Upscaling cervical cancer screening and treatment for women living with HIV at a rural referral hospital in Tanzania: protocol of a before-and-after study exploring HPV testing and novel diagnostics.

BACKGROUND: Cervical cancer (CC) is nearly always caused by persistent human papillomavirus (HPV) infection. It is the most common cancer among women living with HIV (WLWH) and is the leading cause of cancer-related death in women in East Africa, with 10,241 new cases reported in Tanzania in 2020. In 2019, the World Health Organization (WHO) presented a global strategy for the elimination of CC as a public health problem, proposing targets to meet by 2030 for HPV vaccine coverage (90% of all 15-year-old girls), CC screening (70% of all women once at 35 and again at 45 years of age) and treatment delivery, to be scaled at national and subnational levels with a context-sensitive approach. This study aims to evaluate the upscaling of screening and treatment services at a rural referral hospital in Tanzania in order to address the second and third WHO targets. METHODS: This is an implementation study with a before-and-after design performed at St. Francis Referral Hospital (SFRH) in Ifakara (south-central Tanzania). CC screening and treatment services are integrated within the local HIV Care and Treatment Center (CTC). The standard of care, consisting of visualization of the cervix with acetic acid (VIA) and cryotherapy has been up-scaled with self-sampled HPV testing and also involved the introduction of mobile colposcopy, thermal ablation and loop electrosurgical excision procedure (LEEP). Participants are WLWH aged 18 to 65 years. Outcome measures included the percentage of women screened, HPV prevalence and genotype, and adherence to screening, treatment and follow-up plan. Additionally, we will explore the performance of novel diagnostic tests (QG-MPH®, Prevo-Check® and PT Monitor®), which share the features of being manageable and inexpensive, and thus a potential tool for effective triage in HPV high-prevalence cohorts. DISCUSSION: The study will provide relevant information about HPV prevalence and persistence, as well as reproductive and lifestyle indicators in a CC high-risk cohort of WLWH and about upscaling screening and treatment services at the level of a rural referral hospital in Tanzania. Furthermore, it will provide exploratory data on novel assays. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05256862, date of registration 25/02/2022. Retrospectively registered.

Group B streptococcal colonization in elderly women.

BACKGROUND: In non-pregnant adults, the incidence of invasive Group B Streptococcus (GBS) disease is continuously increasing. Elderly and immunocompromised persons are at increased risk of infection. GBS commonly colonizes the vaginal tract, though data on colonization in the elderly are scarce. It is unknown whether the prevalence of GBS colonization is increasing in parallel to the observed rise of invasive infection. We conducted a three-year (2017-2019) prospective observational cross-sectional study in two teaching hospitals in Switzerland to determine the rate of GBS vaginal colonization in women over 60 years and i) to compare the proportions of known risk factors associated with invasive GBS diseases in colonized versus non-colonized women and ii) to evaluate the presence of GBS clusters with specific phenotypic and genotypic patterns in this population. METHODS: GBS screening was performed by using vaginal swabs collected during routine examination from women willing to participate in the study and to complete a questionnaire for risk factors. Isolates were characterized for antibiotic resistance profile, serotype and sequence type (ST). RESULTS: The GBS positivity rate in the elderly was 17% (44/255 positive samples), and similar to the one previously reported in pregnant women (around 20%). We could not find any association between participants' characteristics, previously published risk factors and GBS colonization. All strains were susceptible to penicillin, 22% (8/36) were not susceptible to erythromycin, 14% (5/36) were not susceptible to clindamycin and 8% (3/36) showed inducible clindamycin resistance. Both M and L phenotypes were each detected in one isolate. The most prevalent serotypes were III (33%, 12/36) and V (31%, 11/36). ST1 and ST19 accounted for 11% of isolates each (4/36); ST175 for 8% (3/36); and ST23, ST249 and ST297 for 6% each (2/36). Significantly higher rates of resistance to macrolides and clindamycin were associated with the ST1 genetic background of ST1. CONCLUSIONS: Our findings indicate a similar colonization rate for pregnant and elderly women. TRIAL REGISTRATION: Current Controlled Trial ISRCTN15468519 ; 06/01/2017.

