Improvement in radiation techniques for locally advanced cervical cancer during the last two decades.

Since the National Cancer Institute (NCI) alert of concurrent chemoradiotherapy, radiotherapy has been changed from external beam radiotherapy plus brachytherapy to platinum-based concurrent chemoradiotherapy. Therefore, concurrent chemoradiotherapy plus brachytherapy has become a standard treatment for locally advanced cervical cancer. Simultaneously, definitive radiotherapy has been changed gradually from external beam radiotherapy plus low-dose-rate intracavitary brachytherapy to external beam radiotherapy plus high-dose-rate intracavitary brachytherapy. Cervix cancer is uncommon in developed countries; hence, international collaborations have been critical in large-scale clinical trials. The Cervical Cancer Research Network (CCRN), created from the Gynecologic Cancer InterGroup (GCIG), has investigated various concurrent chemotherapy regimens and sequential methods of radiation and chemotherapy. Most recently, many clinical trials of combining immune checkpoint inhibitors with radiotherapy have been ongoing for sequential or concurrent settings. During the last decade, the method of standard radiation therapy has changed from three-dimensional conformal radiation therapy to intensity-modulated radiation therapy for external beam radiotherapy and from two-dimensional to three-dimensional image-guided approaches for brachytherapy. Recent improvements include stereotactic ablative body radiotherapy and MRI-guided linear accelerator (MRI-LINAC) using adaptive radiotherapy. Here we review the current progress of radiation therapy during the last two decades.

Oxygen saturation targets in pediatric respiratory disease.

BACKGROUND: The present study aimed to assess the appropriate oxygen saturation target in patients with pediatric respiratory diseases by lowering the oxygen saturation target from SpO2 94% to 90%. No previous study has explored appropriate oxygen saturation targets in respiratory diseases other than bronchiolitis. METHODS: The present, prospective, single-arm intervention trial enrolled pediatric inpatients with bronchiolitis, bronchitis, pneumonia, and asthma. The oxygen saturation target was lowered from SpO2 94% to 90% after the patients' general condition improved. The patients continued to be observed for 12 h after achieving SpO2 94%. The duration from the first cut-off point (SpO2 90% for 12 h without oxygen) to the second cut-off point (SpO2 94% for 12 h) was then evaluated. RESULTS: In total, 248 patients completed the study. Patients with bronchiolitis, bronchitis, pneumonia, and asthma had an interval between the two cut-off points of 23.9, 15.5, 19.1, and 13.8 h, respectively, (mean 17.2 h; 95% confidence interval 15.0-19.5). CONCLUSIONS: In generally healthy children, setting the oxygen saturation target at SpO2 90% after confirming improvement in their general condition was safe. The time required for increasing SpO2 from 90% to 94% was longest in the patients with bronchiolitis.

Virological and cytological clearance in laser vaporization and conization for cervical intra-epithelial neoplasia grade 3.

AIM: Cervical intra-epithelial neoplasia (CIN) is the precancerous stage of cervical cancer. Standard treatment for high-grade CIN is conization of the cervix. The risk of preterm birth following conization has been discussed recently. In contrast, laser vaporization is believed not to affect perinatal outcome, but the long-term effectiveness of each surgical procedure is still unclear. The aim of this prospective unmatched-cohort study was therefore to compare virological and cytological clearance and recurrence risk between conization and vaporization for CIN3. METHODS: Subject consisted of CIN3 patients treated at the present hospital between 2007 to 2011 and followed up until December 2014. One hundred and one patients were treated with laser conization, and 137 with vaporization. The surgical procedure was selected on the basis of colposcopy, pathological grade and patient's hope for pregnancy. RESULTS: There were no significant differences in cure rate, human papilloma virus (HPV) clearance rate or recurrence rates between the conization and vaporization groups. Risk ratio of recurrence for each surgical procedure adjusted for age and HPV persistence status were analyzed on Cox proportional hazards modeling. Recurrence risk ratio for patients treated by vaporization was 6.21 (95%CI: 0.65-59.19; P = 0.111) compared with conization and there were no significant differences. No adverse pregnancy outcome was observed in the vaporization group compared with conization. CONCLUSIONS: Laser vaporization is useful for young patients with CIN3 who hope for pregnancy in the future.

Assisted reproductive technique increases the risk of placental polyp.

