Impact of Human Papillomavirus Vaccine Against Anal Human Papillomavirus Infection, Anal Intraepithelial Neoplasia, and Recurrence of Anal Intraepithelial Neoplasia: A Systematic Review and Meta-analysis.

BACKGROUND: We sought to summarize human papillomavirus (HPV) vaccine efficacy/effectiveness (VE) against anal HPV infection and anal intraepithelial neoplasia (AIN). METHODS: We performed literature review and meta-analysis to estimate VE, stratified by age and analytic population (per-protocol efficacy [PPE] or intention-to-treat [ITT] population in clinical trials, or all participants in real-world studies). RESULTS: We identified 6 clinical trials and 8 real-world studies. In participants vaccinated at age ≤26 years (mainly human immunodeficiency virus [HIV]-negative individuals), significant VE against incident/prevalent anal HPV infection was reported in clinical trials, with a higher estimate in PPE (2 studies with 2390 participants; VE, 84% [95% confidence interval (CI), 77%-90%]; I2 = 0%) than ITT (2 studies with 4885 participants; 55%, 39%-67%; I2 = 46%) populations or in real-world studies (4 studies with 2375 participants; 77%, 40%-91%; I2 = 81%). HPV vaccination at age ≤26 years was associated with significant VE in preventing persistent anal HPV infection and AIN. No significant VE against anal HPV infection or AIN was found in persons vaccinated at age >26 years (mainly people living with HIV). CONCLUSIONS: There is strong evidence for high VE against anal HPV infection and AIN in HIV-negative individuals vaccinated at age ≤26 years. However, the lower impact in ITT than in PPE populations and the lack of significant effect in people living with HIV aged >26 years indicates that vaccines have the higher impact in populations with less sexual exposure to anal HPV.

Vulvar Cancer Incidence in the United States and its Relationship to Human Papillomavirus Vaccinations, 2001-2018.

The human papillomavirus (HPV) vaccine was indicated for the prevention of vulvovaginal cancers in 2008, but its impact on the incidence of vulvar cancers within the US is unknown. To determine this, we conducted a secondary analysis of 88,942 vulvar cancer cases among women 20+ years old using the US Cancer Statistics 2001-2018 databases. Data were stratified by tumor behavior (in situ or invasive), age (20-44, 45-64, 65+ years old), race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic), and US census region (Northeast, South, Midwest, West), and incidence rates and average annual percentage changes (AAPC) were calculated by group. Reversing previous trends, the incidence of vulvar carcinoma in situ significantly decreased between 2001 and 2018 among women from all age groups, races/ethnicities, and regions (combined AAPC,  -4.3; 95% confidence interval (CI), -4.7 to -3.8). The incidence of invasive vulvar squamous cell carcinoma decreased significantly among 20- to 44-year-old women (AAPC, -0.8; 95% CI, -1.3 to -0.3), but significantly increased among those 45 to 64 (AAPC, 2.3; 95% CI, 1.8-2.8) and 65+ years old (AAPC, 1.2; 95% CI, 1.1-1.4). Regardless of tumor behavior, incidence was highest among non-Hispanic Whites and the Midwest region. Overall, the significant declines in vulvar carcinoma in situ among all ages, as well as invasive vulvar cancer among younger women, are encouraging and complement other recent data suggesting HPV vaccinations are already reducing anal and cervical cancer incidence. Over time, further declines in vulvar carcinoma incidence are likely as uptake and completion rates of the HPV vaccine increase in the US. PREVENTION RELEVANCE: We found evidence that HPV vaccinations likely contributed to a decrease in the incidences of vulvar carcinoma in situ and invasive vulvar carcinoma among 20- to 44-year-old women between 2001 and 2018. Our data add to the growing evidence that HPV vaccinations are reducing the incidence of HPV-related anogenital cancers.

RPL34-AS1-induced RPL34 inhibits cervical cancer cell tumorigenesis via the MDM2-P53 pathway.

