Phase 1b study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis.

BACKGROUND: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity. METHODS: In this phase 1b study, registered at Clinical. TRIALS: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). FINDINGS: The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n = 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8 months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7 months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients. CONCLUSIONS: i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3 mg/kg i.p. nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks. FUNDING: This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642).

An Update on Prenatal Diethylstilbestrol Exposure and High-Grade Squamous Intraepithelial Lesions of the Lower Genital Tract.

Women with prenatal diethylstilbestrol exposure are excluded from less frequent cervical cancer screening because of their increased neoplasia risk. We report the results of a prospective follow-up study of prenatal diethylstilbestrol exposure and lower genital tract high-grade (grade 2 or higher) squamous intraepithelial lesions (HSIL). The age-adjusted risk of HSIL among diethylstilbestrol-exposed women (n=4,062) was higher than among the diethylstilbestrol unexposed (n=1,837) through age 44 years (hazard ratio 2.03, 95% CI, 1.31-3.14) but not age 45 years or older. Elevated HSIL risk remained higher in diethylstilbestrol-exposed women, after accounting for frequency of cervical cancer screening. Compared with unexposed women, HSIL risk was higher among women with earlier gestational and high-dose diethylstilbestrol exposure. These data confirm the appropriateness of more frequent screening among diethylstilbestrol-exposed women through age 44 years. Whether those aged 45 years or older should continue to have increased screening will require careful weighing of possible risks and benefits.

Combined Oral Contraceptive Use and the Risk of Cervical Cancer: Literature Review.

Cervical cancer (CC) is caused by persistent infection of human papillomavirus of high oncogenic risk (hr-HPV); however, several cofactors are important in its carcinogenesis, such as smoking, multiparity, and prolonged use of oral hormonal contraceptives (COCs). Worldwide, 16% of women use COCs, whereas in Brazil this rate is of ∼ 30%. The safety and adverse effects of COCs are widely discussed in the literature, including the increase in carcinogenic risk. Due to the existence of several drugs, combinations, and dosages of COCs, it is hard to have uniform information in epidemiological studies. Our objective was to perform a narrative review on the role of COCs use in the carcinogenesis of cervical cancer. Several populational studies have suggested an increase in the incidence of cervical cancer for those who have used COCs for > 5 years, but other available studies reach controversial and contradictory results regarding the action of COCs in the development of CC.

O câncer cervical (CC) é causado pela infecção persistente pelo papilomavírus humano de alto risco oncogênico (hr-HPV); entretanto, vários cofatores são importantes na sua carcinogênese, como tabagismo, multiparidade e uso prolongado de contraceptivos hormonais orais (COCs). No mundo, 16% das mulheres usam AOCs, enquanto no Brasil essa taxa é de ∼ 30%. A segurança e os efeitos adversos dos COCs são amplamente discutidos na literatura, incluindo o aumento do risco carcinogênico. Devido à existência de várias drogas, combinações e dosagens de COCs, é difícil ter informações uniformes em estudos epidemiológicos. Nosso objetivo foi realizar uma revisão narrativa sobre o papel do uso de COCs na carcinogênese do câncer cervical. Vários estudos populacionais têm sugerido aumento da incidência de câncer de colo uterino para aquelas que usam COCs há mais de 5 anos, mas outros estudos disponíveis chegam a resultados controversos e contraditórios quanto à ação dos COCs no desenvolvimento do CCU.

Association of urinary arsenic, polycyclic aromatic hydrocarbons, and metals with cancers among the female population in the US.

