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Human papillomavirus (HPV) infection is a necessary factor in the cervical cancer development. Also after treatment for cervical dysplasia, HPV can be present and promote the recurrence of cervical ...

PROBLEM: Regulatory T cells (Treg cells), a small subset of CD4(+) T cells maintaining tolerance by immunosuppression, are proposed contributors to the survival of the fetal semiallograft. We inves ...

High-risk human papillomavirus (hrHPV) infection is the major risk factor for cervical cancer (CxCa). The role of genetic susceptibility in the disease has been suggested, but the existing data lack consistency. We conducted a nested case-control study on 973 CxCa cases and 1,763 matched controls, from two Swedish population-based cohorts to examine the association of common genetic variants with CxCa risk. Human leukocyte antigen (HLA) alleles and 24 other polymorphisms in 14 genes were selected on the basis of reported association or mechanistic plausibility with an HPV infection or cervical cancer development. Genotyping was conducted using multiplex PCR and Luminex technology. A significant association of CxCa with various polymorphisms was observed: rs1800797 in the IL-6 gene (odds ratio [OR] = 0.88, 95% confidence intervals [CI]: 0.79-0.99); rs1041981 in the LTA gene (OR = 0.87, 95% CI: 0.78-0.98), and rs9344 in the CCND1 gene (OR = 1.14, 95% CI: 1.02-1.27), for those individuals carrying the rare allele. Additionally, the alleles 0401 and 1501 of the HLA class II DRB1 locus were associated with an increased risk (OR = 1.23, 95% CI: 1.04-1.45 and OR = 1.29, 95% CI: 1.11-1.50, respectively), and allele 1301 was associated with decreased risk (OR = 0.59, 95% CI: 0.47-0.73). The effects of CCND1 and the HLA*DRB1 alleles were independent of the effect of smoking. We did not find any association of risk with polymorphisms in genes related to the innate immune system. In conclusion, our study provides evidence for genetic susceptibility to CxCa due to variations in genes involved in the immune system and in cell cycle.

Prospective studies elucidating the impact of the treatment of cervical cancer on urinary and climacteric symptoms and sexual life are relatively rare. The aim of this study was to seek information about the occurrence of urinary, climacteric and sexual symptoms in women with cervical cancer before and 1 year after treatment without brachytherapy.This prospective study evaluated 39 women treated for cervical cancer. Data were collected by two questionnaires (before and 1 year after treatment). In order to supplement the data from the questionnaires, some data were selected from the patient's medical records.The number of voluntary micturitions, urgency, urinary incontinence and climacteric symptoms had not increased 1 year after treatment. Vaginal dryness and dyspareunia had increased and sexual desire was reduced 1-year post-treatment.This study has shown that urinary and climacteric symptoms are not frequent 1 year after treatment of cervical cancer without brachytherapy. However, there is an increased occurrence of vaginal dryness and sexual disorders 1-year post-treatment, mainly in the form of dyspareunia and reduced sexual desire. Taken together these symptoms affect the women's quality of life and it is, therefore, crucial that the medical providers become more aware of and skilled to deal with these conditions before and after treatment.

PROBLEM: The uniqueness of the human placenta cannot be replaced by animal models. In vitro studies are compulsory to elucidate the biology of human placenta and require isolation and purification ...

Assess the value of colposcopic evaluation preceding loop electrosurgical excision procedure (LEEP) conisation of cytological high grade squamous intraepithelial lesion (HSIL), and study risk factors for recurrence.Consecutive follow-up among women undergoing LEEP conisation from January 2001 to December 2004.Some 528 LEEP conisations were performed because of suspected or verified cervical dysplasia. On classified samples, cytology, punch biopsy and histopathology of the cone specimen showed cervical intraepithelial neoplasia (CIN)2 or a higher degree in 48.5, 36.2 and 58.6%, respectively. Sensitivity for HSIL out of cytology and colposcopically directed punch biopsy was 74.4 and 73.3%, respectively. Likewise, among 286 women with all 3 samples, positive and negative predictive value for HSIL in Papanicolaou (Pap) smear and punch biopsy was 78.5, 73.2% and 60.3, 63.6%, respectively. Positive cone margins were found in 16.8%. Residual/recurrent disease, defined as any grade of dysplasia at cytological follow-up, was found among 9.4%. Significant risk for recurrent/residual disease was found among those with positive marginal status. Median time from colposcopy to conisation was 2 months.An immediate colposcopically-guided LEEP conisation after HSIL Pap smear may be a safe and time saving strategy. Positive cone margins are a risk factor for residual/recurrent disease.