Ribosomal proteins (RPs) are important components of ribosomes and related to the occurrence and development of tumors. However, little is known about the effects of the RP network on cervical cancer (CC). In this study, we screened differentially expressed RPL34 in CC by high-throughput quantitative proteome assay. We found that RPL34 acted as a tumor suppressor and was downregulated in CC and inhibited the proliferation, migration, and invasion abilities of CC cells. Next, we verified that RPL34 regulated the CC through the MDM2-P53 pathway by using Act D medicine, MDM2 inhibitor, and a series of western blotting（WB）assays. Moreover, an antisense lncRNA, RPL34-AS1, regulated the expression of RPL34 and participated in the tumorigenesis of CC. RPL34 can reverse the effect of RPL34-AS1 in CC cells. Finally, by RNA-binding protein immunoprecipitation (RIP) assay we found that eukaryotic initiation factor 4A3 (EIF4A3), which binds to RPL34-AS1, regulated RPL34-AS1 expression in CC. Therefore, our findings indicate that RPL34-AS1-induced RPL34 inhibits CC cell proliferation, invasion, and metastasis through modulation of the MDM2-P53 signaling pathway, which provides a meaningful target for the early diagnosis and treatment of CC.

Disseminated Bacillus Calmette-Guérin (BCG) infection and acute exacerbation of interstitial pneumonitis: an autopsy case report and literature review.

BACKGROUND: Intravesical administration of Bacillus Calmette-Guérin (BCG) has proven useful for treatment and prevention of recurrence of superficial bladder cancer and in situ carcinoma. However, fatal side effects such as disseminated infections may occur. Early diagnosis and accurate therapy for interstitial pneumonitis (IP) are important because exacerbation of IP triggered by infections is the major cause of death. Although some fatality reports have suggested newly appeared IP after intravesical BCG treatment, to our knowledge, there are no reports which have demonstrated acute exacerbation of existing IP. Moreover, autopsy is lacking in previous reports. We report the case of a patient with fatal IP exacerbation after BCG instillation and the pathological findings of the autopsy. CASE PRESENTATION: A 77-year-old man with a medical history of IP was referred to our hospital because of fever and malaise. He had received an intravesical injection of BCG 1 day before the admission. His fever reduced after the use of antituberculosis drugs, so he was discharged home. He was referred to our hospital again because of a high fever 7 days after discharge. On hospitalisation, he showed high fever and systemic exanthema. Hepatosplenomegaly and myelosuppression were also observed. Biopsies revealed multiple epithelioid cell granulomas with Langhans giant cells of the liver and bone marrow. Biopsy DNA analyses of Mycobacterium bovis in the bone marrow, sputum, and blood were negative. His oxygen demand worsened drastically, and the ground-glass shadow expanded on the computed tomography scan. He was diagnosed with acute exacerbation of existing IP. We recommenced the antituberculosis drugs with steroid pulse therapy, but he died on day 35 because of respiratory failure. The autopsy revealed a diffuse appearance of multiple epithelioid cell granulomas with Langhans giant cells in multiple organs, although BCG was not evident. CONCLUSIONS: We report the first case of acute exacerbation of chronic IP by BCG infection. This is also the first case of autopsy of a patient with acute exacerbation of existing IP induced by intravesical BCG treatment. Whether the trigger of acute IP exacerbation is infection or hypersensitivity to BCG is still controversial, because pathological evidence confirming BCG infection is lacking. Physicians who administer BCG against bladder cancer should be vigilant for acute exacerbation of IP.

Prophylactic salpingectomy for prevention of ovarian cancer at the time of elective laparoscopic cholecystectomy.

BACKGROUND: Most serous ovarian cancers are now understood to originate in the fallopian tubes. Removing the tubes (salpingectomy) likely reduces the risk of developing high-grade serous ovarian cancer. Numerous gynaecological societies now recommend prophylactic (or opportunistic) salpingectomy at the time of gynaecological surgery in appropriate women, and this is widely done. Salpingectomy at the time of non-gynaecological surgery has not been explored and may present an opportunity for primary prevention of ovarian cancer. METHODS: This study investigated whether prophylactic salpingectomy with the intention of reducing the risk of developing ovarian cancer would be accepted and could be accomplished at the time of elective laparoscopic cholecystectomy. Women aged at least 45 years scheduled for elective laparoscopic cholecystectomy were recruited. They were counselled and offered prophylactic bilateral salpingectomy at the time of cholecystectomy. Outcome measures were rate of accomplishment of salpingectomy, time and procedural steps needed for salpingectomy, and complications. RESULTS: A total of 105 patients were included in the study. The rate of acceptance of salpingectomy was approximately 60 per cent. Salpingectomy was performed in 98 of 105 laparoscopic cholecystectomies (93·3 per cent) and not accomplished because of poor visibility or adhesions in seven (6·7 per cent). Median additional operating time was 13 (range 4-45) min. There were no complications attributable to salpingectomy. One patient presented with ovarian cancer 28 months after prophylactic salpingectomy; histological re-evaluation of the tubes showed a previously undetected, focal serous tubal intraepithelial carcinoma. CONCLUSION: Prophylactic salpingectomy can be done during elective laparoscopic cholecystectomy.

