Vaccines against human papillomavirus infections: protection against cancer, genital warts or both?

Since 2006, three vaccines against infections and disease caused by human papillomavirus (HPV) became available in Europe-in 2006 a quadrivalent HPV 6/11/16/18 vaccine, in 2007 a bivalent HPV 16/18 vaccine and in 2015 a nonavalent HPV 6/11/16/18/31/33/45/52/58 vaccine. HPV 16 and 18 are the most oncogenic HPV strains, causing about 70% of cervical and other HPV-related cancers, HPV 6 and 11 cause 85% of all genital warts. The additional types of the polyvalent vaccine account for about 20% of invasive cervical cancer and >35% of pre-cancer. The potential differences between these vaccines caused some debate. All three vaccines give a robust and long-lasting protection against the strains in the various vaccines. The promise of cross-protection against other types (i.e. HPV 31/33/45) and hence a broader cancer protection was not fulfilled because these observations were confounded by the vaccine efficacy against the vaccine types. Furthermore, cross-protection was not consistent over various studies, not durable and not consistently seen in the real world experience. The protection against disease caused by oncogenic HPV strains was not compromised by the protection against low-risk types causing genital warts. The most effective cancer protection to date can be expected by the nonavalent vaccine, data indicate a 97% efficacy against cervical and vulvovaginal pre-cancer caused by these nine HPV types.

From the monovalent to the nine-valent HPV vaccine.

An investigational monovalent human papillomavirus (HPV) 16 virus-like particle vaccine has been shown to prevent persistent infection and cervical disease related to HPV 16 and was proof of concept (2002). Designed to prevent the bulk of invasive cervical cancer, quadrivalent (HPV 6/11/16/18) and bivalent (HPV 16/18) vaccines have been available since 2006 and 2007, respectively. They are highly effective in preventing HPV 16/18-related cervical precancer; the quadrivalent version also prevents genital warts related to HPV 6/11. It has been shown that the precursors of vulvar, vaginal and anal cancer related to the vaccine types are effectively prevented. This led to a paradigm shift from a female-only cervical cancer vaccine to a vaccine for the prevention of HPV-related disease and cancer for both sexes. Vaccination before the start of sexual activity is most effective, and consequently most programs target 9- to 12-year-olds. Additionally, recent studies have proven the noninferior immunoresponse of a two-dose schedule in these age cohorts. Gender-neutral vaccination has become more common; it improves coverage and also provides protection to all males. Recently a nine-valent HPV vaccine (HPV 6/11/16/18/31/33/45/52/58) was licensed; it provides high and consistent protection against infections and diseases related to these types, with ∼90% of cervical and other HPV-related cancers and precancers potentially being avoided. Coverage is key. Efforts must be made to provide HPV vaccination in low-resource countries that lack screening programs. In countries with cervical cancer screening, HPV vaccination will greatly affect screening algorithms.

Cut-off value of initial serum ß-hCG level predicting a successful MTX therapy in tubal ectopic pregnancy: a retrospective cohort study.

OBJECTIVE: To determine the optimal serum ß-hCG cut-off level to predict MTX treatment success in tubal ectopic pregnancy (EP). STUDY DESIGN: Data of 240 women, who presented between 2003 and 2011 at the Department of Gynecology and Obstetrics, Medical University of Vienna, with tubal EP and who received MTX as primary treatment, were retrieved from the hospital information system (KIS). 198 patients could be included for final evaluation. Statistical analysis included area under the ROC curve, maximal Euclidean and Youden index, chi-squared and a five-fold cross validation. RESULTS: The serum ß-hCG level cut-off value was calculated at 2121mlU/ml with a specificity of 76.54% and sensitivity of 80.56% (AUC 0.789; p<0.001). Patients with an initial serum ß-hCG level below 2121mlU/ml (n=131) experienced MTX treatment failure in 5.3% (n=7), compared to 43.3% (n=29) of patients with an initial serum ß-hCG level equal to or above 2121mlU/ml (n=67). There was no statistically significant correlation between clinical symptoms and the MTX therapy outcome (p=0.580; likelihood quotient p=0.716). CONCLUSION: The correct decision of therapy in patients with tubal ectopic pregnancy still represents a challenge. In this study we can conclude that, according to our results there is no endpoint of initial serum ß-hCG levels, which can be clearly used as cut-off value for the optimal management of tubal EP. However, an initial serum ß-hCG level of less than 2121mlU/ml seems to be a good value to expect a successful MTX treatment. Limitations are the retrospective study design and the inability of classifying clinical symptoms like pain as an objective parameter. Wider implications of the findings may include more detailed patient information and more accurate selection of suitable patients for MTX therapy.

Dehydroepiandrosterone in women with premature ovarian failure and Hashimoto's thyroiditis.