High-grade serous peritoneal cancer follows a high stromal response signature and shows worse outcome than ovarian cancer.

In the era of personalized medicine, where transition from organ-based to individualized genetic diagnosis takes place, the tailoring of treatment in cancer becomes increasingly important. This is particularly true for high-grade, advanced FIGO stage serous adenocarcinomas of the ovary (OC), fallopian tube (TC), and peritoneum (PC), which are currently all treated identically. We analyzed three independent patient cohorts using histopathologically classified diagnosis and various molecular approaches (transcriptomics, immunohistochemistry, next-generation sequencing, fluorescent and chromogenic in situ hybridization). Using multivariate Cox regression model, we found that PC is more aggressive compared with advanced-stage OC independent of residual disease as shown by an earlier relapse-free survival in two large cohorts (HR: 2.63, CI: 1.59-4.37, P < 0.001, and HR: 1.66, CI: 1.04-2.63, P < 0.033). In line with these findings, transcriptomic data revealed differentially expressed gene signatures identifying PC as high stromal response tumors. The third independent cohort (n = 4054) showed a distinction between these cancer types for markers suggested to be predictive for chemotherapy drug response. Our findings add additional evidence that ovarian and peritoneal cancers are epidemiologically and molecularly distinct diseases. Moreover, our data also suggest consideration of the tumor-sampling site for future diagnosis and treatment decisions.

Assessing the epidemiological impact on cervical cancer of switching from 4-valent to 9-valent HPV vaccine within a gender-neutral vaccination programme in Switzerland.

BACKGROUND: An infection with high-risk human papillomavirus (HPV) is the obligatory aetiological factor for the development of cervical cancer. In Switzerland, the prevention strategy for cervical cancer is based on primary prevention via HPV vaccination and secondary prevention with an opportunistic screening programme for precancerous lesions. Vaccination is recommended to 11-26 years old male and female persons. The objective of the study was to assess the epidemiological impact on cervical cancer of switching from the currently implemented programme with the 4-valent vaccine to the 9-valent vaccine, in an 11-26 years old gender-neutral vaccination programme in Switzerland. METHODS: A previously validated dynamic transmission model of HPV infections was adapted and calibrated to the Swiss setting assuming an 80% coverage rate in HPV-vaccination and lifelong vaccine type-specific protection. A gender-neutral vaccination programme (males and females) for 11-26 years old with a 9-valent HPV vaccine was compared with the current 11-26 years old gender-neutral 4-valent vaccination programme. Sensitivity analyses were conducted in order to test the impact of lower vaccination coverage rates and a shorter duration of protection on the model outcomes. RESULTS: In Switzerland, a 9-valent gender-neutral vaccination programme would result in an additional prevention of 2979 cervical cancer cases, 13,862 CIN3 and 15,000 CIN2 cases, compared with the 4-valent gender-neutral vaccination programme over 100 years. These additional disease cases avoided would correspond to a 24, 36 and 48% cumulative incidence decrease in cervical cancer, CIN3 and CIN2 cases, respectively. It would also prevent additional 741 cervical cancer-related deaths over 100 years. A substantial additional reduction in cervical cancer and precancerous lesions burden is still observed when varying the vaccination coverage rate from 30 to 60% or reducing the duration of protection from lifelong to 20 years. CONCLUSIONS: The switch to the 9-valent vaccine in Switzerland to prevent cervical diseases showed an important contribution in terms of public health impact compared with the 4-valent vaccine in an 11-26 years old gender-neutral population, even with very conservative assumptions such as low coverage rates or low duration of protection and limiting analysis to only cervical disease.

Sexually transmitted coinfections in patients with anogenital warts - a retrospective analysis of 196 patients.