Systemic single-dose methotrexate treatment is a safe treatment option with a reasonably high success rate, with similar probability of a later intrauterine pregnancy as conventional surgical treat ...

OBJECTIVE: We wished to evaluate the effectiveness of treatment of cervical dysplasia by laser conization in relation to persistence of human papillomavirus after treatment. STUDY DESIGN: Of 203 women referred to colposcopy because of an abnormal Papanicolaou smear, 149 women could be followed up for 3 years. A total of 108 women were treated by carbon dioxide laser excision, 4 women were treated by carbon dioxide laser evaporation, and 37 women were merely followed up. Cervical samples were taken before treatment and at follow-up 3 years later and were analyzed by nested general primer polymerase chain reaction for human papillomavirus deoxyribonucleic acid. RESULTS: Among women treated by laser conization, 82 (73.2%) had positive results for human papillomavirus deoxyribonucleic acid before treatment. Three women (2.7%) had a positive finding at follow-up, but no woman had the same human papillomavirus type on both occasions. Eighty-eight women had grade 1 to grade 3 cervical intraepithelial neoplasia before treatment, whereas during follow-up only 2 squamous cells atypias were found. CONCLUSION: The human papillomavirus genome present before treatment was regularly cleared, and there was also no recurrence of dysplasia. The results suggest that human papillomavirus testing is useful for monitoring the efficacy of treatment and that treatment modalities resulting in clearance of human papillomavirus should be favored.

Smoking, nutrition, parity and oral contraceptive use have been reported as major environmental risk factors for cervical cancer. After the discovery of the very strong link between human papillomavirus (HPV) infection and cervical cancer, it is unclear whether the association of these environmental factors with cervical cancer reflect secondary associations attributable to confounding by HPV, if they are independent risk factors or whether they may act as cofactors to HPV infection in cervical carcinogenesis. To investigate this issue, we performed a population-based case–control study in the Västerbotten county of Northern Sweden of 137 women with high-grade cervical intra-epithelial neoplasia (CIN 2–3) and 253 healthy age-matched women. The women answered a 94-item questionnaire on diet, smoking, oral contraceptive use and sexual history and donated specimens for diagnosis of present HPV infection (nested polymerase chain reaction on cervical brush samples) and for past or present HPV infections (HPV seropositivity). The previously described protective effects of dietary micronutrients were not detected. Pregnancy appeared to be a risk factor in the multivariate analysis (P< 0.0001). Prolonged oral contraceptive use and sexual history were associated with CIN 2–3 in univariate analysis, but these associations lost significance after taking HPV into account. Smoking was associated with CIN 2–3 (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.7–4.0), the effect was dose-dependent (P = 0.002) and the smoking-associated risk was not affected by adjusting for HPV, neither when adjusting for HPV DNA (OR 2.5, CI 1.3–4.9) nor when adjusting for HPV seropositivity (OR 3.0, CI 1.9–4.7). In conclusion, after taking HPV into account, smoking appeared to be the most significant environmental risk factor for cervical neoplasia. © 2000 Cancer Research Campaign

Isotype-specific serum antibody responses against human papillomavirus (HPV) type 16 were evaluated by use of cross-sectional, prospective, and population-based seroepidemiologic studies. IgG1 and IgA were the most abundant isotypes. No sample contained IgG2, and

