Safety profile of the 9-valent human papillomavirus vaccine: assessment in prior quadrivalent HPV vaccine recipients and in men 16 to 26 years of age.

A 9-valent HPV (9vHPV) vaccine has been developed to protect against HPV type 6/11/16/18/31/33/45/52/58-related infection and disease. Previous safety analyses from 7 clinical trials conducted in 9vHPV vaccine recipients 9-26 years of age, including comparisons of 9vHPV and quadrivalent HPV (qHPV) vaccines in girls and women 16-26 years of age, showed that the 9vHPV vaccine was generally well tolerated. Additional safety analyses were conducted to include the results of new clinical studies. The safety profile of the 9vHPV vaccine in prior qHPV vaccine recipients (n = 3756 from 1 randomized controlled trial and 2 open-label extension studies) and young men (n = 248 9vHPV and n = 248 qHPV vaccine recipients from 1 randomized controlled trial) was evaluated. Vaccine was administered as a 3-dose regimen (at Day 1 and Months 2 and 6), and adverse events (AEs) were monitored. The most common AEs were injection-site events (91.1% and 79.0% in prior qHPV vaccine recipients and young men, respectively), the majority of which were mild. Discontinuations due to an AE were rare (0.2% and 0.0% among prior qHPV vaccine recipients and young men, respectively). In young men, the AE profile of the 9vHPV vaccine was generally similar to that of the qHPV vaccine. Overall, the 9vHPV vaccine was generally well tolerated in prior qHPV vaccine recipients and in young men, with an AE profile generally consistent with that previously reported with the broader clinical program.

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.

Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples.

AIM: This work describes the human papillomavirus (HPV) prevalence and the HPV type distribution in a large series of vaginal intraepithelial neoplasia (VAIN) grades 2/3 and vaginal cancer worldwide. METHODS: We analysed 189 VAIN 2/3 and 408 invasive vaginal cancer cases collected from 31 countries from 1986 to 2011. After histopathological evaluation of sectioned formalin-fixed paraffin-embedded samples, HPV DNA detection and typing was performed using the SPF-10/DNA enzyme immunoassay (DEIA)/LiPA25 system (version 1). A subset of 146 vaginal cancers was tested for p16(INK4a) expression, a cellular surrogate marker for HPV transformation. Prevalence ratios were estimated using multivariate Poisson regression with robust variance. RESULTS: HPV DNA was detected in 74% (95% confidence interval (CI): 70-78%) of invasive cancers and in 96% (95% CI: 92-98%) of VAIN 2/3. Among cancers, the highest detection rates were observed in warty-basaloid subtype of squamous cell carcinomas, and in younger ages. Concerning the type-specific distribution, HPV16 was the most frequently type detected in both precancerous and cancerous lesions (59%). p16(INK4a) overexpression was found in 87% of HPV DNA positive vaginal cancer cases. CONCLUSIONS: HPV was identified in a large proportion of invasive vaginal cancers and in almost all VAIN 2/3. HPV16 was the most common type detected. A large impact in the reduction of the burden of vaginal neoplastic lesions is expected among vaccinated cohorts.

Continuous vs interrupted sutures for single-layer closure of uterine incision at cesarean section.

In a non-randomized cohort study, we compared continuous with interrupted sutures for the closure of the lower uterine segment at cesarean section. Eighty-two women, who underwent cesarean section at the Department of Obstetrics at the University Hospital of Vienna between January and May 2000, were included in the study. Thirty-eight patients had single-layer closure of the lower uterine segment and 43 patients had closure with interrupted sutures. There were significant differences in total operating-time (32 min vs 40 min, P=0.001) and in the pre- and postoperative maternal hemoglobin (DeltaHb 0.6 g/dl vs 1.1 g/dl, P<0.01), but there was no significant difference in sonographically diagnosed hematomas (32% vs 21%, P=0.27). No woman had fever, the median hospitalization time was 6 days, and there were no re-admissions. In both groups, the median need for analgesics was 150 mg diclofenac ( P=0.22). Continuous single-layer closure of the lower uterine segment at cesarean section saves operating time, reduces blood loss, and introduces less foreign material into the wound.

A study of non-closure of the peritoneum at vaginal hysterectomy.