BACKGROUND AND OBJECTIVES: Anogenital warts (AGWs) are most commonly caused by low-risk human papillomavirus (HPV) types, and although they are the most frequent viral sexually transmitted infections (STIs), little is known about STI coinfections in affected patients. We therefore sought to assess STI coinfection rates in patients with AGW, specify STI coinfections and calculate the number needed to screen (NNS) for each STI. METHODS: A retrospective cross-sectional study analyzing data sets from AGW patients treated in our clinic between 2008-2016. RESULTS: 142/196 (72 %) patients had been variably screened for infections with HIV, HBV and HCV, Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium and HSV. The STI coinfection rate in all tested patients was 24.6 %, yielding an NNS of 4.1 to detect any STI. Of note, the coinfection rate did not differ significantly between heterosexual men, homosexual men and women, respectively. The NNS for syphilis was 8.4, for HIV 14.0, for HCV 28.5 and for HBV 39.0. The NNS for asymptomatic patients tested for HSV, Chlamydia trachomatis and Mycoplasma genitalium were 1.4, 5.3 and 12.0, respectively. CONCLUSION: Due to the high prevalence of STI coinfections, AGW patients should be screened for other STIs.

Should MMMT still be treated with adjuvant taxane-based combination chemotherapy?

BACKGROUND: Malignant mixed Mullerian tumors of endometrial (MMMT-E) and ovarian (MMMT-O) origin are associated with poor prognosis. Suggestively epithelial-driven tumors, their treatment has shifted from anthracycline or ifosfamide-based towards taxane-based chemotherapy. It remains unclear whether this change associates with better outcomes. PATIENTS AND METHODS: A conjoined Australian and Swiss patient cohort of MMMT-E (N = 103) and MMMT-O (N = 17) was compared to patients with adenocarcinoma of the endometrium (EC, N = 172) and ovary (OC, N = 189). Clinicopathological characteristics, FIGO stage, first-line treatment, and patient outcomes were analyzed. The generated hypothesis was verified in an US-American cohort with high-grade serous ovarian cancer (HGSOC, N = 1290) and MMMT-O (N = 450) using immunohistochemistry and next-generation sequencing. RESULTS: Early stage I/II MMMT-E showed a survival plateau after 2.5 years, with no recurrence or death observed afterwards. Relapse-free survival was significantly worse in MMMT-E treated with platinum/taxanes (P = 0.024) compared to non-taxane regimen. Hypothesizing that also MMMT-O might benefit from an adjuvant non-paclitaxel regimen, a second independent cohort of MMMT-O and HGSOC patients was examined. p53 mutations dominated in both cancers with comparable frequency. PI3KCA and KRAS mutations were less frequent: they were more frequent in MMMT-O than in HGSOC (P = 0.015 and P = 0.018, respectively). MMMT-O responded better to a combination of carboplatin with anthracyclines than with taxanes (73.9% vs. 39.4%). CONCLUSION: Early stage I/II MMMT-E patients have excellent prognosis if no recurrence has appeared within the first 2.5 years. In MMMT-E, platinum/anthracycline or ifosfamide regimen associated with better outcomes than platinum/taxanes regimens. This might also apply to MMMT-O.

Ovarian cancer in Switzerland: incidence and treatment according to hospital registry data.

OBJECTIVE: The methods used to diagnose and classify ovarian cancer have changed over the past decade. We used hospital registry data to assess the incidence, treatment durations and hospital costs of ovarian cancer in Switzerland. METHODS: We carried out a retrospective analysis of a hospital registry covering all inpatient care episodes in Switzerland between 1998 and 2012. Ovarian cancer incidence was assessed by identifying patients with a first ovarian cancer diagnosis as the main reason for hospital stay after an event-free period. We assessed the duration and cost of ovarian cancer treatment sequences as well as the evolution of hospital patient volume over time. RESULTS: The average age-adjusted incidence rate was 14.6 per 100,000 women per year between 2004 and 2012. This rate is substantially higher (+35.5%) than the corresponding rate published by the National Institute for Cancer Epidemiology and Registration (NICER). Hospital patient volume was low in most cases, with more than 40% of patients treated in hospitals with fewer than 20 cases per year. However, the share of patients treated in hospitals with more than 30 cases per year has increased substantially since 2009. CONCLUSIONS: We found a substantial difference between the ovarian cancer incidence estimate based on hospital registry data and the corresponding estimate by NICER. The reasons for this substantial difference should be carefully explored. A case-wise comparison could determine whether the difference is due to over- or under-reporting in one of the two registries. The low ovarian cancer patient volume in many hospitals is in conflict with the numbers required for certified specialised cancer centres. The recent increase in patient volume in specialised cancer centres, however, might reflect a growing understanding of the needs and requirements of comprehensive cancer care.