Many human papillomavirus (HPV) genotypes are associated with cervical carcinoma. We demonstrate the utility of an innovative technique for genotyping of HPV in cervical tissue samples. This method provides an accurate means of identification of the specific HPV genotypes present in clinical specimens. By using the MY09-MY11 and the GP5 + -GP6 + consensus primer pairs, HPV sequences were amplified by nested PCR from DNA isolated from cervical smear samples. This led to the production of an approximately 140-bp PCR product from the L1 (major capsid) gene of any of the HPVs present in the sample. PCR was performed with a deoxynucleoside triphosphate mixture which resulted in the incorporation of deoxyuridine into the amplified DNA product at positions where deoxythymidine would normally be incorporated at a frequency of about once or twice per strand. Following the PCR, the product was treated with an enzyme mix that contains uracil N -glycosylase (UNG) and endonuclease IV. UNG removes the uracil base from the nucleotide, and endonuclease IV cleaves the phosphodiester bond at this newly formed abasic site, producing fragments of various sizes. By having end labeled one of the amplification primers, a DNA ladder which is analogous to a “T-sequencing ladder” was produced upon electrophoresis of the products. By comparing this T-sequencing ladder to the known sequences of HPVs, the genotypes of unknown HPV isolates in samples were assigned. Data showing the utility of this technique for the rapid analysis of clinical samples are presented.

Objective: Our purpose was to determine the predictive values of primary or secondary screening for cervical human papillomavirus infection for cytologic detection of cervical intraepithelial neoplasia. Study Design: Most of the 254 women referred for colposcopy in Vasterbotten County in Sweden during October 1993 through December 1995 and 320 age-matched women from the general population were screened for human papillomavirus deoxyribonucleic acid by nested general-primer polymerase chain reaction. Results: Ninety-six percent of women with high-grade cervical intraepithelial neoplasia had human papillomavirus, compared with 4% of women with normal findings (odds ratio 606; 95% confidence interval 137 to 5607). Thirty-seven percent of referred women and 48% of referred women >39 years old had mostly minor cytologic abnormalities with no human papillomavirus. The human papillomavirus–associated positive predictive value for cervical intraepithelial neoplasia was 76% in the colposcopy group and 11% in the general population, whereas the negative predictive value was >97% in both populations. Conclusion: Testing for human papillomavirus deoxyribonucleic acid seems diagnostically useful among women referred for colposcopy. (Am J Obstet Gynecol 1998;179:1497-502.)

Human papillomavirus (HPV) infection is a necessary factor in the cervical cancer development. Also after treatment for cervical dysplasia, HPV can be present and promote the recurrence of cervical disease. In the present study, the aim was to perform a long-term follow-up on the ability of HPV testing with genotyping, as compared with cytology, to predict recurrence of high-grade cervical intraepithelial neoplasia and to evaluate the effectiveness of treatment with loop electrosurgical excision procedure (LEEP) conization. Cervical samples for HPV DNA testing and cytological analysis were obtained from 178 women with abnormal smears referred for treatment with LEEP conization. These women were scheduled for HPV DNA testing and Pap smears before and 3, 6, 12, 24, and 36 months after treatment. Three years after treatment 3.1% (N = 4) of women were still persistently HPV-positive with the same type as had been detected at treatment. Recurrent or residual cervical intraepithelial neoplasia II+ in histopathology was found among 9 (5.1%) women during follow-up. All of these women had type-specific HPV-persistence (sensitivity 100% [95% CI 63-100%] and specificity 94.7% [89.8-97.4%]), but only 7/9 had abnormal cytology (sensitivity 77.8% [40.2-96.1%] and specificity 94.7% [89.8-97.4%]). No recurrent or residual disease was found among women with any other patterns of HPV positivity (e.g., type change or fluctuating positivity) (sensitivity 0% [95% CI 0-37.1%] and specificity 80.5% [73.5-86.0%]). In conclusion, only type-specific HPV persistence predicted recurrent or residual disease, and HPV genotyping appears useful to improve the specificity when using HPV testing in post-treatment follow-up.