The purpose of this study was to clarify the risk factors and outcomes of placental polyp. This retrospective study was conducted on 1645 patients delivered or aborted in Sapporo Medical University from 2007 through 2011. Transvaginal color Doppler ultrasonography, hysteroscopy, contrast-enhanced MRI or 3D-CT angiography were performed. There were 1532 deliveries and 113 abortions. Seventy-one (4.3%) were ART-conceived and the remaining 1574 (95.7%) were non-ART pregnancies. Fifteen (0.91%) cases were confirmed as having placental polyp. Nine cases of placental polyp were identified among the 1574 (0.57%) as non-ART-related pregnancies, and 6 were identified among the 71 (8.5%) as ART-related pregnancies. Thus, pregnancies achieved through ART showed 20x greater incidence of complicating placental polyp than pregnancies achieved through without ART (p = 9.02 × 10(-6); odds ratio, 19.59; 95% confidence interval, 5.27-72.84, logistic regression analysis). Evaluation of blood flow within the polyp showed that in five of seven patients with low blood flow, the polyps spontaneously dropped off 79-115 days postpartum. Thus, ART-related pregnancies may be a risk factor of placental polyp, and spontaneous drop-off of the polyp is often observed in cases with low blood flow within the mass.

Weight reduction and pioglitazone ameliorate polycystic ovary syndrome after removal of a Sertoli-stromal cell tumor.

This report presents an unusual case of Sertoli-stromal cell tumor and polycystic ovary syndrome successfully treated with weight reduction and an insulin-sensitizing agent. A 22-year-old woman, gravida 0, para 0, visited our hospital for the first time with a 12-year history of secondary amenorrhea and hypertrichosis. Transvaginal ultrasonography revealed a solid tumor in the right ovary. Right salpingo-oophorectomy was performed and pathological examination confirmed a Sertoli-stromal cell tumor. The patient's serum androgen levels declined postoperatively, but remained above normal. Pioglitazone treatment for 6 months also significantly reduced serum androgen levels, but they still remained above normal. However, after losing 12 kg of body weight, the patient's serum androgen levels declined to normal, and spontaneous menstruation became regular. Weight reduction with pioglitazone is an effective means of treating hyperandrogenism.

Continuous follicle-stimulating hormone exposure from pituitary adenoma causes periodic follicle recruitment and atresia, which mimics ovarian hyperstimulation syndrome.

CONTEXT: Follicle-stimulating hormone (FSH)-secreting pituitary adenoma is usually a nonfunctioning tumor, but in rare cases it may develop into ovarian hyperstimulation. Several reports have revealed that serum FSH levels are normal to slightly high in patients with combined FSH-secreting pituitary adenoma with ovarian hyperstimulation. This finding is different from iatrogenic ovarian hyperstimulation syndrome (OHSS), which is associated with extremely high levels of FSH. OBJECTIVE: To describe the clinical course of two patients who developed OHSS from FSH-secreting pituitary adenoma. RESULTS: Endocrine studies of the two cases revealed that FSH levels were normal or slightly increased, but luteinizing hormone levels were low to undetectable. Their estradiol (E2) levels were intriguing: levels fluctuated drastically over 6 weeks in Case 1, but stayed flat in Case 2. Ultrasonographic examinations showed bilaterally enlarged multicystic ovaries, and magnetic resonance imaging indicated pituitary tumors. Transsephenoidal resection of the tumors ameliorated the symptoms and pathological diagnosis revealed FSH-secreting pituitary adenomas. CONCLUSION: As is not the case in iatrogenic OHSS, even a small to moderate amount of FSH stimulation, which is continuously secreted by a pituitary adenoma, can cause ovarian hyperstimulation. Although FSH-secreting pituitary adenoma can cause ovarian hyperstimulation, an extremely high amount of E2 biosynthesis from granulosa cells seldom occurs.

Simultaneous presentation of tubal and primary abdominal pregnancies following clomiphene citrate treatment.

Abdominal pregnancy is a rare condition that is potentially life-threatening for the mother. We present a case of simultaneous ectopic pregnancies (EPs) in the right fallopian tube and in the vesicouterine pouch. A 26-year-old woman had undergone prior ovulation induction with clomiphene citrate and human chorionic gonadotropin (hCG) at an outside hospital for unexplained infertility. The patient was referred to our hospital for a suspected ectopic pregnancy at 6 weeks gestation. Transvaginal ultrasonography detected a viable fetus at the anterior left side of the uterus; therefore, we suspected a left tubal pregnancy. However, laparoscopic surgery revealed that EPs were located in both the left vesicouterine pouch and in the right fallopian tube. Resection of the right salpinx and abdominal implant were performed. Histopathological examination confirmed the simultaneous presentation of a primary abdominal pregnancy and a right tubal pregnancy. After surgery, the patient's serum hCG level returned to normal. Concurrent EPs and abdominal pregnancy are very rare. However, it should be noted that reproductive technologies sometimes cause unusual clinical situations. A thorough abdominal inspection is needed.