Human Papillomavirus (HPV) Detection in Cytologic Specimens: Similarities and Differences of Available Methodology.

Accumulating evidence regarding the causative role of human papillomavirus (HPV) in a wide range of malignant and nonmalignant diseases highlights the importance of HPV testing. This study describes and discusses the efficacy and characteristics of 4 well-established and commercially available tests. Here, 181 cytologic specimens from cervical smears were analyzed using the HPV SIGN PQ (Diatech) and the Linear Array (Roche) method. Discrepant results were further studied with the Real Time High-Risk HPV (Abbott) method and the INNO-LiPA (Fujirebio) method. Of 181 cytologic specimens, 61 (34%) showed discrepant results. High-risk HPV was not detected in 9 cases by HPV SIGN PQ, in 16 cases by Linear Array, in 10 cases by Real Time High-Risk HPV, and in 6 cases by INNO-LiPA, respectively. Lack of DNA detection or problems in interpreting the result were seen in 9 cases with HPV SIGN PQ, 8 cases with Linear Array, 3 cases with Real Time High-Risk HPV, and 3 cases with INNO-LiPA, respectively. This study indicates that the choice of HPV detection method has a substantial influence on the HPV risk classification of tested PAP smears and clinical follow-up decisions.

Intrapartum detection of Group B streptococci colonization by rapid PCR-test on labor ward.

OBJECTIVE: Group B streptococci (GBS) may lead to early onset neonatal sepsis with severe morbidity and mortality of newborns. Intrapartum detection of GBS is needed. The objective was to compare a PCR-based test performed in the laboratory versus labor ward. STUDY DESIGN: 300 patients were included prospectively. In phase I, swabs were analyzed by selective culture and rapid PCR in the laboratory. In phase II, swabs were analyzed accordingly, but the PCR test was conducted in labor ward. Test performances were analyzed and compared. RESULTS: In phase I the rapid PCR test had a sensitivity of 85.71% and a specificity of 95.9%. The GBS colonization rate was 18.67%. Overall 8.5% of the PCR results were invalid. In phase II the PCR test showed a sensitivity of 85.71% and a specificity of 95.65%. The GBS colonization rate was 23.3%. Overall 23.5% of swabs tested with PCR were invalid. Initiation of specific, short 2-hour training for operating personnel in the labor ward reduced the invalid test rate to 13.4%. CONCLUSION: The rapid PCR-based test yields adequate results to identify GBS colonization when performed in labor ward. In order to reduce the number of invalid tests a short training period is needed.

Management of human papillomavirus-related gynecological malignancies.

Human papillomavirus (HPV) infections affect women in every age group and in various benign, premalignant as well as malignant gynecological conditions. As a benign condition, condylomata acuminata of the whole female genital tract can be observed, transmitted by low risk HPV types 6 and 11, whilst dysplastic changes of the vulva appear as vulvar intraepithelial neoplasia, of the vagina as vaginal intraepithelial neoplasia and of the cervix as cervical intraepithelial neoplasia, and are caused by high risk HPV types most notably 16 and 18. These dysplastic changes give rise to precursor lesions of vulvar and cervical cancer, both driven via immune regression and potentially hormonal changes by promoting the malignant transformation profile of HPV subtypes. Attributes which can support this process are smoking, immunodeficiency, vitamin deficiency, stress, vaginal infections and hormonal influence. The causal relationship between persistent infection with high-risk HPV genotypes and vulvar and cervical cancer has been clearly demonstrated and is stronger than the relationship observed between smoking and lung cancer. New global cancer prevention can be envisaged by implementing vaccination against HPV in young women, with 2 vaccines currently approved by the Food and Drug Administration: the quadrivalent Gardasil (HPV-6, -11, -16, -18) and the bivalent Cervarix (HPV-16, -18).