resulting images were maps, showing the distribution of tracer molecules at a predefined time interval after perfusion of the tracer into the vital (term) cotyledon. Spatial resolution was routinely better than 1 microm and temporal resolution was approximately 5s. At timepoints up to 10 min after intravital application into the fetal vascular circulation, tracer was associated with capillaries in the villous structures, and no tracer was observed in the syncytiotrophoblast. Clear distinction was achieved between the four tissue compartments relevant to placental transfers, thus providing a novel technology capable of generating high-quality data concerning the regulation of transfers of any molecule that can bear a fluorescent tag. The potential applications of this methodology lie in analyses of factors influencing the rates of fetomaternal and maternofetal exchanges (for example, drugs), and of functional responses of the placental regulation to pathophysiological conditions such as hypoxia.