Galectin-1 (gal-1) is expressed at the feto-maternal interface and plays a role in regulating the maternal immune response against placental alloantigens, contributing to pregnancy maintenance. Both decidua and placenta contribute to gal-1 expression and may be important for the maternal immune regulation. The expression of gal-1 within the placenta is considered relevant to cell-adhesion and invasion of trophoblasts, but the role of gal-1 in the immune evasion machinery exhibited by trophoblast cells remains to be elucidated. In this study, we analyzed gal-1 expression in preimplantation human embryos and first-trimester decidua-placenta specimens and serum gal-1 levels to investigate the physiological role played by this lectin during pregnancy. The effect on human leukocyte antigen G (HLAG) expression in response to stimulation or silencing of gal-1 was also determined in the human invasive, proliferative extravillous cytotrophoblast 65 (HIPEC65) cell line. Compared with normal pregnant women, circulating gal-1 levels were significantly decreased in patients who subsequently suffered a miscarriage. Human embryos undergoing preimplantation development expressed gal-1 on the trophectoderm and inner cell mass. Furthermore, our in vitro experiments showed that exogenous gal-1 positively regulated the membrane-bound HLA-G isoforms (HLA-G1 and G2) in HIPEC65 cells, whereas endogenous gal-1 also induced expression of the soluble isoforms (HLA-G5 and -G6). Our results suggest that gal-1 plays a key role in pregnancy maternal immune regulation by modulating HLA-G expression on trophoblast cells. Circulating gal-1 levels could serve as a predictive factor for pregnancy success in early human gestation. Fil: Tirado González, Irene. Medicine University Berlin; Alemania Fil: Freitag, Nancy. Medicine University Berlin; Alemania Fil: Barrientos, Gabriela Laura. Medicine University Berlin; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Shaikly, Valerie. University Of Essex; Reino Unido. Assisted Reproduction and Gynaecology Centre; Reino Unido Fil: Nagaeva, Olga. Universidad de Umea; Suecia Fil: Strand, Magnus. Universidad de Umea; Suecia Fil: Kjellberg, Lennart. Universidad de Umea; Suecia Fil: Klapp, Burghard F.. Medicine University Berlin; Alemania Fil: Mincheva Nilsson, Lucia. Universidad de Umea; Suecia Fil: Cohen, Marie. Laboratoire d’Hormonologie; Suiza Fil: Blois, Sandra M.. Medicine University Berlin; Alemania

Background: Epidemiologic data and animal models suggest that, despite the predominant role of human papillomavirus infection, sex steroid hormones are also involved in the etiology of invasive cervical carcinoma (ICC). Methods: Ninety-nine ICC cases, 121 cervical intraepithelial neoplasia grade 3 (CIN3) cases and 2 control women matched with each case for center, age, menopausal status and blood collection–related variables, were identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Circulating levels of testosterone (T) and estradiol (E2); dehydroepiandrosterone sulfate (DHEAS); progesterone (premenopausal women); and sex hormone–binding globulin (SHBG) were measured using immunoassays. Levels of free (f) T and E2 were calculated from absolute concentrations of T, E2, and SHBG. Odds ratios (ORs) and 95% confidence intervals (CI) were computed using regularized conditional logistic regression. Results: Among premenopausal women, associations with ICC were observed for fT (OR for highest vs. lowest tertile = 5.16, 95% CI, 1.50–20.1). SHBG level was associated with a significant downward trend in ICC risk. T, E2, fE2, and DHEAS showed nonsignificant positive association with ICC. Progesterone was uninfluential. Among postmenopausal women, associations with ICC were found for T (OR = 3.14; 95% CI, 1.21–9.37), whereas E2 and fT showed nonsignificant positive association. SHBG level was unrelated to ICC risk in postmenopausal women. No associations between any hormone and CIN3 were detected in either pre- or postmenopausal women. Conclusions: Our findings suggest for the first time that T and possibly E2 may be involved in the etiology of ICC. Impact: The responsiveness of cervical tumors to hormone modulators is worth exploring. Cancer Epidemiol Biomarkers Prev; 20(12); 2532–40. ©2011 AACR.