BACKGROUND: Cancers that primarily affect women in the US include breast, uterine, and cervical cancers. There may be associations between these different types of cancer in women and environmental pollutant exposure. PURPOSE: This study aimed to assess seven species of arsenic, six polycyclic aromatic hydrocarbon (PAH) compounds, and fourteen different metal concentrations in urine and their correlation with cancer among women. METHODS: We conducted a cross-sectional analysis using 2011--2012 to 2015-2016 National Health and Nutrition Examination Survey data (n = 4,956) and logistic regression modeling of the complex weighted survey design. RESULTS: Breast cancer was inversely correlated with arsenocholine (3rd quantile), monomethylarsonic acid (4th quantile), manganese (4th quantile), and antimony (3rd, 4th quantiles). Cervical cancer was inversely correlated with 3-hydroxyfluorene (3rd quantile), molybdenum (2nd, 4th quantiles), antimony (3rd quantile), tin (4th quantile), and thallium (4th quantile) exposure and positively associated with arsenic acid (3rd quantile), arsenobetaine (2nd, 4th quantiles). Uterine cancer was correlated with 1-hydroxynaphthalene (3rd, 4th quantiles), 2-hydroxynaphthalene (4th quantile), 1-hydroxyphenathrene (2nd, 4th quantiles), 1-hydroxypyrene (3rd quantile), cobalt (2nd, 3rd quantiles) and inversely with mercury (4th quantile). CONCLUSION: This study determined breast cancer and arsenic and some metal species exposure, indicating an inverse association. Arsenic acid and arsenobetaine exposure showed a positive correlation with cervical cancer. For uterine cancer, the correlations for the PAH compounds and cobalt showed a positive correlation, and the arsenic species and mercury were inversely associated. Further research is required to establish or refute the findings.

Latin America and the Caribbean Code Against Cancer 1st Edition: Medical interventions including hormone replacement therapy and cancer screening.

Prostate, breast, colorectal, cervical, and lung cancers are the leading cause of cancer in Latin America and the Caribbean (LAC) accounting for nearly 50% of cancer cases and cancer deaths in the region. Following the IARC Code Against Cancer methodology, a group of Latin American experts evaluated the evidence on several medical interventions to reduce cancer incidence and mortality considering the cancer burden in the region. A recommendation to limit the use of HRT was issued based on the risk associated to develop breast, endometrial, and ovarian cancer and on growing concerns related to the over-the-counter and without prescription sales, which in turn bias estimations on current use in LAC. In alignment with WHO breast and cervical cancer initiatives, biennial screening by clinical breast examination (performed by trained health professionals) from the age of 40 years and biennial screening by mammography from the age of 50 years to 74, as well as cervical screening by HPV testing (either self-sampling or provider-sampling) every 5-10 years for women aged 30-64 years, were recommended. The steadily increasing rates of colorectal cancer in LAC also led to recommend colorectal screening by occult blood testing every two years or by endoscopic examination of the colorectum every 10 years for both men and women aged 50-74 years. After evaluating the evidence, the experts decided not to issue recommendations for prostate and lung cancer screening; while there was insufficient evidence on prostate cancer mortality reduction by prostate-specific antigen (PSA) testing, there was evidence of mortality reduction by low-dose computed tomography (LDCT) targeting high-risk individuals (mainly heavy and/or long-term smokers) but not individuals with average risk to whom recommendations of this Code are directed. Finally, the group of experts adapted the gathered evidence to develop a competency-based online microlearning program for building cancer prevention capacity of primary care health professionals.

A Review of Tisotumab Vedotin-tftv in Recurrent or Metastatic Cervical Cancer.

OBJECTIVE: To evaluate the safety and efficacy of tisotumab vedotin-tftv (TV), a first-in-class vectorized anti-tissue factor (TF) antibody-drug conjugate (ADC), for the treatment of recurrent or metastatic cervical cancer. DATA SOURCES: A literature search of ClinicalTrials.gov, Embase, and PubMed was conducted using the terms tisotumab vedotin AND cervical cancer from inception to June 30, 2022. STUDY SELECTION AND DATA EXTRACTION: All applicable publications, package inserts, meeting abstracts, and clinical trials involving TV in the treatment of cervical cancer were reviewed. DATA SYNTHESIS: TV is a fully human TF-specific monoclonal antibody conjugated to monomethyl auristatin E, which serves as a highly potent cytotoxic payload. In the pivotal phase II InnovaTV 204 clinical trial, TV demonstrated an objective response rate of 24% (95% confidence interval [CI], 16%-33%). The mean duration of response was 8.3 months. Common toxicities included abdominal pain, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, dry eye, epistaxis, nausea/vomiting, and peripheral neuropathy. Unique and/or serious adverse events warranting careful monitoring include ocular complications, hemorrhaging, peripheral neuropathies, fetal-embryo toxicity, pneumonitis, and immunogenicity. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Recurrent or metastatic cervical cancer remains a high-risk disease with limited treatment options. Using ADCs to target tumors with aberrant expression of TF appears to be a viable treatment strategy. CONCLUSIONS: TV is the first Food and Drug Administration-approved TF-directed ADC. With a manageable safety profile and promising anticancer activity, TV warrants consideration as a novel targeted agent for the treatment of recurrent or metastatic cervical cancer. Further studies are required to determine the optimal place in therapy for TV.

