Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012‐2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2‐3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type‐specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type‐specific RCs between CIN1 and CIN2‐3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type‐specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2‐3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2‐3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01‐4.98), followed by HPV31 (2.51, 1.54‐5.24), HPV18 (2.43, 1.59‐4.32), HPV35 (1.56, 0.43‐8.36), HPV33 (1.01, 0.49‐3.31), HPV52 (0.99, 0.76‐1.33), and HPV58 (0.97, 0.75‐1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71‐2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14‐0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9‐valent vaccine contributed to 89.7% (95% CI, 88.7‐90.7) of CIN2‐3/AIS and 93.8% (95% CI, 92.4‐95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9‐valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.     

Successful remission using metyrapone in an elderly patient with Cushing disease accompanied by generalized edema

An 82-year-old woman was referred to our hospital because of hypoalbuminemia and generalized edema. Hypercortisolemia was subsequently found as the levels of serum cortisol and plasma adrenocorticotropic hormone (ACTH) sampled in a fasting morning were 140 pg/mL and 41.9 μg/dL, respectively. These hormones were not suppressed after taking low-dose dexamethasone the previous night and increased to a mild extent in response to administration of corticotrophin-releasing hormone, suggesting presence of pituitary adenoma producing ACTH (Cushing's disease). However, intrasella localization of pituitary adenoma could not be determined by magnetic resonance imaging. Soon after administration of metyrapone was started in an attempt to reduce her cortisol levels, the patient suffered from severe pneumonia. The pulmonary infection and peripheral edema were improved with decreases in cortisol levels by continuing metyrapone administration with antibiotics and finally she was discharged from the hospital on foot. Metyrapone is a useful therapeutic choice to achieve a remission of cortisol levels in the elderly patients with Cushing's disease in association with serious hypercortisolemia impending severe infection.     

Functional expression of a proliferation-related ligand in hepatocellular carcinoma and its implications for neovascularization

AIM: To detect the expression of a proliferation-related ligand on human hepatocellular carcinoma (HCC) cell lines (SK-Hep1, HLE and HepG2) and in culture medium. METHODS: APRIL expression was analyzed by Western blotting in HCC cell lines. Effects of APRIL to cell count and angiogenesis were analyzed, too. RESULTS: Recombinant human APRIL (rhAPRIL) increased cell viability of HepG2 cells and, in HUVEC, rhAPRIL provided slight tolerance to cell death from serum starvation. Soluble APRIL (sAPRIL) from HLE cells increased after serum starvation, but did not change in SK-Hepl or HepG2 cells. These cells showed down-regulation of VEGF after incubation with anti-APRIL antibody. Furthermore, culture medium from the HCC cells treated with anti-APRIL antibody treatment inhibited tube formation of HUVECs. CONCLUSION: Functional expression of APRIL might contribute to neovascularization via an upregulation of VEGF in HCC.     

Leukocytapheresis (LCAP) for Management of Fulminant Ulcerative Colitis with Toxic Megacolon

Leukocytapheresis (LCAP) is a method of therapeutic apheresis to remove patients peripheral leukocytes by extracorporeal circulation. Previous studies showed that LCAP for the treatment of ulcerative colitis (UC) was more effective and had fewer adverse effects compared to high-dose steroid therapy. However, there are no reports on the application of LCAP for UC patients with toxic megacolon (TM). This study reports the effectiveness and safety of LCAP in treating patients with severe or fulminant UC with TM. Six patients were enrolled in this study and LCAP sessions were performed three times per week for 2 weeks, followed by four further times in the next 4 weeks. After completion of therapy, four patients improved in TM and went into the remission stage of UC. The average Rachmilewitz clinical activity index of these four patients improved from 19.5 to 1. The remaining two patients had to undergo colectomy, however, the symptoms had been mitigated by LCAP and the operations were completed without any problems. These results suggest that LCAP is an additional effective and safe option for TM management in preventing colectomy or for bridging to a safer operation.     

Effects of right atrial pacing preference in prevention of paroxysmal atrial fibrillation: Atrial Pacing Preference study (APP study).

BACKGROUND: Several preliminary studies have indicated that atrial pacing can prevent atrial tachyarrhythmias. The suggested mechanisms by which pacing may be effective include suppression of premature atrial beats. METHODS AND RESULTS: The Atrial Pacing Preference (APP; Guidant, St Paul, MN, USA) algorithm allows the pacemaker to maintain a pacing rate slightly higher than the sinus rate. The preventive effects of APP on paroxysmal atrial fibrillation (AF) were studied in 51 patients (70+/-11 years). Nine patients did not complete the protocol. The pacemaker was programmed in random order to APP off and APP on at 3 different settings (ie, 8, 16 and 32 cycles) for 4 weeks each, using a cross-over design. Percentage atrial pacing was lower in APP off than at the other settings. Premature beat counts were greater in APP off than at the other settings. There was a significant difference in mode switch episode counts between APP off and the most effective setting (3,818+/-15,356 vs 596+/-1,719; p<0.01). CONCLUSIONS: The APP algorithm is a promising method for preventing atrial tachyarrhythmia in patients with an implanted pacemaker and AF. Optimizing the setting of the APP algorithm is an important issue in the prevention of AF.     