Distinctive features of female-to-male transsexualism and prevalence of gender identity disorder in Japan.

INTRODUCTION: The prevalence of transsexualism is thought to differ among socio-geographic backgrounds, and little is known about its prevalence in Japan. Polycystic ovary syndrome (PCOS), which is known to be associated with insulin resistance and metabolic syndrome, is often seen in female-to-male (FTM) transsexual patients. Consequently, detection of PCOS is an important part of health care for these individuals. AIM: The purpose of this study was to assess the prevalence of transsexuality in Japan, as well as the incidences of PCOS and insulin resistance among Japanese FTM transsexual patients. METHODS: One hundred four male-to-female (MTF) and 238 FTM Japanese transsexual patients were studied. Medical histories, including histories of menstrual cycling and hormone treatment, were taken. To exclude other diseases, such as congenital adrenal hyperplasia and hormone-secreting tumors, thorough medical assessments, including transvaginal or transrectal ultrasonography and measurement of serum hormone levels and insulin resistance indexes, were performed. MAIN OUTCOME MEASURES: The diagnosis of PCOS was based on the Rotterdam 2003 criteria. RESULTS: Based on demographic statistics, the prevalences of MTF and FTM transsexuality are about 3.97 and 8.20 per 100,000 people, respectively, making the MTF-to-FTM ratio about 1:2. Of the FTM transsexual patients studied, 128 had not taken hormones before their initial assessment (untreated group); the remaining 50 self-administered androgen. Among the untreated group, 32.0% were diagnosed with PCOS, 30.1% were insulin-resistant, and 31.1% showed hypoadiponectinemia. CONCLUSIONS: The sex ratio among Japanese transsexuals is different than among Caucasians. PCOS and insulin resistance are common findings in FTM transsexual patients at initial presentation.

Remarkable features of ovarian morphology and reproductive hormones in insulin-resistant Zucker fatty (fa/fa) rats.

BACKGROUND: Zucker fatty (fa/fa) rats are a well-understood model of obesity and hyperinsulinemia. It is now thought that obesity/hyperinsulinemia is an important cause of endocrinological abnormality, but to date there have been no reports on the changes in ovarian morphology or the ovarian androgen profile in rat models of obesity and insulin resistance. METHODS: In this study we investigated the effects of obesity and hyperinsulinemia on ovarian morphology and the hormone profile in insulin-resistant Zucker fatty rats (5, 8, 12 and 16 weeks of age, n = 6-7). RESULTS: Ovaries from 5-week-old fatty rats had significantly greater total and atretic follicle numbers, and higher atretic-to-total follicle ratios than those from lean rats. Ovaries from 12- and 16-week-old fatty rats showed interstitial cell hyperplasia and numerous cysts with features of advanced follicular atresia. In addition, serum testosterone and androstenedione levels significantly declined in fatty rats from age 8 to 16 weeks, so that fatty rats showed significantly lower levels of serum testosterone (12 and 16 weeks) and androstenedione (all weeks) than lean rats. This may reflect a reduction of androgen synthesis during follicular atresia. Serum adiponectin levels were high in immature fatty rats, and although the levels declined significantly as they matured, it remained significantly higher in fatty rats than in lean rats. On the other hand, levels of ovarian adiponectin and its receptors were significantly lower in mature fatty rats than in lean mature rats or immature fatty rats. CONCLUSIONS: Our findings indicate that ovarian morphology and hormone profiles are significantly altered by the continuous insulin resistance in Zucker fatty rats. Simultaneously, abrupt reductions in serum and ovarian adiponectin also likely contribute to the infertility seen in fatty rats.

Successful uterus-preserving surgery for treatment of chemotherapy-resistant placenta increta.

Treatment of placenta increta often entails abdominal total hysterectomy. We present a case of placenta increta in which 3-dimensional computed tomography shows very high blood flow to the placenta, even after chemotherapy with methotrexate. Nonetheless, we were able to remove the region of the uterus that had been invaded by chorionic villi. Massive bleeding during the operation was prevented by ligation of the hypogastric artery and local injection of vasopressin. The combination of chemotherapy and partial resection of the uterus is quite a unique treatment for placenta increta patients. This approach enabled preservation of the uterus and the patient's fertility. We suggest this procedure could be one of the treatments for patients who have placenta increta and wish to retain their fertility.

Outcomes of planned delivery delay in pregnant patients with invasive gynecologic cancer.