Population pharmacokinetics modeling and exposure-response analyses of cemiplimab in patients with recurrent or metastatic cervical cancer.

A population pharmacokinetic (PopPK) model was previously developed for cemiplimab in patients with solid tumors, including advanced cutaneous squamous cell carcinoma (CSCC). Here, we update the existing PopPK model and characterize exposure-response relationships using efficacy and safety data obtained in patients with recurrent or metastatic cervical cancer (R/M CC). To improve model stability and robustness of the existing PopPK model in 1062 patients, the random-effect error model was revised, and structural covariates were removed from the base model to be tested in the covariate analysis. The updated model was used for external validation of cemiplimab pharmacokinetics (PK) in patients with R/M CC on cemiplimab monotherapy (350 mg every 3 weeks intravenously) from a phase III study (NCT03257267). Exposure-response relationships for cemiplimab efficacy (overall survival [OS], progression-free survival [PFS], duration of response [DOR], objective response rate [ORR]), and safety (immune-related adverse events [irAEs]) were analyzed in 295 patients with R/M CC from the aforementioned study. The updated PopPK model showed improved stability with 94.8% successful bootstrap runs vs. 47.6% in the prior model. Cemiplimab exposure was similar across tumor types, including basal cell carcinoma, CSCC, and non-small cell lung cancer. External validation showed the updated model adequately described cemiplimab PK in patients with R/M CC. In exposure-response efficacy analyses, Cox proportional hazard modeling (CPHM) showed no trend between exposure and OS, Kaplan-Meier plots showed no trend between exposure and PFS or DOR, and logistic regression analyses conducted on ORR showed no exposure-response relationship. In exposure-response safety analyses, CPHM showed no trend between exposure and irAEs.

Risk of clear-cell adenocarcinoma of the vagina and cervix among US women with potential exposure to diethylstilbestrol in utero.

PURPOSE: Women exposed to diethylstilbestrol (DES) in utero were at elevated risk of clear-cell adenocarcinoma of the vagina and cervix (CCA) as young women. Previous research suggested that this elevated risk of CCA may persist into adulthood. We extended a published analysis to measure CCA risk as these women aged. METHODS: Standardized incidence ratios (SIR) compared CCA risk among women born from 1947 through 1971 (the DES-era) to CCA risk among the comparison group of women born prior to 1947, using registry data that covered the US population. RESULTS: Incidence rates of CCA among both cohorts increased with age. Among the DES-era birth cohort, higher rates of CCA were observed across all age groups except 55-59 years. SIR estimates had wide confidence intervals that often included the null value. CONCLUSIONS: Results are consistent with prior research and suggest an elevated risk of CCA in midlife and at older ages among women exposed in utero to DES. These results highlight unresolved issues regarding cancer risk among aging DES daughters and appropriate screening guidance. The examination of population-based cancer surveillance data may be a useful tool for monitoring trends in the incidence of other rare cancers over time among specific birth cohorts.

Metformin and Cervical Cancer Risk in Patients with Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea.