ANTECEDENTES: La mayoría de carcinomas serosos de ovario se originan en las trompas de Falopio. La exéresis de las trompas (salpingectomía) probablemente reduce el riesgo de desarrollar un carcinoma seroso ovárico de alto grado. Numerosas sociedades ginecológicas recomiendan efectuar una salpingectomía profiláctica (u oportunista) en el momento de una cirugía ginecológica en determinadas mujeres, y esta conducta está ampliamente difundida. Sin embargo, no se ha analizado la realización de la salpingectomía durante cirugías no ginecológicas como forma de prevención primaria del carcinoma ovárico. MÉTODOS: Determinar si la salpingectomía profiláctica con intención de reducir el riesgo de desarrollar cáncer de ovario sería aceptada y podría llevarse a cabo durante una colecistectomía laparoscópica electiva. Se reclutaron mujeres ≥ 45 años de edad programadas para colecistectomía laparoscópica electiva. A todas ellas se les aconsejó y ofreció la realización de una salpingectomía bilateral profiláctica en el momento de su colecistectomía. Las variables analizadas fueron la tasa de realización de la salpingectomía, la duración y las etapas quirúrgicos para efectuar este procedimiento, y las complicaciones. RESULTADOS: La aceptación de la salpingectomía fue aproximadamente del 60%. La salpingectomía se realizó en 98 de 105 colecistectomías laparoscópicas (93%) y no se pudo realizar en 7 pacientes (7%) por escasa visibilidad o adherencias. La mediana del tiempo quirúrgico adicional fue de 13 (rango 4-45) minutos. No hubo complicaciones atribuibles a la salpingectomía. Una paciente presentó cáncer de ovario 28 meses después de la salpingectomía profiláctica; la reevaluación histológica de las trompas mostró un carcinoma intraepitelial seroso focal tubárico (serous tubal intraepithelial carcinoma, STIC) no detectado previamente. CONCLUSIÓN: La salpingectomía profiláctica se puede realizar durante la colecistectomía laparoscópica electiva.

Human papillomavirus vaccination and prevention of intraepithelial neoplasia and penile cancer: review article.

PURPOSE OF REVIEW: The objective of the current article is to promote a literature revision of the relationship between the prevention of intraepithelial neoplasms (PeIN) and invasive penile cancer, and human papillomavirus (HPV) vaccination, aiming to enumerate the pros and cons of immunization. RECENT FINDINGS: The immunization against the HPV is sufficiently safe and many countries have incorporated the vaccine to their immunization calendar. Compared with men, the sampling size and the evidence quality of scientific researches among the female population are more robust. Some randomized and nonrandomized studies suggest that vaccination reduces the incidence of genital warts and no PeIN and penile cancer cases were developed in the vaccinal group. However, 70% of patients can evolve with the neoplasia despite having been immunized and even among HPV infected patients, only 1% will develop cancer. SUMMARY: The studies about vaccination against HPV and prevention on penile cancer are conflicting and the main academic urology societies still have not incorporated vaccination of men in their guidelines. Future studies are necessary to confirm the efficiency and cost-benefit of the vaccine in men to prevent intraepithelial neoplasms and invasive penile cancer.

Risk of Anal Cancer Following Benign Anal Disease and Anal Cancer Precursor Lesions: A Danish Nationwide Cohort Study.