Regulatory T cells (Treg cells), a small subset of CD4(+) T cells maintaining tolerance by immunosuppression, are proposed contributors to the survival of the fetal semiallograft. We investigated Treg cells in paired decidual and peripheral blood (PB) samples from healthy women in early pregnancy and PB samples from non-pregnant women.Distribution, location, cytokine mRNA, and phenotype were assessed in CD4(+) CD25(+) Treg cells from paired samples using immunohistochemistry, immunofluorescence, flow cytometry, and real-time quantitative RT-PCR.The presence and in situ distribution of CD4(+) Foxp3(+) Treg cells in decidua are hereby demonstrated for the first time. Three Foxp3(+) cell populations, CD4(+) CD25(++) Foxp3(+), CD4(+) CD25(+) Foxp3(+), and CD4(+) CD25(-) Foxp3(+), were enriched locally in decidua. In contrast, no statistically significant difference in numbers of circulating Treg cells between pregnant and non-pregnant women was found. The Foxp3(+) cells expressed the surface molecules CD45RO, CTLA-4, CD103, Neuropilin-1, LAG-3, CD62L, and TGFβ1 mRNA consistent with Treg phenotype. The population of CD4(+) CD25(-) Foxp3(+) cells, not described in human decidua before, was enriched 10-fold compared with PB in paired samples. Their cytokine expression was often similar to Th3 profile, and the Foxp3 mRNA expression level in CD4(+) CD25(-) cells was stable and comparable to that of CD4(+) CD25(+) Treg cells implying that the majority of CD4(+) CD25(-) Foxp3(+) cells might be naïve Treg cells.(i) There is a local enrichment of Treg cells in decidua (ii) The exclusive accumulation of decidual CD4(+) CD25(-) Foxp3(+) cells suggests an additional reservoir of Foxp3(+) naïve Treg cells that can be converted to 'classical' Treg cells in uterus.

Udgivelsesdato: 2010-Sep-17 Some dietary factors could be involved as co-factors in cervical carcinogenesis but evidence is inconclusive. There is no data about the effect of fruits and vegetables intake (F&V) on cervical cancer from cohort studies.We examined the association between the intake of F&V and selected nutrients and the incidence of carcinoma in-situ (CIS) and invasive squamous cervical cancer (ISC) in a prospective study of 299,649 women, participating in the European Prospective Investigation Into Cancer and Nutrition (EPIC) study. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95%CI).A calibration study was used to control measurement errors in the dietary questionnaire.After a mean of 9 years of follow-up, 253 ISC and 817 CIS cases were diagnosed. In the calibrated model, we observed a statistically significant inverse association of ISC with a daily increase in intake of 100g of total fruits (HR 0.83; 95%CI 0.72-0.98) and a statistically nonsignificant inverse association with a daily increase in intake of 100 g of total vegetables (HR 0.85: 95%CI 0.65-1.10). Statistically nonsignificant inverse associations were also observed for leafy vegetables, root vegetables, garlic and onions, citrus fruits, vitamin C, vitamin E, and retinol for ISC. No association was found regarding beta-carotene, vitamin D and folic acid for ISC. None of the dietary factors examined were associated with CIS. Our study suggests a possible protective role of fruit intake and other dietary factors on ISC, that need to be confirmed on a larger number of ISC cases.

Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. The present study is a targeted candidate gene follow-up based on: i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease Epidermodysplasia Verruciformis (EV), and ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and cervical cancer. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNP) harbouring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III (CINIII) or invasive cervical cancer (ICC) and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 (ORGGvsAA = 0.6, 95% CI: 0.3 - 0.9, p = 0.02) and rs16970849 (ORAGvsGG = 0.8, 95% CI: 0.66 - 0.98, p = 0.03). The present data supports the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.