The aim of this case-controlled study was to determine whether non-closure of the peritoneum is detrimental in vaginal hysterectomy. 233 patients who underwent total vaginal hysterectomy (TVH) or laparoscopically assisted vaginal hysterectomy (LAVH) at the University of Vienna/Austria were analyzed. Cohorts of patients were formed according to their peritonealization status (open, n=117, vs closed peritoneum, n=116) and further stratified according to the type of surgical procedure: simple TVH ( n=115), TVH with concurrent vaginal repair and/or urinary incontinence surgery ( n=91) and LAVH ( n=27). No significant differences could be observed in analyzed surgical outcome (operation time, blood loss and analgesia). Complications (fever, infection, hemorrhage or revision) were similar whether the peritoneum was closed or not. After simple TVH, resumption of bowel function took place earlier in patients with open peritoneum than in those where it had been sutured (1.9 vs 2.4 days, P=0.001). No readmission for prolapse of the vaginal vault was recorded. Non-closure of the peritoneum at vaginal hysterectomy appears to be safe. Omission of peritoneal closure reduces the potential risk of injury and has a beneficial effect on bowel function.

Port site metastases after laparoscopic lymph node staging of cervical carcinoma.

The literature revealed only six cases of cervical carcinoma metastatic to a port site after laparoscopic lymphadenectomy. A woman with a poorly differentiated squamous cell carcinoma of the cervix had port site metastases after laparoscopic lymph node staging. The frequency of this event might be higher than expected. Therefore, surgeons should reduce mechanical irritation of port sites and spillage of tumor cells.

Leiomyosarcoma of the vulva. A case report.

BACKGROUND: Leiomyosarcoma of the vulva is a rare mesenchymal tumor. Biologic features of a low grade tumor were investigated by an immunohistochemical workup. CASE: A 38-year-old woman presented with a slowly growing vulvar mass. Surgical treatment was performed, and a low grade leiomyosarcoma of the vulva was diagnosed. Immunohistochemical reactions were performed with monoclonal antibodies against desmin, vimentin, smooth muscle actin, cytokeratin, S-100 protein, estrogen, progesterone and androgen receptor, p53 protein, Ki-67 antigen, leukocyte common antigen and polyclonal antibodies to factor VIII-related antigen. Expression of estrogen, progesterone and androgen receptor was present in addition to a moderate number of Ki-67-positive cells and absence of p53 protein overexpression and lymphatic cell infiltration besides adequate microvessel density for smooth muscle tumors. Since the immunohistochemical markers indicated a less aggressive tumor, any further adjuvant therapy was rejected. The patient was without recurrence 24 months later. CONCLUSION: The immunohistologic profile proved the low histologic grade of vulvar leiomyosarcoma. The findings helped to estimate prognosis and plan therapy.

Signal-amplified colorimetric in situ hybridization for assessment of human papillomavirus infection in cervical lesions.

Detection and typing of human papillomavirus (HPV) infection may have a major impact in cervical-screening and follow-up. In this study various commercially available techniques for the detection of HPV were evaluated. HPV-status was determined in 86 samples of cervical cancer by PCR and direct sequencing, catalyzed signal amplified colorimetric DNA in situ hybridization (CSAC- ISH) (GenPoint system, DAKO), immunohistochemistry (IHC) and in 12 selected cases also by conventional, non-amplified ISH. Twenty-one samples of cervical intraepithelial neoplasias grade III (CIN III) were investigated by CSAC-ISH, conventional ISH and by IHC, in corresponding PAP smears HPV-detection and typing was performed by CSAC-ISH and Hybrid Capture test II (HC). In additional 20 PAP smears HPV typing was performed using HC and a novel immunocytochemical system for HPV detection and-typing. CSAC-ISH showed good correlation with PCR analysis in cervical cancers: In 87% of PCR positive cases, HPV infection was also detected by CSAC- ISH (66/76). HPV 16 was detected in 75% of PCR-positive cases (44/59), HPV 18 in 71% of PCR positive cases (5/7). CSAC-ISH detected HPV 31 in only 29% of PCR positive cases (2/7), and HPV 33 in 64% of PCR-positive cases (23/36). Nevertheless, CSAC-ISH- false negative cases for HPV 31 or 33 were nearly always combined infections with other HPV types, which were detectable by CSAC-ISH in most cases. CSAC-ISH revealed HPV infection in 20 of 21 HC-positive cervical smears, while in corresponding biopsies (CIN III) CSAC-ISH detected 100% of HPV infections. Conventional, non-amplified ISH showed significantly lower sensitivity compared with CSAC-ISH, and immunocyto- and -histochemistry were of very low sensitivity for detection of HPV. CSAC-ISH is an easy-to-handle method for detection and typing of cervical HPV infection, and shows sufficient sensitivity for clinical practice.

[Non-closure of peritoneum at cesarean section. Results from repeat cesarean sections]. / Offenes Peritoneum bei Sectio caesarea: Ergebnisse der Re-Sectio.