BACKGRUOUND: Cervical cancer is a prevalent malignancy that is a major health problem for women worldwide. The cancer-preventive properties of metformin are well-known, but insufficient data have been reported regarding its relationship to cervical cancer. Therefore, in a nationwide population-based study, we investigated the association between metformin use and cervical cancer incidence in patients with newly diagnosed type 2 diabetes. METHODS: This retrospective cohort study used the Korean National Health Insurance claims database. Individuals newly diagnosed with type 2 diabetes between January 2005 and December 2009 were included. The occurrence of cervical cancer was explored by matching for age, economic status, region of residence, and use of anti-diabetic medication. RESULTS: In total, 66,013 metformin users and 64,756 non-users were analyzed. Cervical cancer occurred in 219 metformin users (0.33%) and 274 metformin non-users (0.42%) (hazard ratio [HR], 0.783; 95% confidence interval [CI], 0.655 to 0.036; P=0.007). Moreover, cervical cancer risk was considerably reduced in those treated with a high dose (>1,200,000 mg) or for an extended period (≥2,000 days) compared to non-users (HR, 0.151; 95% CI, 0.093 to 0.243; P<0.001; and HR, 0.141; 95% CI, 0.077 to 0.258; P<0.001). The incidence was also significantly lower in metformin users among those over 50 years old (HR, 0.791; 95% CI, 0.650 to 0.961; P<0.001). CONCLUSION: Metformin use in patients with newly diagnosed diabetes was associated with a lower risk of cervical cancer in Korea. Furthermore, a significant association was found between the use of metformin and cervical cancer in a dose- and duration-dependent manner and among those over 50 years old.

Risk of precancerous cervical lesions in women using a hormone-containing intrauterine device and other contraceptives: a register-based cohort study from Denmark.

STUDY QUESTION: Is the risk of high-grade precancerous cervical lesions and/or is the risk of lesion progression increased in users of a hormone-containing intrauterine device (HIUD) compared with users of other contraceptive methods. SUMMARY ANSWER: Women starting use of HIUD had the same subsequent risk of cervical intraepithelial neoplasia 3+ (CIN3+) as copper IUD (CIUD) users, and both groups tended to have lower risks than oral contraceptives (OC) users. WHAT IS KNOWN ALREADY: HIUDs may cause inflammatory and immunosuppressive changes that may potentially affect the risk of persistent human papillomavirus infection and precancerous cervical lesions. STUDY DESIGN, SIZE, DURATION: A Danish population-based cohort study was conducted using register data from 2008 to 2011 on 26-50-year-old users of HIUD (n = 60 551), CIUD (n = 30 303), or OC (n = 165 627). PARTICIPANTS/MATERIALS, SETTING, METHODS: Within each user group, women were divided into two groups; normal cytology or abnormal diagnosis before start of contraceptive use (baseline). Follow-up histology and cytology diagnoses were registered during the 5 years after baseline. Adjusted relative risks (aRR) and 95% CI were calculated for precancerous cervical lesions in HIUD users compared with CIUD and OC users. MAIN RESULTS AND THE ROLE OF CHANCE: Women with normal cytology at baseline: at follow-up HIUD users had the same risk of CIN3 or higher (3+) as CIUD users; aRR 1.08 (95% CI 0.94-1.22). For the HIUD and CIUD groups compared with OCs, the risks of CIN3+ were lower: aRR 0.63 (95% CI 0.57-0.69) and aRR 0.58 (95% CI 0.52-0.65), respectively. The same was observed for CIN2 risks: aRR 0.86 (95% CI 0.76-0.96) and aRR 0.68 (95% CI 0.58-0.79) for HIUD and CIUD groups, respectively. Women with abnormal diagnosis at baseline: a lower progression risk, except for CIN2+ at baseline, was observed in HIUD users compared with OC users. Similar progression risks were found in HIUD and CIUD users. There were no differences between the three contraceptive groups in persistence or regression of present lesions. LIMITATIONS, REASONS FOR CAUTION: We adjusted for age, education, and region of residence as a proxy for socio-economic factors. Data on smoking and sexual behavior were not available thus we cannot exclude some differences between the three user groups. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that women may safely use HIUDs. STUDY FUNDING/COMPETING INTEREST(S): A.P. Møller Foundation for the Advancement of Medical Science, Else and Mogens Wedell-Wedellborgs Fund, Direktør Emil C. Hertz og Hustru Inger Hertz Fund, and the Fund for Development of Evidence Based Medicine in Private Specialized Practices. EL is principle investigator for a study with HPV-test-kits provided by Roche. The other authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Effect of Andaliman (Zanthoxylum acanthopodium DC.) Methanol Extract on Rat's Kidney and Liver Histology Induced by Benzopyrene.