BACKGROUND: Human papillomavirus (HPV) is associated with the majority of anal high-grade intraepithelial neoplasia (AIN) and anal cancers. Little is known about the risk of anal cancer following a diagnosis of benign anal disease and AIN. METHODS: Using data from nationwide, population-based Danish registries, a cohort of 126,174 individuals with either non-neoplastic anal disease or AIN 1 to 3 during 1970 to 2016 was followed until first occasion of anal cancer. Information on HIV status was obtained from the Danish HIV Cohort Study. The absolute risk of anal cancer was estimated using the Aalen-Johansen estimator taking into account censoring at emigration and end of follow-up and competing risk at time of death. Standardized incidence ratios (SIR) for anal cancer among individuals with non-neoplastic anal disease, including inflammatory lesions, hemorrhoids, and polyps, were estimated in Poisson models. Sex-, age-, and calendar period-specific national population rates were estimated using the Danish National Pathology Registry. RESULTS: Anal cancer risk increased with increasing severity of lesions, reaching 4% 5 years after diagnosis of AIN3. Even among those with non-neoplastic anal lesions, particularly inflammatory lesions, anal cancer risk was significantly higher than expected from Danish national anal cancer rates (SIR = 2.8; 95% confidence intervals, 2.3-3.2). The absolute 5-year risk of anal cancer following AIN3 was considerably higher among HIV-positive (14.1%) than HIV-negative (3.2%) individuals. CONCLUSIONS: Anal cancer risk increases with increasing severity of lesions and is especially high among HIV-positive individuals. IMPACT: Vaccination against HPV is important in the prevention of both high-grade AIN and anal cancer.

Sistema antioxidante enzimático en mujeres con diagnóstico de Atipias celulares y Neoplasia Intraepitelial Cervical grado I / Enzymatic antioxidant system in women diagnosed with cell atypia and grade I cervical intraepithelial neoplasia

Introducción: El virus de papiloma humano per se no es capaz de desarrollar todas las transformaciones neoplásicas en el cérvix uterino, de manera que factores de riesgo como los genéticos, ambientales, estilo de vida sexual y el desbalance oxidativo podrían contribuir a la enfermedad. Objetivo: Determinar el comportamiento del sistema enzimático antioxidante en mujeres con atipia de células escamosas de significado indeterminado y neoplasia intraepitelial cervical grado I. Métodos: Se conformaron tres grupos de estudio: el primero incluyó 30 mujeres con diagnóstico de atipias, el segundo se constituyó con 40 mujeres con neoplasia intraepitelial grado I y el tercero consistió en 30 mujeres con citología negativa tomadas como control, provenientes de la consulta de Patología de Cuello del Agustín Gómez Lubián de Santa Clara. Mediante métodos espectrofotométricos se determinaron los niveles de actividad enzimática superóxido dismutasa y catalasa así, como las concentraciones de glutatión reducido. Las comparaciones se realizaron con el programa SPSS, versión 18. Resultados: En el grupo de atipias aunque los tres parámetros tuvieron una tendencia a la disminución no hubo diferencias significativas con respecto al control. Mientras que el grupo de neoplasia grado I evidenció disminución significativa de los tres indicadores estudiados al ser comparados con el grupo control. Conclusiones: Se constató afectación del sistema antioxidante enzimático en el grupo de neoplasia grado I, lo cual podría considerarse un cofactor importante en la progresión de las lesiones en el cérvix uterino(AU)

Introduction: Human papillomavirus per se can not carry out all the neoplastic transformations occurring in the uterine cervix. Genetic and environmental risk factors as well as sexual behavior and oxidative imbalance may also play a role. Objective: Determine the behavior of the enzymatic antioxidant system in women with squamous cell atypia of indeterminate significance and grade I cervical intraepithelial neoplasia. Methods: Three study groups were formed. The first group included 30 women diagnosed with atypia, the second group was made up of 40 women with grade I intraepithelial neoplasia, and the third or control group consisted of 30 women with negative cytology from Agustín Gómez Lubián Cervical Pathology service in Santa Clara. Spectrophotometric methods were used to determine the levels of superoxide dismutase and catalase enzymatic activity, as well as the concentrations of reduced glutathione. Comparisons were made with the SPSS software, version 18. Results: In the atypia group the three parameters showed a decreasing tendency, but differences with respect to the control group were not significant. In the grade I neoplasia group, however, a significant reduction was found of the three study indicators when compared with the control group. Conclusions: Damage to the enzymatic antioxidant system was observed in the grade I neoplasia group. This could be considered to be an important cofactor in the progress of uterine cervix lesions(AU)

A Randomized Phase II Trial of Pioglitazone for Lung Cancer Chemoprevention in High-Risk Current and Former Smokers.