During mammalian pregnancy maternal-fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. Exosomes are membrane nanovesicles with defined morphology, which are secreted from endosomal multivesicular bodies (MVB) upon fusion with the plasma membrane. Previously, we reported that the MHC class I chain-related (MIC) proteins A and B, human ligands of the activating NK cell receptor NKG2D, are expressed by placenta, sorted to MVB of syncytiotrophoblast and probably released via MIC-bearing exosomes. In this report, we show that the second family of human NKG2D ligands, the UL-16 binding proteins (ULBP), is also expressed by placenta. Importantly, this expression was not due to placental CMV infection. Immunoelectron microscopy disclosed that ULBP1–5 are produced and retained in MVB of the syncytiotrophoblast on microvesicles/exosomes. Using human placenta explant cultures and different assays, we demonstrate that exosomes bearing NKG2D ligands are released by human placenta. Isolated placental exosomes carried ULBP1–5 and MIC on their surface and induced down-regulation of the NKG2D receptor on NK, CD8+, and γδ T cells, leading to reduction of their in vitro cytotoxicity without affecting the perforin-mediated lytic pathway. Release of placental NKG2D ligands via exosomes is an alternative mechanism for generation of bioactive soluble form of these ligands. These findings highlight a role for NKG2D ligand-bearing placental exosomes in the fetal immune escape and support the view of placenta as a unique immunosuppressive organ.

The uniqueness of the human placenta cannot be replaced by animal models. In vitro studies are compulsory to elucidate the biology of human placenta and require isolation and purification of villous trophoblasts, which can be used in molecular and functional studies. Constant improvement in the isolation technique is required to obtain a high yield of pure trophoblast cells with high viability and well preserved morphology.Optimized isolation procedure for human villous trophoblasts based on mild enzymatic treatment, Percoll gradient centrifugation and additional purification step involving positive or negative immunoselection on magnetic beads is described.A simple and effective isolation protocol gave a reasonably high yield of villous trophoblast cells with high purity and viability, and excellent morphology as assessed by flow cytometry and electron microscopy.This protocol provides an efficient, optimized method for isolation and enrichment of villous trophoblast cells, suitable for phenotypic, ultrastructural, molecular and functional analyses and for establishment of primary cultures.

The local immune privilege of the fetus is created by the placenta. Fas ligand (FasL) expression in trophoblast has been implied as one of the mechanisms of fetal tolerance. However, the expression of membranal FasL by trophoblast has failed to explain this role of FasL. Two objections can be raised: (1) there have been contradictions considering which trophoblast cells, syncytiotrophoblast (ST) or cytotrophoblast, express FasL; (2) in vivo and in vitro studies have shown that the membranal form of FasL evokes inflammatory response and thus may promote fetal rejection. Using different assays and the FasL-specific antibody G247-4 we demonstrate beyond doubt that in vivo, (1) FasL is produced by and stored in the first trimester human ST only and (2) the human ST lacks surface membranal FasL. Instead, FasL, loaded in microvesicles, is stored in cytoplasmic granules. These results complement the recent in vitro studies of the microvesicular form of FasL secretion by cultured trophoblast cells, and suggest that placental FasL is synthesized by villous ST, stored in microvesicular form and secreted as exosomes. Secretion of the exosome-associated form of FasL may be one mechanism by which the placenta promotes a state of immune privilege. Additionally, FasL expression in Hofbauer cells is also demonstrated.

Objectives: Reproductive outcome after laparoscopy or laparotomy performed for treatment of ectopic pregnancy. Methods: Data of 104 women were collected by a questionnaire and from medical records. Results: No differences in pregnancy rate were found comparing the two different operative procedures. Women with a normal contralateral fallopian tube had a better pregnancy rate compared with those with a damaged contralateral tube. Conclusions: The crucial factor for future reproductive outcome after surgical treatment of ectopic pregnancy is the status of the contralateral tube.