Valuable markers for contrast-induced nephropathy in patients undergoing cardiac catheterization

Background Contrast-induced nephropathy (CIN) frequently complicates cardiac catheterization, so the objectives of present study were to investigate the usefulness of cystatin C before catheterization and establish a cut-off level for CIN, and to examine the changes in cystatin C and several other markers in patients with and without CIN. Methods and Results Prospective study of consecutive 87 patients who underwent elective catheterization: moderate renal disease defined as glomerular filtration rate 30-59 ml . min(-1) .1.73 mm(-2); cystatin C and creatinine (Cr), urinary liver-type fatty acid-binding protein (L-FABP), alpha(1), beta(2) microglobulins, N-acetyl-beta-D-glucosaminidase, and microalbumin were measured immediately before, and 1, 2, and 3 days after catheterization. CIN occurred in 18 patients and receiver-operating characteristic analysis showed a higher area-under-the-curve for cystatin C compared with serum Cr (0.933 vs 0.832 p=0.012). At a cut-off level of >1.2 mg/L, cystatin C before catheterization exhibited 94.7% (95% confidence interval: 0.851-1.015) sensitivity and 84.8% specificity for detecting CIN. Cystatin C levels were higher in CIN patients than in those without CIN, even before catheterization (cystatin C: 1.08+/-0.22 vs 1.36+/-0.28 mg/L, p=0.007). Urinary L-FABP was increased on days 1 and 2 in patients with moderate renal disease. Conclusion Cystatin C was useful for predicting the occurrence of CIN. Urinary L-FABP was the only marker of transient renotubular damage. (Circ J 2008; 72: 1499 - 1505).     

Tristetraprolin (TTP) gene polymorphisms in patients with rheumatoid arthritis and healthy individuals

Tristetraprolin (TTP) is an intracellular protein that modulates the production of cytokines, including TNFα, by binding to and destabilizing the mRNAs of these cytokines. Therefore, differences in TTP gene expression may affect the severity of inflammatory diseases, such as rheumatoid arthritis (RA). We searched for polymorphisms in the human TTP gene and for this purpose, we sequenced the entire TTP gene in 20 Japanese individuals (ten with RA and ten healthy volunteers) and found one single nucleotide polymorphism (SNP) in the promoter region. We analyzed this SNP (A/G) by restriction fragment length polymorphism method in 155 RA patients and 100 control subjects. While the frequency of A allele in this SNP was similar in RA patients (74.5%) and controls (76.0%), the disease duration in RA patients with genotype GG was shorter than that of patients with genotypes AA/AG and RA patients with genotype GG had a higher probability of being treated with infliximab. We studied the difference in promoter activity between the two alleles by luciferase assay and found that the promoter activity of TTP promoter region with allele A was around two-fold higher than that with allele G. We conclude that this SNP in the promoter region of the TTP gene mildly affects promoter activity, and thus, may influence the disease activity of inflammatory disorders including RA.     

Management of symptoms in step-down therapy of gastroesophageal reflux disease

OBJECTIVE: Majority of studies on gastroesophageal reflux disease (GERD) that include patients with or without erosive disease have documented the efficacy of proton pump inhibitors (PPIs) as well as their superiority to H(2)-receptor antagonist (H(2)-RA). The purpose of this study was to clarify the difference in quality of GERD treatment with PPIs and H(2)-RA in step-down protocol using lansoprazole. METHODS: Forty-three patients with reflux esophagitis were randomly divided into three groups and assessed by severity score; group 1 received 30 mg lansoprazole initially and maintenance therapy with a standard dose H(2)-RA; group 2 received 30 mg of lansoprazole initially and maintenance therapy of 15 mg lansoprazole; and group 3 received 15 mg of lansoprazole once daily for 16 weeks. If the patients experienced symptomatic recurrence while on H(2)-RA, they were switched to PPI maintenance. RESULTS: Heartburn, regurgitation and dysphagia were hardly found in any group at 8 weeks after 15 mg or 30 mg lansoprazole treatment. After 8 weeks, however, heartburn and regurgitation recurred at 50% and 78.6%, respectively, in the stepped down to famotidine group, and quality of life (QOL) was significantly impaired. Endoscopic ultrasonography (EUS) analysis showed reduction of the submucosal layer without any change in the mucosal surface in the stepped down to famotidine group. CONCLUSIONS: Step-down lansoprazole therapy is considered very effective in terms of rapid effect, long-term effect and high quality GERD treatment.     

Postoperative changes in protein-induced vitamin K absence or antagonist II levels after hepatectomy in patients with hepatocellular carcinoma: relationship to prognosis

Background. α-Fetoprotein (AFP) has been used as a marker for hepatocellular carcinoma (HCC). However, AFP levels are often high in patients with chronic hepatitis or cirrhosis. Protein-induced vitamin K absence or antagonist II (PIVKA-II) is more sensitive for the diagnosis of HCC and prediction of patient survival. Changes in these markers after treatment may reflect treatment curability and patient outcome. Methods. We conducted a retrospective analysis of prognosis of 63 HCC patients with high preoperative levels of AFP and PIVKA-II who underwent hepatectomy and examined the relationship between postoperative changes in both markers at 1 month and patient survival. Subjects were divided into three groups according to changes in these tumour markers after hepatectomy: normalization (N) group, decreased but still above the normal level (D) group and unchanged (U) group. Results. There were no significant differences in the numbers of patients who developed tumour recurrence between changes in AFP and PIVKA-II. Survival analysis showed no significant differences in tumour-free and overall survivals between groups with respect to AFP level. The PIVKA-II-N group showed significantly better tumour-free and overall survival compared with the D and U groups (p<0.01). Multivariate analysis that included other prognostic factors identified changes in PIVKA-II level as a significant and independent prognostic factor associated with overall survival. Discussion. Although changes in AFP did not correlate with patient prognosis, normalization of PIVKA-II was significantly associated with good patient survival after hepatectomy. Normalization of PIVKA-II after hepatectomy reflected the efficacy of treatment and is a suitable predictor of prognosis in HCC patients.