OBJECTIVES: A number of publications advocate the short-term advantages of peritoneal nonclosure at cesarean section. However, currently there are no hard data available about long-term results and the repeat cesareans. MATERIAL AND METHODS: The study group of this retrospective analysis consisted of 30 women who underwent a repeat cesarean delivery, after a previous cesarean without closure of the visceral and parietal peritoneum. The control group (n = 31) had undergone peritoneal closure at the primary operation. All cesareans were performed at the same institution between 04/01/1997 and 12/31/1998 (first operation), and 01/01/1999 and 06/30/2000 (repeat operation). RESULTS: The mean operation time was 38.9 (+/- 11.6) minutes in the study group and 44.2 (+/- 13.6) minutes in controls (p = 0.05). The mean incision-delivery time was 6.7 (+/- 3.2) minutes in the study group and 9.1 (+/- 3.9) minutes in controls (p < 0.01). No difference in intraoperative blood loss was observed between the two groups. In each cohort one case with significant intraabdominal adhesions was observed. CONCLUSION: Our results indicate that nonclosure of the peritoneum at primary cesarean section does not promote intraabdominal adhesions. This appears to be beneficial for the repeat cesareans.

Interleukin-8 serum level shift in patients with ovarian carcinoma undergoing paclitaxel-containing chemotherapy.

BACKGROUND: Paclitaxel has been described to induce interleukin-8 (IL-8) transcription and secretion in human ovarian carcinoma cells. The objective of this study was to investigate possible clinical implications of the effect of paclitaxel on IL-8 serum levels in patients suffering from ovarian carcinoma. METHODS: Thirty-one patients with ovarian carcinoma who were treated with combination chemotherapy consisting of paclitaxel and carboplatin entered the study. IL-8 serum levels and CA 125 serum levels were detected three times for each patient directly before chemotherapy, after three cycles of chemotherapy, and after six cycles of chemotherapy. In addition, serum samples from 59 healthy, age-matched women were obtained. A quantitative human IL-8 immunoassay was used to determine the IL-8 serum levels. RESULTS: Seventy-eight percent of patients responded to chemotherapy, with 61% achieving a complete response and 16% achieving a partial response. The median IL-8 serum level before chemotherapy was 75 pg/mL (range, 2.7-903.3 pg/mL), the level during chemotherapy was 23.75 pg/mL (range, 0.5-248.2 pg/mL), and the level after chemotherapy was 17.65 pg/mL (range, 0.6-377.0 pg/mL). The median IL-8 serum level in controls was 15.6 pg/mL (range, 1.4-106.3 pg/mL). The authors found a statistically significant decrease in both IL-8 serum levels (P < 0.05 and P < 0.05) and CA 125 serum levels (P < 0.05 and P < 0.05) from the first to the second measurement and from the first to the third measurement, respectively. They found no correlation between the shifts of IL-8 serum levels and CA 125 serum levels during chemotherapy. CONCLUSIONS: The authors found a significant decrease in IL-8 serum levels in patients undergoing a paclitaxel-containing chemotherapy regimen, indicating that IL-8 possibly acts as a useful monitoring marker in patients with ovarian carcinoma.

Is the formation of a bladder flap at cesarean necessary? A randomized trial.

OBJECTIVE: To evaluate the effects of not forming a bladder flap at lower-segment cesarean delivery. METHODS: A total of 102 women who underwent cesarean delivery were prospectively randomized to one of two groups. In the study group (n = 53), a cesarean was performed without formation of a bladder flap. In the control group (n = 49), cesarean was performed with formation of a bladder flap before the uterine incision. RESULTS: There were differences of median skin incision-delivery interval (5 versus 7 minutes, P <.001), median total operating time (35 versus 40 minutes, P =.004), and median blood loss (Delta hemoglobin 0.5 versus 1 g/dL, P =.009) in favor of the study group. Postoperative microhematuria was reduced in the study group (21% versus 47%, P <.01). The median need for analgesics was reduced in the study group (75.0 mg diclofenac versus 150.0 mg, P <.001), and there was a lower percentage of patients receiving analgesics 2 or more days after cesarean in the study group (26.4% versus 55.1%, P =.006). There was no difference in bowel function. CONCLUSION: Omission of the bladder flap provides short-term advantages such as reduction of operating time and incision-delivery interval, reduced blood loss, and need for analgesics. Long-term effects remain to be evaluated.

Preperitoneal lipoleiomyoma of the abdominal wall in a postmenopausal woman.