BACKGROUND AND OBJECTIVE: The andaliman fruits have anti-inflammatory, antioxidant activity and a strong inhibition in antitumor activity. The purpose of this study was to analyze the effect of extract andaliman on rat's kidney and liver histology induced by benzopyrene. MATERIALS AND METHODS: The rats model of cancer-induced benzopyrene. This research consists of 5 groups; K-: Control, K+: Cancer model rats, P1: A dose of 100 mg per b.wt. per day of andaliman, P2: A dose of 200 mg per b.wt. per day and P3: A dose of 400 mg kg-1 b.wt., per day for 30 days. On the 31st day, performed surgically on the subjects. RESULTS: There were significant differences in the value of narrowing of the renal tubules (p<0.001), kidneys cells necrosis (p<0.01), hydrophilic degeneration (p<0.001), parenchymatous degeneration (p<0.01) and necrosis (p<0.001) in the liver after given the extract andaliman. CONCLUSION: Andaliman methanol extract repairs the damage of the liver and kidney of rats induced by benzopyrene. Andaliman can be recommended as a drug to repair the necrosis in the liver and kidneys caused by cancer.

Oral contraceptives use and risk of cervical cancer-A systematic review & meta-analysis.

BACKGROUND: Role of Oral Contraceptive (OC) as a risk factor for cervical cancer remained controversial and unclear. OBJECTIVE: To evaluate risk of cervical cancer in OC users and non-users through a comprehensive systematic review. SEARCH STRATEGY: Literature search conducted in databases from January 1990 till August 2019 using various search terms. SELECTION CRITERIA: Primary research studies that evaluated and assessed the association of OC use with cervical cancer with study design of case control or cohort types published in English language. DATA COLLECTION AND ANALYSIS: PRISMA guided review was done by two independent researchers. Effect size estimated by pooled Odds ratio with 95 % Confidence Interval (CI) in random effect models on OC pill use for the risk of cervical cancer. RESULTS: Review included 19 studies. Overall risk of invasive cancer on OC use was found to be significant with unknown status of HPV OR (95 % CI) as 1.51 (1.35, 1.68) and for unknown HPV as 1.66 (1.24, 2.21). Adenocarcinoma, squamous cell carcinoma and carcinoma in situ had significant association with OR (95 % CI) of 1.77 (1.4, 2.24), 1.29 (1.18, 1.42) and 1.7 (1.18, 2.44) respectively. CONCLUSION: OC pills use had a definite associated risk for developing cervical cancer specially for Adenocarcinoma and longer duration of OC pills use.

Oral contraceptive and intrauterine device use and the risk of cervical intraepithelial neoplasia grade III or worse: a population-based study.

OBJECTIVE: Hormonal contraceptive use has been associated with the development of cervical cancer, although inconsistent results are reported on the association with intrauterine device (IUD) use. The aim of this study was to evaluate the association between the type of contraceptive use and the development of cervical intraepithelial neoplasia grade III or worse (CIN3+). METHODS: A retrospective population-based cohort study including women aged 29-44 years attending the cervical cancer screening program with normal cytology between 2005 and 2009 identified from the Dutch Pathology Registry. Subgroups with at least 5 years registered use of an oral contraceptive (OC) or IUD were compared with non-users. Risk ratios of CIN3+ were estimated per contraceptive type. RESULTS: 702,037 women were included with a median follow-up of 9.7 years, of which 6705 (0.96%) and 559 (0.08%) women developed CIN3 and cervical cancer, respectively. IUD use was associated with an increased risk of developing CIN3+ (risk ratio (RR) 1.51, 95% confidence interval (CI) 1.32-1.74), and OC use was associated with an increased risk of developing CIN3+ (RR 2.77, 95%CI 2.65-3.00) and cervical cancer (RR 2.06, 95%CI 1.52-2.79). The risk of developing CIN3+ and cervical cancer was higher for OC users compared with IUD users (RR 1.83, 95%CI 1.60-2.09 and RR 1.70, 95%CI 1.00-2.90, respectively). CONCLUSIONS: Both OC use and IUD use were associated with an increased risk of developing CIN3+. However, for women with a contraceptive wish, an IUD seems safer than an OC as the risk of developing CIN3+ and cervical cancer was higher for OC users.

eIF4E is a critical regulator of human papillomavirus (HPV)-immortalized cervical epithelial (H8) cell growth induced by nicotine.