Lung cancer chemoprevention, especially in high-risk former smokers, has great potential to reduce lung cancer incidence and mortality. Thiazolidinediones prevent lung cancer in preclinical studies, and diabetics receiving thiazolidinediones have lower lung cancer rates which led to our double-blind, randomized, phase II placebo-controlled trial of oral pioglitazone in high-risk current or former smokers with sputum cytologic atypia or known endobronchial dysplasia. Bronchoscopy was performed at study entry and after completing 6 months of treatment. Biopsies were histologically scored, and primary endpoint analysis tested worst biopsy scores (Max) between groups; Dysplasia index (DI) and average score (Avg) changes were secondary endpoints. Biopsies also received an inflammation score. The trial accrued 92 subjects (47 pioglitazone, 45 placebo), and 76 completed both bronchoscopies (39 pioglitazone, 37 placebo). Baseline dysplasia was significantly worse for current smokers, and 64% of subjects had mild or greater dysplasia at study entry. Subjects receiving pioglitazone did not exhibit improvement in bronchial dysplasia. Former smokers treated with pioglitazone exhibited a slight improvement in Max, while current smokers exhibited slight worsening. While statistically significant changes in Avg and DI were not observed in the treatment group, former smokers exhibited a slight decrease in both Avg and DI. Negligible Avg and DI changes occurred in current smokers. A trend toward decreased Ki-67 labeling index occurred in former smokers with baseline dysplasia receiving pioglitazone. While pioglitazone did not improve endobronchial histology in this high-risk cohort, specific lesions showed histologic improvement, and further study is needed to better characterize responsive dysplasia.

Practice parameters for the diagnosis and treatment of anal intraepithelial neoplasia (AIN) on behalf of the Italian Society of Colorectal Surgery (SICCR).

Squamous cell carcinoma (SCC) of the anus is a human papilloma virus (HPV) related malignancy that is preceded by anal intraepithelial neoplasia (AIN) making this cancer, at least theoretically, a preventable disease. In the past 10 years the diagnosis, management and nomenclature of AIN has dramatically changed. Increased life expectancy in human immunodeficiency virus (HIV) positive patients due to highly active antiretroviral therapy (HAART) has caused an increase in the incidence of SCC of the anus. While many experts recommend screening and treatment of anal high-grade squamous intraepithelial lesion (HSIL), there is no consensus on the optimal management these lesions. Therefore, there is a need to review the current evidence on diagnosis and treatment of AIN and formulate recommendations to guide management. Surgeons who are members of the Italian Society of Colorectal Surgery (SICCR) with a recognized interest in AIN were invited to contribute on various topics after a comprehensive literature search. Levels of evidence were classified using the Oxford Centre for Evidence-based Medicine of 2009 and the strength of recommendation was graded according to the United States (US) preventive services task force. These recommendations are among the few entirely dedicated only to the precursors of SCC of the anus and provide an evidence-based summary of the current knowledge about the management of AIN that will serve as a reference for clinicians involved in the treatment of patients at risk for anal cancer.

Retrospective study of a 16 year cohort of BRCA1 and BRCA2 carriers presenting for RRSO: Prevalence of invasive and in-situ carcinoma, with follow-up.

