Optimal preoperative autologous blood storage volume required in surgeries for placenta previas and low-lying placentas.

AIM: The high rate of stored preoperative autologous blood wastage is concerning. This study analyzed patients who provided preoperative autologous blood donations (PABDs) for massive bleeding during surgery for placenta previas and low-lying placentas, and investigated the optimal PABD storage volume required to avoid allogeneic transfusion. METHODS: Of 386 patients who provided PABDs at our hospital from 2008 to 2013, 269 patients with placenta previas or low-lying placentas were retrospectively analyzed. The PABD storage volumes were stratified into four groups based on the amounts stored, and the allogeneic transfusion usage frequencies were compared. RESULTS: A total of 124 patients (46.1%) received PABDs and 12 patients (4.5%) received allogeneic transfusions. The average PABD volume wasted was 23 940 mL/year. The allogeneic transfusion utilization rate was significantly higher in the 1- to 300-mL group (17.2%) than in the 301- to 600-mL (1.69%), 601- to 900-mL (3.82%), and 901- to 1200-mL (0%) groups (P < 0.05). The PABD cut-off volume for avoiding allogeneic blood transfusion was 300 mL, and the odds ratio for ≤300-mL PABD in a multivariate analysis was 14.3 (95% confidence interval 1.3-149.3; P = 0.03). The maximum surgical blood order schedule was 2.16 units (432 mL), and the surgical blood order equation was 2.15 units (430 mL). CONCLUSION: The allogeneic transfusion utilization rate did not differ between the 600-mL group and the groups with higher PABD storage volumes; hence, storing 600 mL of PABD was appropriate for surgery for placenta previas and low-lying placentas.

Human leukocyte antigen class II DRB1*1302 allele protects against cervical cancer: At which step of multistage carcinogenesis?

We investigated the role of human leukocyte antigen (HLA) class II alleles in multistage cervical carcinogenesis. Cross-sectional analysis for HLA association with cervical cancer included 1253 Japanese women: normal cytology (NL, n = 341), cervical intraepithelial neoplasia grade 1 (CIN1, n = 505), CIN grade 2 or 3 (CIN2/3, n = 96), or invasive cervical cancer (ICC, n = 311). The HLA class II allele frequencies were compared by Fisher's exact test or the χ(2) -test. The Bonferroni adjustment corrected for multiple comparisons. Among the study subjects, 454 women with low-grade squamous intraepithelial lesion cytology were prospectively monitored by cytology and colposcopy every 3-4 months to analyze cumulative risk of CIN3 within the next 10 years in relation to HLA class II alleles. HLA class II DRB1*1302 allele frequency was similar between women with NL (11.7%) and CIN1 (11.9%), but significantly decreased to 5.2% for CIN2/3 and 5.8% for ICC (P = 0.0003). Correction for multiple testing did not change this finding. In women with low-grade squamous intraepithelial lesion cytology, the cumulative risk of CIN3 diagnosed within 10 years was significantly reduced among DRB1*1302-positive women (3.2% vs. 23.7%, P = 0.03). In conclusion, the two different types of analysis in this single study showed the protective effect of the DRB1*1302 allele against progression from CIN1 to CIN2/3.

Association between carotenoids and outcome of cervical intraepithelial neoplasia: a prospective cohort study.

BACKGROUND: It has been suggested that micronutrients such as alpha-tocopherol, retinol, lutein, cryptoxanthin, lycopene, and alpha- and beta-carotene may help in the prevention of cervical cancer. Our aim was to investigate whether serum concentrations and/or dietary intake of micronutrients influence the regression or progression of low-grade cervical abnormalities. METHODS: In a prospective cohort study of 391 patients with cervical intraepithelial neoplasia (CIN) grade 1-2 lesions, we measured serum micronutrient concentrations in addition to a self-administered questionnaire about dietary intake. We evaluated the hazard ratio (HR) adjusted for CIN grade, human papillomavirus genotype, total energy intake and smoking status. RESULTS: In non-smoking regression subjects, regression was significantly associated with serum levels of zeaxanthin/lutein (HR 1.25, 0.78-2.01, p = 0.024). This benefit was abolished in current smokers. Regression was inhibited by high serum levels of alpha-tocopherol in smokers (p = 0.042). In progression subjects, a significant protective effect against progression to CIN3 was observed in individuals with a medium level of serum beta-carotene [HR 0.28, 95 % confidence interval (CI) 0.11-0.71, p = 0.007), although any protective effect from a higher level of serum beta-carotene was weaker or abolished (HR 0.52, 95 % CI 0.24-1.13, p = 0.098). Increasing beta-carotene intake did not show a protective effect (HR 2.30, 95 % CI 0.97-5.42, p = 0.058). CONCLUSIONS: Measurements of serum levels of carotenoids suggest that regression is modulated by smoking status. Maintaining a medium serum level of beta-carotene has a protective effect for progression; however, carotene intake is not correlated with serum levels of carotenoids.