BACKGROUND: Pregnancy with invasive gynecologic cancer is a rare condition. It is still unclear whether we can choose planned delay in treatment until maturation of the fetus as a treatment modality for this condition. If there are no adverse effects from the cancer and there is improvement of neonatal outcomes, this treatment modality might be an option for patients with this condition. METHODS: Eight pregnant patients were diagnosed as having invasive gynecologic cancer between January 1998 and December 2007. Five of them, (four with invasive uterine cervical cancer and one with ovarian cancer) chose planned delay in treatment. The pregnancy courses and prognoses of these patients were studied. RESULTS: The period of planned delay in treatment varied from 2 weeks to 19 weeks. The period was shorter for patients who had complications. The pain caused by the cancer was the main obstacle to this treatment modality in two patients (one with advanced ovarian cancer and one with uterine cervical cancer). No apparent tumor growth, elevation of tumor markers, or complications induced by the cancer itself were detected in the remaining three patients. Only the patient with advanced ovarian cancer died of the primary disease after the delivery. Fetal outcome was uniformly good for the delayed-treatment group. All the babies are growing well, and no fetal deaths or neonatal deaths occurred. CONCLUSION: Planned delay in treatment to allow for fetal maturity is acceptable in pregnant patients with certain types of invasive gynecologic cancers.

Implication of membrane localization of target mRNA in the action of a small RNA: mechanism of post-transcriptional regulation of glucose transporter in Escherichia coli.

Accumulation of phosphosugars such as glucose-6-phosphate causes a rapid degradation of ptsG mRNA encoding the major glucose transporter IICB(Glc) in an RNase E/degradosome-dependent manner. The destabilization of ptsG mRNA is caused by a small antisense RNA (SgrS) that is induced by phosphosugar stress. In this study, we analyzed a series of ptsG-crp translational fusions to identify the mRNA region required for the rapid degradation of ptsG mRNA. We found that the ptsG-crp mRNA is destabilized in response to phosphosugar stress when it contains the 5' portion of ptsG mRNA corresponding up to the first two transmembrane domains (TM1 and TM2) of IICB(Glc). The destabilization of ptsG-crp mRNA was largely eliminated by frameshift mutations in the transmembrane region. The IICB(Glc)-CRP fusion proteins containing more than two transmembrane domains were localized at the membrane. The efficient destabilization of ptsG-crp mRNA was restored when TM1 and TM2 of IICB(Glc) were replaced by part of the LacY transmembrane region. We conclude that the membrane-targeting property of IICB(Glc) protein rather than the particular nucleotide or amino acid sequence is required for the efficient degradation of ptsG mRNA in response to metabolic stress. The stimulation of ptsG-crp mRNA degradation was completely eliminated when either the hfq or sgrS gene is inactivated. The efficient mRNA destabilization was observed in the absence of membrane localization when translation was reduced by introducing a mutation in the ribosome-binding site in the cytoplasmic ptsG-crp mRNA. Taken together, we conclude that mRNA localization to the inner membrane coupled with the membrane insertion of nascent peptide mediates the Hfq/SgrS-dependent ptsG mRNA destabilization presumably by reducing second rounds of translation.

Beta-trace protein, a new marker of GFR, may predict the early prognostic stages of patients with type 2 diabetic nephropathy.

The relationship between serum levels of beta-trace protein (BTP) or serum creatinine (s-Cr) and the prognostic stages of type 2 diabetic nephropathy was determined. Serum samples from 174 patients with type 2 diabetes were obtained from Juntendo University Hospital, Tokyo, and Juntendo Urayasu Hospital, Chiba, Japan. They were classified into four groups according to the Report of the Ministry of Health and Welfare of Japan (1991, p 251-256) as follows: Stage I (normoalbuminuric stage), Stage II (microalbuminuric stage), Stage IIIA (macroalbuminuric stage without renal dysfunction), Stage IIIB (macroalbuminuric stage with renal dysfunction), and Stage IV (renal failure stage). Among these patients, 68 were Stage I, 29 Stage II, 32 Stage IIIA, 17 Stage IIIB, and 28 Stage IV. Levels of serum BTP were measured using the nephelometric assay on a BNA II analyzer (Dade Behring Diagnostics, Marburg, Germany). The mean levels of serum BTP in Stage IIIA were significantly higher than those in Stage I or II (P < 0.00001, P < 0.002, respectively). However, the mean levels of s-Cr in Stage IIIA were not significantly higher than that in Stage I or II. In conclusion, serum BTP was a good marker for the identification of early renal impairment in type 2 diabetes.