OBJECTIVES: Carriers of BRCA1 and BRCA2 mutations are at increased risk of high grade serous carcinoma and are therefore offered risk-reducing salpingo-oophorectomy (RRSO) by 40-45 years. Most of these carcinomas are believed to arise in the fallopian tube from serous tubal intraepithelial carcinoma (STIC). We conducted a retrospective study on the prevalence of high grade serous carcinoma and STIC in BRCA1/2 carriers presenting for RRSO, and their follow-up. METHODS: Consecutive BRCA1/2 carriers presenting for an RRSO at Erasmus MC (2000-2016) were studied. SEE-FIM pathology protocol was followed from 2010 onwards. For the cases with carcinoma and/or STIC, the histology was reviewed and immunohistochemistry (p53 & MIB-1) was performed. Next Generation Targeted Sequencing (NGTS) for TP53 mutation was used to establish clonality in 2 cases. RESULTS: Of the 527 included patients, 68% were BRCA1, 31.6% were BRCA2, and 0.4% carried both mutations. The prevalence of high grade serous carcinoma was 2.3% (12/527); 59% of these were of tubal origin. High grade serous carcinoma was more common in patients operated on after the recommended age (p = 0.03). Isolated STIC was present in 0.8% (4/527). Two BRCA1 carriers with isolated STIC at RRSO developed peritoneal serous carcinoma >7 years later. Identical TP53 mutations in the peritoneal serous carcinoma and the preceding STIC established their clonal origin. CONCLUSIONS: High grade serous carcinoma is more common in BRCA1/2 carriers presenting for RRSO after the recommended age, and is more often of tubal origin. Longer follow up of patients with STIC at RRSO should be considered.

HPV vaccine in the treatment of usual type vulval and vaginal intraepithelial neoplasia: a systematic review.

BACKGROUND: HPV DNA is found in almost 80% of VIN/VaIN. Current management is inadequate, with high recurrence rates. Our objective was to review the literature regarding the role of HPV vaccine in secondary prevention and treatment of VIN/VaIN. METHODS: Database searches included Ovid Medline, Embase, Web of Science, The Cochrane Library and Clinicaltrials.gov . Search terms included HPV vaccine AND therapeutic vaccine* AND VIN OR VAIN, published in English with no defined date limit. Searches were carried out with a UCL librarian in March 2018. We included any type of study design using any form of HPV vaccine in the treatment of women with a histologically confirmed diagnosis of VIN/VaIN. We excluded studies of other lower genital tract disease, vulval/vaginal carcinoma and prophylactic use of vaccines. The outcome measures were lesion response to vaccination, symptom improvement, immune response and HPV clearance. RESULTS: We identified 93 articles, 7 studies met our inclusion criteria; these were uncontrolled case series. There were no RCTs or systematic reviews identified. Reduction in lesion size was reported by all 7 studies, symptom relief by 5, HPV clearance by 6, histological regression by 5, and immune response by 6. CONCLUSIONS: This review finds the evidence relating to the use of HPV vaccine in the treatment of women with VIN/VaIN is of very low quality and insufficient to guide practice. Further longitudinal studies are needed to assess its use in prevention of progression to cancer.

cd44 deletion suppresses atypia in the precancerous mouse testis.

Loss-of-function of RHAMM causes hypofertility and testicular atrophy in young mice, followed by germ cell neoplasia in situ (GCNIS) of the testis, cellular atypia, and development of the testicular germ cell tumor (TGCT) seminoma. These pathologies reflect the risk factors and phenotypes that precede seminoma development in humans and-given the high prevalence of RHAMM downregulation in human seminoma-link RHAMM dysfunction with the aetiology of male hypofertility and GCNIS-related TGCTs. The initiating event underlying these pathologies, in RHAMM mutant testis, is premature displacement of undifferentiated progenitors from the basal compartment. We hypothesized that cd44 (both cancer initiating cell- and oncogenic progression marker) will drive GCNIS development, induced by RHAMM-loss-of-function in the mouse. We report that cd44 is expressed in a specific subset of GCNIS testes. Its genetic deletion has no effect on GCNIS onset, but it ameliorates oncogenic progression. We conclude that cd44 expression, combined with RHAMM dysfunction, promotes oncogenic progression in the testis.

Prevention and control of neoplasms associated with HPV in high-risk groups in Mexico City: The Condesa Study / Prevención y control de neoplasias asociadas a VPH en grupos de alto riesgo de la Ciudad de México: el Estudio Condesa

Abstract: Objective: To evaluate the effectiveness of a combined strategy of human papillomavirus virus (HPV) vaccination and high-risk HPV screening to reduce the occurrence of anogenital and oropharyngeal neoplasms among men who have sex with men, people with HIV, homeless people, transgender women, female sex workers and rape victims. Materials and methods: This mixed methods study evaluates the effectiveness of a combined vaccination-screening strategy to reduce HPV prevalence/incidence and occurrence of cervical intraepithelial neoplasms grade 2+ and/or anal intraepithelial neoplasms grade 2+, using Kaplan-Meier. The time-to-event method will evaluate time from positive results for specific anogenital HPV to incidence of anogenital lesions containing that HPV type. Results: People vaccinated against HPV and screened for HPV as a primary test will have lower prevalence and incidence of HPV infection and consequently lower frequency of HPV-related anogenital and oropharyngeal lesions. Conclusions: This study will generate scientific evidence on effectiveness of a combined vaccination-screening strategy to reduce the burden of HPV-associated neoplasms.