Tobacco smoke is known as a cofactor in the development of cervical precancer and cancer caused by human papillomavirus (HPV). The main component in cigarette smoke, nicotine, can be concentrated more strongly in cervical mucus than in blood and it has been implicated as a cocarcinogen that promotes a serial of cancers development through multiple prosurvival pathways. Although the mechanisms of nicotine-induced cell proliferation have been well studied in some epithelial cells, the molecular mechanism of its action in cervical epithelial cells is still unclear. The aims of this study were to investigate the detailed mechanism by which nicotine could induce cervical cancer growth. We found that nicotine simultaneously activates AKT/mTOR pathway in HPV-immortalized cervical epithelial (H8) cell line, followed by elevation of 4EBP1/eIF4E axis expression and its translational activity with dose-dependent and time-dependent manners. Besides, nicotine decreases eIF4E-4EBP1 binding activity in H8 cell line, which is associated with increased expression of phospho-4EBP1 at threonine 70. We therefore chose to evaluate whether this effect on eIF4E was involved in nicotine-induced proliferation. Remarkably, eIF4E knockdown by small interfering RNA diminishes its translation activity to the downstream targets including c-Myc, VEGF, CyclinD1 and Bcl-2. What is more, eIF4E knockdown inhibits cellular growth and colony formation after nicotine treatment. Note as well that eIF4E-specific siRNA could also suppress cell proliferation by decelerating the G0/G1-S transition of H8 cell treated with nicotine. Taken together, it can be concluded that nicotine promotes H8 cell proliferation by activating AKT/mTOR pathway, as well as 4EBP1/eIF4E axis and its translational activity. Furthermore, phosphorylation of 4EBP1 induced by nicotine has been shown to cause dissociation of 4EBP1/eIF4E and eIF4E may serve as a promising determinant of nicotine activity in vitro.

Oral bisphosphonate use and the risk of female breast, ovarian, and cervical cancer: a nationwide population-based cohort study.

Bisphosphonate use was not associated with the risk of female breast, ovarian, or cervical cancer. The results according to bisphosphonate type or concurrent drug uses were not associated with the cancer risk. The protective effect of bisphosphonate use on female breast cancer was significant in the low comorbidity group. PURPOSE: Despite the antitumor mechanisms, the effect of bisphosphonates on the risk of cancer is still unclear. We investigated the association between oral bisphosphonate use and the development of female breast, ovarian, and cervical cancer. METHODS: We accomplished a population-based cohort study using the National Health Insurance Services (NHIS) database. A total of 204,525 participants were included in a cohort, and we identified the incident cases of each cancer from 2007 to 2013. We assessed cumulative bisphosphonate exposure from 2003 to 2006 using the defined daily dose (DDD) system. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were presented to assess the association between bisphosphonate use and cancer incidence using multivariate Cox proportional hazard regression models. Subgroup analyses were performed to assess cancer development according to risk factors and concurrent drug use. RESULTS: There was a total of 1547, 266, and 370 incident cases of female breast, cervical, and ovarian cancer, respectively, during the study period of 1,367,294 person-years. Bisphosphonate exposure was not significantly associated with risk of female breast (adjusted HR (aHR), 0.78; 95% CI, 0.60-1.02), ovarian (aHR, 1.30; 95% CI, 0.82-2.07), nor cervical cancer (aHR, 0.70; 95% CI, 0.44-1.12). Further subgroup analyses also revealed no statistically significant effects of bisphosphonate use with various risk factors and concurrent drug use. CONCLUSIONS: Our study showed no significant associations between bisphosphonate exposure and female breast, cervical, and ovarian cancer. In the future, large prospective studies or a meta-analysis would be needed to verify the associations.

Cytologic patterns of cervical adenocarcinomas with emphasis on factors associated with underdiagnosis.