[Effective usage of nutrition assessment proteins in patients with diabetic nephropathy].

We investigated the relationship between the levels of serum albumin (ALB), serum transthyretin (TTR) or retinol binding protein (RBP) and those of serum cystatin C or clinical gradings in patients with diabetic nephropathy. Serum samples were obtained from 85 patients with type 2 diabetic nephropathy in our hospital. The levels of serum ALB, TTR, RBP and cystatin C were measured by the Dade Behring assay system using the automated Dade Behring Nephelometer II (BN II). The grades of diabetic nephropathy were classified into five groups according to Report of the Ministry of Health and Welfare, Japan. The serum levels of RBP showed a significant correlation between the serum levels of cystatin C and the grades of diabetic nephropathy. However, the serum levels of TTR were not significantly correlated with those of serum cystatin C or the grades of diabetic nephropathy. In this study, the serum levels of TTR were not influenced by renal function although those of RBP and ALB were influenced by renal function. In spite of clinical usefulness in the nutritional assessment of healthy controls and hemodialysis patients, RBP and ALB are not suitable nutrition marker in patients with chronic renal failure. However, TTR is suitable marker in patients with chronic renal failure.

Serum cystatin C may predict the early prognostic stages of patients with type 2 diabetic nephropathy.

We determined the relationship between levels of serum cystatin C or serum creatinine (s-Cr) and prognostic stages of type 2 diabetic nephropathy. Serum samples from 174 patients with type 2 diabetes were obtained from Juntendo University Hospital, Tokyo and Juntendo Urayasu Hospital, Chiba, Japan. They were classified into four groups according to the Report of the Ministry of Health and Welfare of Japan as follows: Stage I (normoalbuminuric stage), Stage II (microalbuminuric stage), Stage IIIA (macroalbuminuric stage without renal dysfunction), Stage IIIB (macroalbuminuric stage with renal dysfunction), and Stage IV (renal failure stage). Among these patients, 68 were Stage I, 29 Stage II, 32 Stage IIIA, 17 Stage IIIB, and 28 Stage IV. The levels of serum cystatin C were measured using the Dade Behring Cystatin C assay with automated Dade Behring Nephelometer II (BNII) (Dade Behring Marburg GmbH, Germany). The mean levels of serum cystatin C in Stage IIIA were significantly higher than those in Stage I or II (P<0.00001, P<0.0005, respectively). The mean levels of serum cystatin C in Stage IIIB and Stage IV were also significantly higher than those in Stage I (P<0.00001). However, the mean levels of serum creatinine (s-Cr) in Stage IIIA were not significantly higher than those in Stage I or II. The levels of s-Cr in Stage IIIB and Stage IV were significantly higher than those in Stage I (P<0.00001). Receiver operating characteristic (ROC) plots demonstrated that the area under the curve (AUC) of cystatin C (0.76) was greater than that of s-Cr (0.66). As an early prognostic marker of type 2 diabetic nephropathy, serum cystatin C was better than s-Cr in terms of sensitivity and specificity. It appears that the levels of serum cystatin C may predict early prognostic stages of patients with type 2 diabetic nephropathy.

Urinary levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), and renal injuries in patients with type 2 diabetic nephropathy.

We examined the correlation among the levels of urinary monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), hyperglycemia, and renal injuries in patients with type 2 diabetic nephropathy. The levels of urinary MCP-1, IL-8, protein excretion, blood urea nitrogen (BUN), serum creatinine (s-Cr), glycohemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) were measured in 24 patients with type 2 diabetic nephropathy and 14 healthy adults as controls. Diabetic nephropathy was classified into three stages: stage 1 = normoalbuminuric, stage 2 = microalbuminuric, and stage 3 = macroalbuminuric. All of the patients showed normal ranges in renal function tests. Levels of urinary MCP-1 in all patients with diabetic nephropathy were significantly higher than those in healthy adults (P < 0.05). The levels of urinary MCP-1 in patients with diabetic nephropathy increased gradually according to the clinical stage of this disease. In contrast, the levels of urinary IL-8 in patients with diabetic nephropathy increased in stages 2 and 3. There was a significant correlation between the levels of urinary IL-8 and those of HbA1c. High glucose may stimulate MCP-1 and/or IL-8 production and their excretion into the urine independently of the phases or pathological lesions of this disease. It appears that IL-8 increased in the early stage of diabetic nephropathy, and MCP-1 increased in the advanced stage of this disease. It was concluded that measurement of urinary MCP-1 and IL-8 may be useful for evaluating the degree of renal injuries in patients with type 2 diabetic nephropathy.