OBJECTIVE: Extrauterine leiomyomas are rare events. These tumors may be easily misdiagnosed as ovarian tumors at the clinical investigation. We present the first case of an otherwise healthy postmenopausal woman, hysterectomized 20 years ago, who developed a preperitoneal lipoleimoyoma in the 30-year-old scar of a Pfannenstiel incision. The patient received continuous hormone replacement therapy (HRT) for 5 years with 1.25 mg conjugated estrogen and 5 mg medrogeston per day. METHODS: In sections of the tumor, immunohistochemical reactions with antibodies against actin, desmin, vimentin, estrogen and progesterone receptors and factor VIII related antigen was performed. RESULTS: Histologic findings revealed cellular fascicles of spindle-shaped smooth muscle cells in a whorled arrangement. Mitotic figures were absent. Central degenerative changes and focal edema were observed. Between muscle fascicles, a significant amount of fat cells (20% of tumor volume) was visible. Leiomyocytes showed immunohistochemicaly positive reactions with actin, desmin, vimentin, and steroid hormone receptors. Based on these findings, the tumor was diagnosed as lipoleiomyoma. CONCLUSIONS: Origin of the tumor of smooth muscle cells of vessels located in the abdominal wall and development under influence of oral steroids seems most probable. HRT appears to promote the development of extrauterine leiomyomas in postmenopausal women.

Systemic methotrexate treatment of interstitial pregnancy--magnetic resonance imaging (MRI) as a valuable tool for monitoring treatment.

OBJECTIVE: Interstitial pregnancy occurs in 2-4% of ectopic pregnancies and is defined as implantation of the trophoblast in the interstitial part of the tuba uterina. Therefore the term intramural pregnancy can also be found in the literature. In 20% of the cases that progress beyond 12 weeks of amenorrhea a potentially life-threatening rupture of the uterus occurs, leading to a maternal mortality rate of 2.5%. According to the literature until a few years ago diagnosis was mainly made intraoperatively, and resulted in cornual resection or hysterectomy per laparotomy. Better methods of diagnosis and treatment of interstitial pregnancy can help to decrease morbidity and mortality associated with this condition. PATIENTS: We describe two cases of interstitial pregnancies that were eventually diagnosed and also monitored by magnetic resonance imaging (MRI) after systemic methotrexate treatment. Both patients were uniparous and experienced their second spontaneous pregnancy. METHODS: Treatment consisted of four doses (50 mg/m2 body surface area) of systemic intramuscular methotrexate alternating with four doses (6 mg) of intramuscular folic acid. When beta-hCG levels were undetectable, MRI results were compared with pre-therapeutic MRI findings. RESULTS: In patients A and B, beta-hCG levels were undetectable 64 and 88 days after initiation of methotrexate treatment, while magnetic resonance imaging revealed nearly equally persisting interstitial pregnancies. They initially presented as hyperintense lesions with hypointense zones and changed into a hypointense lesion with a central hyperintense area for patient A, and a completely hyperintense lesion for patient B at the time of negative beta-hCG levels in follow-up MRI. CONCLUSION: Systemic methotrexate treatment with an intramuscular regimen is effective in the treatment of interstitial pregnancy. MRI has the ability of correct tissue differentiation and objective three-dimensional measuring of interstitial pregnancy. We therefore propose this imaging modality as a valuable tool for monitoring systemic methotrexate treatment of interstitial pregnancy that should be used additionally to beta-hCG clearance curves.

Trends in vulvar neoplasia. Increasing incidence of vulvar intraepithelial neoplasia and squamous cell carcinoma of the vulva in young women.

OBJECTIVE: To determine trends in the epidemiology of vulvar intraepithelial neoplasia (VIN) and squamous cell carcinoma (SCC) of the vulva in a Central European sample during the last decade. STUDY DESIGN: A total of 366 women with VIN 2 and 3 (n = 128) or vulvar SCC (n = 238) presented within two four-year periods separated by one decade (1985-1988 and 1994-1997). We performed a retrospective analysis of the clinicopathologic records of the cohorts. RESULTS: The number of women with high grade VIN (n = 29 vs. 99) tripled during the last decade, while the incidence of vulvar SCC remained stable. In women < or = 50 years old, the incidence of high grade VIN increased by 392% (n = 12 vs. 59) and of invasive vulvar cancer by 157% (n = 7 vs. 18). In the earlier cohort there were 7/126 (5%) women with invasive vulvar SCC under the age of 50 and, in the latter cohort, 18/112 (16%, P < .01). CONCLUSION: Over the past decade a striking increase occurred in the incidence of VIN and an increase in invasive vulvar SCC in young women.

Serum levels of progesterone in patients with preeclampsia.

In a matched pair-study study we investigated the hitherto controversially discussed serum levels of progesterone in 40 women with severe preeclampsia (PE) and 40 normotensive controls. Serum levels were determined by applying a sandwich enzyme-linked immunosorbent assay (ELISA). Median serum levels of progesterone in preeclamptic women and in controls were not statistically significant (P = 0.73). Our study indicates that the absence of altered serum levels of progesterone may not reflect the potential role of this hormone in preeclampsia.