BACKGROUND: New cervical cancers continue to be diagnosed despite the success of Papanicolaou (Pap) tests. In an effort to identify pitfalls that limit the diagnosis of adenocarcinoma, the authors reviewed the cytologic characteristics of endocervical adenocarcinomas in their patient population. METHODS: Liquid-based cytology slides from 45 women who had concurrent, histologically confirmed cervical adenocarcinomas were reviewed retrospectively and semiquantitatively for 25 key cytologic traits. The original sign-out diagnosis, available clinical findings, and high-risk human papillomavirus (HR HPV) results also were noted. RESULTS: Abundant tumor cellularity, nuclear size from 3 to 6 times normal, abundant 3-dimensional tumor cell groups, round cell shape, and cytoplasmic neutrophils characterized the 23 cases that were identified correctly as adenocarcinomas. Key reasons for undercalls included low tumor cellularity and low-grade columnar morphology; these also tended to correlate with low-grade or unusual adenocarcinoma variants on histology. Overall, 73% of adenocarcinomas had a concurrent positive HR HPV test. CONCLUSIONS: Most endocervical adenocarcinomas can be diagnosed accurately in cases with classical features, but some cases continue to be problematic when evaluated based on cytologic features alone. Reflex HPV testing may help increase Pap test sensitivity for challenging cases that have atypical glandular cells of undetermined significance. Occasional cases with negative HR HPV test results remain of concern.

Squamous cell carcinoma of the cervix arising in a patient on adalimumab � a need for cervical screenings in patients on tumor necrosis factor inhibitors.

Adalimumab, a tumor necrosis factor (TNF) inhibitor, has been approved for treatment of hidradenitis suppurativa. We report a case of cervical cancer in a patient with hidradenitis suppurativa taking adalimumab, which prompted discontinuation of the medication. Physicians should obtain a detailed cervical medical history before putting a female patient on a TNF inhibitor. Patients on TNF inhibitors who have pre-existing cervical issues such as human papillomavirus (HPV), dysplasia, or high grade intraepithelial lesions should be counseled about an increased risk of developing squamous cell carcinoma (SCC) of the cervix while on a TNF inhibitor. Furthermore, patients on TNF inhibitors should comply with the national screening guidelines for cervical cancer and be tested for human papillomavirus.

Epithelial oestrogen receptor α is dispensable for the development of oestrogen-induced cervical neoplastic diseases.

Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa) development. Oestradiol (E2 ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin (K14) promoter. E2 mainly functions through oestrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not in the stroma. We found that E2 induced cervical epithelial cell proliferation in epithelial ERα-deficient mice. We also found that E2 promoted the development of CIN and CxCa in epithelial ERα-deficient K14E7 mice and that all neoplastic epithelial cells were negative for ERα. In addition, proliferation indices were similar between ERα- and ERα+ CxCa. These results indicate that epithelial ERα is not necessary for E2 -induced CIN and CxCa. Taking these findings together, we conclude that stromal ERα rather than epithelial ERα mediates oncogenic E2 signalling in CxCa. Our results support stromal ERα signalling as a therapeutic target for the disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The risk of cervical atypia in oral contraceptive users.

BACKGROUND: The interactions of oral contraceptive (OC) use, risk of human papillomavirus (HPV) infection and associated cellular atypia are complex. We investigated the association between history of OC-use, and cytological or histopathological abnormalities in a cohort of non-HPV vaccinated originally 16-17-year-old women participating the PATRICIA trial for 4 years. METHODS: The total number of hepatitis A-virus (control) vaccine recipients participating in the clinical PATRICIA trial in Finland was 2399. Nine-hundred and ninety-nine women returned questionnaires on living conditions-life habits and sexual health after completing the study. Mean age at answering the questionnaire at the end of the clinical trial was 22 years. Age at sexual debut varied between 12 and 16 years for majority of the women. Cervical cytological samples were obtained every 6 months throughout the PATRICIA trial. The relative risk of cervical atypia associated with time since start of oral contraceptives use was calculated as odds ratio (OR) with 95% confidence interval (CI) using logistic regression. RESULTS: Compared to never-users, the smoking and age-at-sexual-debut adjusted relative risk of cervical intraepithelial neoplasia grade 1 (CIN1) in women who had started the use of oral contraceptives for more than 1 year was low (OR 0.2, 95% CI: 0.1-0.7). Risk of cytological atypia was also reduced (OR 0.6) albeit not significantly (95% CI: 0.3-1.3). CONCLUSIONS: Use of oral contraceptives does not increase the risk of cervical atypia but when established might instead be protective.