We evaluated dehydroepiandrosterone sulfate (DHEAS) levels in premature ovarian failure (POF) patients with and without Hashimoto's thyroiditis, and the impact of DHEA supplementation on thyroid autoantibodies. In a retrospective case series, we included 67 women with spontaneous POF who received estrogen/gestagen replacement with or without DHEA (30 mg/day) for 3 months. Women who were seropositive for thyroglobulin antibodies and/or thyroperoxidase autoantibodies (n = 30) revealed lower pretherapeutic DHEAS levels (1.2 µg/ml, range 0.4-2.9 µg/ml vs. 1.9 µg/ml, range 0.2-3.9 µg/ml; p < 0.001). DHEAS showed an inverse correlation with both thyroglobulin antibodies (r = -0.426, p < 0.001) and thyroperoxidase autoantibodies (r = -0.362, p = 0.002). When treated with additional DHEA, significant decreases were found for thyroperoxidase autoantibodies (median 85.0 IU/ml, range 41-600 IU/ml vs. median 51.0 IU/ml, range 20-589 IU/ml; p = 0.005) but not for thyroglobulin antibodies.

Sequential cervical length screening in pregnancies after loop excision of the transformation zone conisation: a retrospective analysis.

OBJECTIVE: To review our experience with a screening programme that included four sequential cervical length (CL) measurements from 16 to 22( ) weeks of gestation. DESIGN: Historical cohort study. SETTING: Tertiary-care centre in a university hospital. POPULATION: There were 312 singleton pregnancies in 321 women with a previous large loop excision of the transformation zone (LLETZ), and 62 pregnancies after a second-trimester miscarriage in a previous pregnancy. METHODS: The CL measurements were performed by transvaginal ultrasound at 16, 18, 20, and 22 completed weeks of gestation. MAIN OUTCOME MEASURES: Early preterm delivery before 34 completed weeks of gestation. RESULTS: Early preterm delivery was found in 7.4%. The CL at 16 completed weeks of gestation was smaller in the LLETZ group (36 mm, interquartile range 30-40 mm) compared with the control group (38 mm, interquartile range 32-42 mm; P = 0.040). For the analysis of risk factors for early preterm delivery after LLETZ, only cases with a complete data set were included (n = 145). In a multivariate analysis, two parameters remained significantly predictive, with CL at 16 completed weeks of gestation being the most significant measure (P < 0.001, OR 0.90, 95% CI 0.83-0.98), followed by conception using IVF treatment (P = 0.031, OR 0.64, 95% CI 1.54-34.80). CONCLUSIONS: Even as early as 16 weeks of gestation, women with early preterm delivery reveal a significantly lower CL than those without. Dynamics in the CL do not add to this information.

Prenatal sonography can predict degree of placental invasion.

OBJECTIVE: To evaluate whether the maximum degree of placental invasion (placenta accreta, increta or percreta) can be predicted with ultrasound imaging, using criteria developed in our department. METHODS: This was a retrospective study of all 232 patients at risk for placental invasion who were part of a routine screening program for placental invasion from January 2001 to January 2011. The whole placenta was scanned in a systematic manner using both gray-scale ultrasound and color-flow mapping. Sonographic findings were compared with the clinical outcome during and after delivery and the histomorphological examination of the placenta. RESULTS: Placental invasion was suspected by ultrasound in 40 (17.2%) patients and was clinically/histopathologically confirmed in a total of 35 (15.1%) patients. The sensitivity, specificity and positive and negative predictive values of ultrasound for placental invasion were 91.4% (95% CI, 77.6-97.0%), 95.9% (95% CI, 92.2-97.9%), 80.0% (95% CI, 65.2-89.5%) and 98.4% (95% CI, 95.5-99.5%), respectively. No case of placenta increta (n = 7) or percreta (n = 17) was diagnosed as showing normal placentation or placenta accreta on ultrasound, giving an overall accuracy for the differentiation between normal placentation/placenta accreta and placenta increta/percreta of 100%. CONCLUSION: Our data suggest that prediction of the degree of placental invasion is possible using prenatal ultrasound, with high overall accuracy.

Dexmedetomidine as an adjuvant to ropivacaine prolongs peripheral nerve block: a volunteer study.