Do neutralizing antibody responses generated by human papillomavirus infections favor a better outcome of low-grade cervical lesions?

To determine the role of neutralizing antibody generated by human papillomavirus (HPV) infections, baseline levels of serum neutralizing antibodies directed against HPV 16 and cervical HPV DNA were determined in 242 unvaccinated women with low-grade cervical abnormalities, who were then monitored by cytology and colposcopy every 4 months. In women infected with HPV 16 (n = 42), abnormal cytology persisted longer in those positive for HPV 16-specific neutralizing antibodies at baseline (median time to cytological regression: 23.8 vs. 7.2 months). Progression to cervical precancer (cervical intraepithelial neoplasia grade 3) within 5 years occurred only among women carrying HPV 16-specific neutralizing antibodies (P = 0.03, log-rank test). In women infected with types other than HPV 16 (n = 200), detection of HPV 16-specific neutralizing antibodies was not correlated with disease outcome. In conclusion, development of specific neutralizing antibodies following natural HPV 16 infection did not favor a better outcome of low-grade cervical lesions induced by HPV 16 or by other types; rather, detection of neutralizing antibodies generated by current infection may reflect viral persistence and thus help identify those who are at high risk of disease progression.

HLA class II DRB1*1302 allele protects against progression to cervical intraepithelial neoplasia grade 3: a multicenter prospective cohort study.

OBJECTIVE: Genetic variations in human leukocyte antigens (HLA) class II regions may influence the risk of cervical cancer by altering the efficiency of the immune responses to human papillomavirus antigens. This prospective study was designed to evaluate the effects of HLA class II alleles on the natural course of cervical precursor lesions. METHODS: We followed a total of 454 Japanese women with cytological low-grade squamous intraepithelial lesion (LSIL) and histological cervical intraepithelial neoplasia grades 1 to 2 (CIN1-CIN2). Patients were tested for HLA class II alleles and cervical human papillomavirus DNA at the time of entry and then monitored by cytology and colposcopy every 4 months for a mean follow-up of 39.0 months. We analyzed cumulative probabilities of cytological regression to at least 2 consecutive negative Papanicolaou tests and histological progression to biopsy-positive CIN3. RESULTS: During the follow-up period, 39 lesions progressed to CIN3, and 282 lesions regressed to normal cytology. Progression to CIN3 did not occur in DRB1*1302-positive women, and this protective effect of DRB1*1302 was statistically significant (P = 0.03). Low-grade squamous intraepithelial lesion regressed to normal cytology more quickly in DRB1*1302-positive women than in DRB1*1302-negative women (median time, 8.9 months vs 14.2 months), although the difference was not statistically significant (P = 0.16). The risk of LSIL persistence or progression to CIN3 within 5 years was not affected by any other HLA class II alleles. CONCLUSION: By using a prospective study design, we demonstrated the protective effect of the DRB1*1302 allele against progression to CIN3 among Japanese women with LSIL.

Subsequent risks for cervical precancer and cancer in women with low-grade squamous intraepithelial lesions unconfirmed by colposcopy-directed biopsy: results from a multicenter, prospective, cohort study.

OBJECTIVE: To investigate the natural course of low-grade squamous intraepithelial lesions (LSILs) that cannot be histologically confirmed by colposcopy-directed biopsy. METHODS: In a multicenter, prospective, cohort study of Japanese women with LSILs, we analyzed the follow-up data from 64 women who had a negative biopsy result at the initial colposcopy (biopsy-negative LSIL) in comparison with those from 479 women who had a histologic diagnosis of cervical intraepithelial neoplasia grade 1 (LSIL/CIN1). Patients were monitored by cytology and colposcopy every 4 months for a mean follow-up period of 39.0 months, with cytologic regression defined as two consecutive negative smears and normal colposcopy. RESULTS: In women with biopsy-negative LSILs, there were no cases of CIN3 or worse (CIN3+) diagnosed within 2 years; the difference in the 2-year risk of CIN3+ between the two groups was marginally significant (0 vs. 5.5%; P = 0.07). The cumulative probability of cytologic regression within 12 months was much higher in the biopsy-negative LSIL group (71.2 vs. 48.6%; P = 0.0001). The percentage of women positive for high-risk human papillomaviruses (hrHPVs) was significantly lower in the biopsy-negative LSIL group than in the LSIL/CIN1 group (62.1 vs. 78.4%; P = 0.01); however, the 12-month regression rate of biopsy-negative LSIL was similar between hrHPV-positive and -negative women (67.3 vs. 74.4%, P = 0.73). CONCLUSION: In women with biopsy-negative LSILs, the risk of CIN3+ diagnosed within 2 years was low; furthermore, approximately 70% underwent cytologic regression within 12 months, regardless of HPV testing results. Biopsy-negative LSILs may represent regressing lesions rather than lesions missed by colposcopy.