As conservative management of ectopic pregnancy becomes more routine, attention is being paid to the long-term effects of treatment with either methotrexate (MTX) or surgery. This study describes the authors' experience with management of ectopic pregnancy in routine clinical practice and assesses pregnancy outcome after treatment. From 1995 through 1997, 107 patients with possible ectopic pregnancy were seen at Umea Hospital. After evaluation with a combination of transvaginal ultrasonography and serial measurement of β-human chorionic gonadotropin (β-hCG) levels. Spontaneous abortion was diagnosed in 18 women. The remaining 89 patients make up the study population. Patients in hemodynamic shock, in severe pain, with β-hCG levels greater than 7500 IU/liter, with ectopic pregnancy greater than 35 mm, with large intraabdominal bleeding, or who had other pelvic surgery planned were treated with open or laparoscopic surgery. If reabsorption of ectopic pregnancy was suspected because of declining β-hCG levels, the patient was managed expectantly, i. e., she was closely observed until her diagnosis was certain. Women who were hemodynamically stable, without severe pelvic pain, and with β-hCG levels less than 700 IU/liter were treated with MTX. They received a single intramuscular dose of 50 mg/m 2 MTX, followed by serial measurements of serum β-hCG levels taken on days 1, 2, 4, and 7. A second dose of 50 mg/m 2 was given if β-hCG levels declined less than 15% between days 4 and 7. Patients were followed weekly until their levels dropped below 10 IU/liter. The treatment regimen was converted to surgery if the patient developed severe, intractable pelvic pain associated with hemodynamic instability or peritoneal irritation. In all, 26 patients were treated with MTX, 46 underwent laparoscopy or laparotomy, and 17 were managed expectantly. Except for lower β-hCG levels, the women in the MTX group were similar in clinical and demographic characteristics to those in the surgical group. Twenty of the 26 MTX patients (77%) achieved successful remission of β-hCG levels with 2 requiring a second dose of MTX. There was no relationship seen between the pretreatment β-hCG levels and the length of time to resolution (mean 24 ′ 9 days). More than seven (7.4 ′ 1.8) clinic visits were needed for each MTX patient. The reasons for conversion to surgical treatment in the MTX group included persistent elevated β-hCG levels in one patient, intractable pain in two, ongoing intraabdominal bleeding in two, and delay of a second dose of MTX in one. There were no significant differences found between those treated successfully with MTX and those whose MTX treatment failed. Three of the 17 women who were managed expectantly required surgical treatment. In all, 55, of the 89 women (62%) underwent surgery for ectopic pregnancy. A total of 70 of the study subjects expressed a desire for another pregnancy. By August 2000, 64% of the eligible MTX patients, 51.4% of the eligible surgery patients, and 31% of the eligible patients treated expectantly had achieved an intrauterine pregnancy.

OBJECTIVE: We wished to evaluate the effectiveness of treatment of cervical dysplasia by laser conization in relation to persistence of human papillomavirus after treatment. STUDY DESIGN: Of 203 women referred to colposcopy because of an abnormal Papanicolaou smear, 149 women could be followed up for 3 years. A total of 108 women were treated by carbon dioxide laser excision, 4 women were treated by carbon dioxide laser evaporation, and 37 women were merely followed up. Cervical samples were taken before treatment and at follow-up 3 years later and were analyzed by nested general primer polymerase chain reaction for human papillomavirus deoxyribonucleic acid. RESULTS: Among women treated by laser conization, 82 (73.2%) had positive results for human papillomavirus deoxyribonucleic acid before treatment. Three women (2.7%) had a positive finding at follow-up, but no woman had the same human papillomavirus type on both occasions. Eighty-eight women had grade 1 to grade 3 cervical intraepithelial neoplasia before treatment, whereas during follow-up only 2 squamous cells atypias were found. CONCLUSION: The human papillomavirus genome present before treatment was regularly cleared, and there was also no recurrence of dysplasia. The results suggest that human papillomavirus testing is useful for monitoring the efficacy of treatment and that treatment modalities resulting in clearance of human papillomavirus should be favored.

(1982). Der Simplicissimus und die Slawen, 1896–1914. Scando-Slavica: Vol. 28, No. 1, pp. 69-90.