BACKGROUND: Dexmedetomidine is an α-2-receptor agonist which might be used as an additive to local anaesthetics for various regional anaesthetic techniques. We therefore designed this prospective, double-blinded, controlled volunteer study to investigate the effects of dexmedetomidine as an adjuvant to ropivacaine on peripheral nerve block. METHODS: Ultrasound-guided ulnar nerve block (UNB) was performed in 36 volunteers with either 3 ml ropivacaine 0.75% (R), 3 ml ropivacaine 0.75% plus 20 µg dexmedetomidine (RpD), or 3 ml ropivacaine 0.75% plus systemic 20 µg dexmedetomidine (RsD). UNB-related sensory and motor scores were evaluated. RESULTS: Sensory onset time of UNB was not different between the study groups, whereas motor onset time was significantly faster in Group RpD when compared with the other study groups [mean (sd)] [21 (15) vs 43 (25) min in Group RsD and 47 (36) min in Group R, P<0.05 Group RpD vs other groups]. The duration of sensory block was 350 (54) min in Group R, 555 (118) min in Group RpD, and 395 (40) min in Group RsD (P<0.01 Group RpD vs other groups, P<0.05 Group RsD vs Group R). Motor block duration was similar to the duration of sensory block. CONCLUSIONS: A profound prolongation of UNB of ∼60% was detected with perineural dexmedetomidine when added to 0.75% ropivacaine. The systemic administration of 20 µg dexmedetomidine resulted in a prolongation of ∼10% during UNB with 0.75% ropivacaine. Eudra-CT No.: 2012-000030-19.

Infant acute lymphoblastic leukemia - combined cytogenetic, immunophenotypical and molecular analysis of 77 cases.

We used karyotyping, fluorescence in situ hybridization (FISH), Southern blotting, and RT-PCR in order to analyze prospectively 77 infants (less than 1 year of age) with acute lymphoblastic leukemia for the occurrence of 11q23/MLL rearrangements and/or other cytogenetic abnormalities. Out of the 69 informative samples we found an 11q23/MLL rearrangement in 42 cases (61%). Regarding only pro-B ALL cases, the incidence of 11q23/MLL rearranged cases, however, reached more than 90% The infants were treated within the therapy studies ALL-BFM90, ALL-BFM95 and CoALL-05-92. For patients with an adequate follow-up of 4 years the event-free survival of the 11q23/MLL-positive and 11q23/MLL-negative group was 0.2 or 0.64, respectively (P = 0.024). The monoclonal antibody 7.1. (moab 7.1) does not react with normal hematopoetic precursors or mature blood cells but was shown to specifically react with leukemic cells bearing a rearrangement of chromosome 11q23 or the MLL gene, respectively. We, therefore, specifically addressed the question whether the reactivity of moab 7.1, as determined by flow cytometry, may substitute for molecular testing of an 11q23/MLL rearrangement in this cohort of infant ALLs. Reactivity of moab 7.1 indicated a 11q23/MLL rearrangement with a specificity of 100%. However, five of the 11q23/MLL-positive cases did not react with moab 7.1 indicating a sensitivity of 84% only. Three of these five moab 7.1-negative but 11q23/MLL-positive cases could be identified by their unique expression pattern of CD65s and/or CD15. Thus, 95% of all 11q23/MLL-positive ALL cases in infancy may be identified by flow cytometry based on their expression of CD15, CD65s and/or moab 7.1.

Absence of point mutations within the AML-1 gene in patients with MDS/AML and loss of chromosome 5q or 7.

There is increasing evidence that the acute myeloid leukemia 1 (AML-1) gene plays a versatile role in hematopoiesis, and its inactivation has been described in various hematopoetic disorders, e.g., leukemia or familial thrombocytopenia. AML-1 can be affected by various mechanisms, such as chromosomal translocations or point mutations. On the other hand, the specific underlying molecular lesions in myelodysplastic syndromes (MDS) or leukemias with aberrations of chromosomes 5q or 7, respectively, are largely unknown. Despite extraordinary scientific effort no specific genes on chromosome 5q or 7, which act as tumor suppressors, have definitely been identified. Therefore, it has recently been speculated that the AML-1 gene, even if distantly located on chromosome 21q22, may be involved in leukemogenesis in patients with aberrations at chromosome 5q or monosomy 7 [2]. Therefore, we sequenced all exons of the AML-1 gene in 15 patients with MDS/AML and deleted chromosome 5q or 7q, respectively. None of the patients analyzed had any AML-1 mutation.

Lethal and teratogenic effects in two successive generations of the HLG mouse strain after radiation exposure of zygotes -- association with genomic instability?

We analysed the transmission of lethal and teratogenic events to the subsequent generation in HLG/Zte mice after exposure of the zygote stage to 1 Gy X-rays. As observed in previous studies, our results on teratogenic events occurring in the same generation, which was exposed during the zygote stage, reveal a significantly higher risk for the induction of gastroschisis. Interesting new insights came from the study of lethal and teratogenic effects in the generation obtained after mating female mice, which were exposed during their zygote stage, to unexposed males. An approximately 2-fold higher level of damage was manifest in this generation compared with controls, expressed mainly as a significant increase of prenatal mortality (P<0.01). Although there was an increase in the number of malformed fetuses on day 19 of gestation (6.5% cases of gastroschisis compared to 3.5% in the controls), the frequency of gastroschisis in the exposed group was just not statistically significant (P>0.05). These results are in line with the hypothesis that genomic instability is involved in the damage seen after radiation exposure of the zygote stage of HLG mice.