Predicting the progression of cervical precursor lesions by human papillomavirus genotyping: a prospective cohort study.

Only a subset of cervical precursor lesions progress to cervical cancer and because of the lack of the predictive markers, it cannot be ascertained which lesions will progress or not. To estimate the risk of disease progression associated with human papillomavirus (HPV) genotypes, we followed 570 Japanese women with cytological LSIL (low-grade squamous intraepithelial lesion) and histological CIN (cervical intraepithelial neoplasia) grade 1-2 lesions (479 CIN 1; 91 CIN 2) at 3 to 4 month intervals for a mean follow-up period of 39.1 months. At entry, we detected HPV DNA in cervical samples by polymerase chain reaction-based methodology. Over the period of follow-up period, 46 lesions progressed to CIN 3 while 362 regressed to normal cytology. Women with multiple HPV infections were more likely to have persistent lesions (hazard ratio [HR] for regression, 0.65; 95% confidence interval [CI], 0.42-1.02; p = 0.07); however, multiple infections did not increase the risk of progression (HR for progression, 1.04; 95% CI, 0.37-2.94; p = 0.94). After adjusting for CIN grade and women's age, HRs for progression to CIN 3 (vs. women with low-risk types or negative for HPV DNA) varied markedly by HPV genotype: type 16 (11.1, 95% CI: 1.39-88.3); 18 (14.1, 0.65-306); 31 (24.7, 2.51-243); 33 (20.3, 1.78-231); 35 (13.7, 0.75-251); 52 (11.6, 1.45-93.3); 58 (8.85, 1.01-77.6); other high-risk types (4.04, 0.47-34.7). HPV 45 was not detected in our study subjects. The cumulative probability of CIN 3 within 5 years was 20.5% for HPV 16, 18, 31, 33, 35, 52 and 58; 6.0% for other high-risk types; 1.7% for low-risk types (p = 0.0001). In conclusion, type-specific HPV testing for women with LSIL/CIN 1-2 lesions is useful for identifying populations at increased or decreased risk of disease progression.

Tobacco smoking and regression of low-grade cervical abnormalities.

The role of tobacco smoking in the multistage carcinogenesis at the cervix is not fully understood because of a paucity of prospective data. To assess the relationship between smoking and spontaneous regression of cervical precursor lesions, a total of 516 women with low-grade squamous intraepithelial lesion (LSIL) were monitored by cytology and colposcopy every 4 months. Probability of LSIL regression within 2 years was analyzed in relation to smoking behaviors, with regression defined as at least two consecutive negative Pap smears and normal colposcopy. Women's age, initial biopsy results, and human papillomavirus (HPV) genotypes were included in the multivariate models for adjustments. Our study subjects included 258 never-smokers and 258 smokers (179 current and 79 former smokers). During a mean follow-up time of 39.8 months, 320 lesions regressed to normal cytology. Probability of regression within 2 years was significantly lower in smokers than in never-smokers (55.0%vs 68.8%, P = 0.004). The risk of LSIL persistence increased with smoking intensity and duration and with younger age at starting smoking (P = 0.003, P < 0.001, and P = 0.03, respectively). Smokers had twice as high a risk of persistent HPV infection compared to never-smokers (odds ratio, 2.50; 95% confidence interval, 1.30-4.81; P = 0.006). In young women, passive smoking since childhood reduced probability of regression within 2 years (56.7%vs 85.9%, P < 0.001). Further adjustments for a wide range of cervical cancer risk factors did not change the findings. In conclusion, tobacco smoking may interfere with regression of cervical precursor lesions. Childhood exposure to second-hand smoke may increase a risk of persistent cervical abnormalities among young women.

Five-year results of cyclic semi-high dose neoadjuvant chemotherapy supported by autologous peripheral blood stem-cell transplantation in patients with advanced ovarian cancer.