Resumen: Objetivo: Evaluar la efectividad de una estrategia combinada de vacunación contra el virus de papiloma humano (VPH) y tamizaje de VPH de alto riesgo para reducir neoplasias anogenitales y orofaringeas entre hombres que tienen sexo con hombres, personas con VIH, personas en situación de calle, mujeres transgénero, trabajadoras sexuales y víctimas de violación. Material y métodos: Este estudio evaluará la efectividad de una estrategia combinada de vacunación y tamizaje para reducir la ocurrencia de neoplasias intraepiteliales cervicales grado 2+ o neoplasias intraepiteliales anales grado NIA2+ utilizando Kaplan-Meier. Se evaluará tiempo de resultados positivos para tipos específicos de VPH anogenital a incidencia de lesiones anogenitales con ese tipo de VPH. Resultados: Las personas vacunadas contra VPH y con tamizaje de VPH tendrán menor prevalencia e incidencia de infecciones por VPH y por ende menor frecuencia de lesiones anogenitales y orofaringeas relacionadas con VPH. Conclusiones: Este estudio generará evidencia científica sobre la efectividad de una estrategia combinada de vacunación y tamizaje para reducir la carga de neoplasias asociadas al VPH.

[Beyond actinic keratoses: Field cancerization of the skin]. / Au-delà des kératoses actiniques, le champ de cancérisation cutané.

Lesions occurring in actinic keratoses (AK) form erythematous, squamous, crusty and keratotic papules that appear on skin chronically exposed to the sun due to ultraviolet radiation. They are formed by the proliferation of atypical keratinocytes limited to the epidermis and may progress to squamous cell carcinoma in situ and to cutaneous squamous cell carcinoma (CEC). Although low, the metastatic risk associated with the CEC is not negligible. The concept of field cancerization was introduced in 1953 following studies of neoplastic lesions of the oral mucosa. A cancer field is a normal-looking pre-tumoral zone with subclinical, multifocal anomalies, which may constitute a base for new neoplastic lesions. Such fields are frequently seen in areas of photo-exposed skin and around the edges of AK and CEC. In this event, treatment should not be limited to visible or palpable AK lesions, and if a cancer field is suspected, treatment involving the physical destruction or elimination of atypical keratinocytes from the entire area should be considered. Such an approach may improve the long-term prognosis, reduce treatment costs and ensure optimal cosmetic outcome.

Prevention and control of neoplasms associated with HPV in high-risk groups in Mexico City: The Condesa Study.

OBJECTIVE: To evaluate the effectiveness of a combined strategy of human papillomavirus virus (HPV) vaccination and high-risk HPV screening to reduce the occurrence of anogenital and oropharyngeal neoplasms among men who have sex with men, people with HIV, homeless people, transgender women, female sex workers and rape victims. MATERIALS AND METHODS: This mixed methods study evaluates the effectiveness of a combined vaccination-screening strategy to reduce HPV prevalence/incidence and occurrence of cervical intraepithelial neoplasms grade 2+ and/or anal intraepithelial neoplasms grade 2+, using Kaplan-Meier. The time-to-event method will evaluate time from positive results for specific anogenital HPV to incidence of anogenital lesions containing that HPV type. RESULTS: People vaccinated against HPV and screened for HPV as a primary test will have lower prevalence and incidence of HPV infection and consequently lower frequency of HPV-related anogenital and oropharyngeal lesions. CONCLUSIONS: Thisstudy will generate scientific evidence on effectiveness of a combined vaccination-screening strategy to reduce the burden of HPV-associated neoplasms.

OBJETIVO: Evaluar la efectividad de una estrategia combinada de vacunación contra el virus de papiloma humano (VPH) y tamizaje de VPH de alto riesgo para reducir neoplasias anogenitales y orofaringeas entre hombres que tienen sexo con hombres, personas con VIH, personas en situación de calle, mujeres transgénero, trabajadoras sexuales y víctimas de violación. MATERIAL Y MÉTODOS: Este estudio evaluará la efectividad de una estrategia combinada de vacunación y tamizaje para reducir la ocurrencia de neoplasias intraepiteliales cervicales grado 2+ o neoplasias intraepiteliales anales grado NIA2+ utilizando Kaplan-Meier. Se evaluará tiempo de resultados positivos para tipos específicos deVPH anogenital a incidencia de lesiones anogenitales con ese tipo de VPH. RESULTADOS: Las personas vacunadas contra VPH y con tamizaje de VPH tendrán menor prevalencia e incidencia de infecciones por VPH y por ende menor frecuencia de lesiones anogenitales y orofaringeas relacionadas con VPH. CONCLUSIONES: Este estudio generará evidencia científica sobre la efectividad de una estrategia combinada de vacunación y tamizaje para reducir la carga de neoplasias asociadas al VPH.

[Non-melanoma skin cancer : Pathogenesis, prevalence and prevention]. / Nichtmelanozytärer Hautkrebs : Pathogenese, Prävalenz und Prävention.

Non-melanoma skin cancer (NMSC) is the most common malignancy of the light-skinned population with an enormous socioeconomic impact. Historically known as incurable under the term noli me tangere (transl. do not touch me), today various non-melanocytic cutaneous neoplasms are grouped as NMSC. The most common of these, basal cell carcinoma, squamous cell carcinoma and actinic keratoses as carcinomas in situ, are increasingly called keratinocyte carcinoma. Today, the pathogenesis and risk factors of NMSC are relatively well understood, which has led to multiple treatment options, the recognition of NMSC as an occupational disease in Germany and a variety of prevention approaches. Although there is largely general consensus in the dermatological world, knowledge of affected high-risk groups in NMSC and prevention is still very low. The development of target group-oriented awareness and prevention campaigns are therefore urgently needed.

Management of precancerous anal intraepithelial lesions in human immunodeficiency virus-positive men who have sex with men: Clinical effectiveness and cost-effectiveness.

BACKGROUND: Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at disproportionately high risk for anal cancer. There is no definitive approach to the management of high-grade squamous intraepithelial lesions (HSIL), which are precursors of anal cancer, and evidence suggests that posttreatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves HSIL treatment effectiveness. The objectives of this study were to evaluate the optimal HSIL management strategy with respect to clinical effectiveness and cost-effectiveness and to identify the optimal age for initiating HSIL management. METHODS: A decision analytic model of the natural history of anal carcinoma and HSIL management strategies was constructed for HIV-positive MSM who were 27 years old or older. The model was informed by the Surveillance, Epidemiology, and End Results-Medicare database and published studies. Outcomes included the lifetime cost, life expectancy, quality-adjusted life expectancy, cumulative risk of cancer and cancer-related deaths, and cost-effectiveness from a societal perspective. RESULTS: Active monitoring was the most effective approach in patients 29 years or younger; thereafter, HSIL treatment plus adjuvant qHPV vaccination became most effective. When cost-effectiveness was considered (ie, an incremental cost-effectiveness ratio [ICER] < $100,000/quality-adjusted life-year), do nothing was cost-effective until the age of 38 years, and HSIL treatment plus adjuvant qHPV vaccination was cost-effective beyond the age of 38 years (95% confidence interval, 34-43 years). The ICER decreased as the age at HSIL management increased. Outcomes were sensitive to the rate of HSIL regression or progression and the cost of high-resolution anoscopy and biopsy. CONCLUSIONS: The management of HSIL in HIV-positive MSM who are 38 years old or older with treatment plus adjuvant qHPV vaccination is likely to be cost-effective. The conservative approach of no treatment is likely to be cost-effective in younger patients. Cancer 2017;123:4709-4719. © 2017 American Cancer Society.

Glycogen synthase kinase-3ß ablation limits pancreatitis-induced acinar-to-ductal metaplasia.

Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3ß) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3ß promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3ß attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK-3ß ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3ß regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3ß participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.