BACKGROUND: To achieve anti-ovarian tumor responses similar to those obtained with high-dose chemotherapy but with milder side effects, we developed a treatment protocol in which semi-high dose multi-cycle neoadjuvant chemotherapy was supported by autologous peripheral blood stem-cell transplantation (auto-PBSCT). METHODS: Seventeen patients with advanced ovarian cancer were enrolled in this study. Two cycles of semi-high dose neoadjuvant chemotherapy, using carboplatin (AUC, 8.75; average dose, 621 mg/m(2)) and etoposide (average dose, 960 mg/m(2)) were supported by auto-PBSCT and followed by cytoreductive surgery and further chemotherapy. Each patient was followed for at least 5 years. RESULTS: This treatment schedule achieved an overall response rate of 70.6% in 17 patients with stage III or stage IV ovarian cancer. The 5-year disease-free survival rate was 52.9% (95% confidence interval, 29.2%-76.6%) and the median survival time was 63 months (95% confidence interval, 16-79 months). Thus, we obtained superior treatment outcomes in these 17 patients in comparison with published conventional protocols. CONCLUSION: Cyclic semi-high dose neoadjuvant chemotherapy supported by auto-PBSCT may be tolerable and favorable for patients with advanced ovarian cancer. To achieve anti-ovarian tumor responses similar to those obtained with high-dose chemotherapy but with milder side effects, we developed a treatment protocol in which semi-high dose multi-cycle neoadjuvant chemotherapy was supported by autologous peripheral blood stem-cell transplantation (auto-PBSCT).

Analysis of HLA-DRB1*0901-binding HPV-16 E7 helper T cell epitope.

AIM: This study sought to determine the human papillomavirus (HPV)-16 E7 epitopes that would be presented by HLA-DR molecules to CD4-positive T cells in patients with cervical carcinoma. METHODS: HLA-DR binding assays were performed using HPV-16 E7-derived synthetic peptides and, after incubation with these DR-binding peptides, helper T cell frequencies were analyzed in patients whose HLA and HPV genotypes were confirmed. RESULTS: We determined that the E7d peptide, 61CDSTLRLCVQSTHVDIRTL80E, was bound by HLA-DRB1*0901. An increased frequency (0.3-2.4%) of type 2 helper T cell responses was found in HLA-DRB1*0901-positive patients with cervical dysplasia and carcinoma. We found that when IL-12 was combined with E7d-peptide stimulation in vitro, the frequency of type 1 helper T cell responses also increased in patients with carcinoma. CONCLUSION: Thus HPV-16 E7d peptide as an HLA-DRB1*0901-restricted helper T cell epitope might usefully be incorporated into an understanding of the immunological mechanism and immunotherapy for this disease.

Human papillomavirus type 16 E6 variants and HLA class II alleles among Japanese women with cervical cancer.

The enhanced oncogenicity of particular human papillomavirus type 16 (HPV16) E6 variants is population-dependent, implying the involvement of additional genetic cofactors. This study was designed to investigate the association between E6 variants and human leukocyte antigen (HLA) polymorphism within a Japanese population. Fifty-seven women with HPV16-positive cervical cancer were analyzed for E6 sequence variation and its relationship to HLA class II alleles. Compared with local controls (n = 138) and published controls (n = 916), DRB1*1501 and DQB1*0602 frequencies were significantly increased among patients with HPV16 E6 prototype (n = 11). Additionally, DRB1*1502 was positively associated with a particular E6 variant designated D25E (n = 25), although we could not find a significant association between HLA class II alleles and L83V variants (n = 16). Our observations suggest that a specific match between E6 variant proteins and HLA types may contribute to HPV16-related cervical carcinogenesis.

Platelet transfusion refractoriness caused by a mismatch in HLA-C antigens.

BACKGROUND: HLA-C antigens have been thought to be of little significance in determining the efficacy of platelet transfusions. However, six alloimmunized patients were encountered who were refractory to platelet transfusions because of anti-HLA-Cw3, -Cw3, -Cw7, or -Cw8. STUDY DESIGN AND METHODS: Between 1995 and the present, 88 patients with hematologic malignancies became refractory to random-donor platelet transfusions due to HLA antibodies. HLA-A- and HLA-B-compatible platelet transfusions were successful in boosting platelet levels with 82 of the patients. This study concerns the remaining six HLA-immunized patients who were refractory to HLA-A- and HLA-B-compatible platelet transfusions. The response to the platelet transfusions was assessed by calculating both 1- and 24-hour posttransfusion CCIs for each transfusion. RESULTS: The average CCI(1 hour) and CCI(24 hours) in all patients were 20.0 and 12.8 for HLA-A-, HLA-B-, and HLA-C-compatible transfusions and were 1.4 and 1.2 for HLA-A- and HLA-B-compatible but HLA-C-incompatible transfusions, respectively (p < 0.001). CONCLUSION: These findings clearly indicate that matching of the HLA-C antigens is also required in some alloimmunized patients to obtain the effectiveness of platelet transfusions.