Ovarian reserve may influence the outcome of bone mineral density in patients with long-term use of dienogest.

OBJECTIVE: Long-term administration of dienogest, which is known to have effect on bone mineral density, is frequently done in patients with endometriosis and adenomyosis, but a few studies focused on the bone mineral density changes after finishing the long-term therapy. This study aimed to reveal the factors that adversely affect lumbar bone mineral density. METHOD: Fifty-seven premenopausal women who visited our hospital were diagnosed as either endometriosis or adenomyosis, and they were treated by dienogest for more than 115 weeks (26.5 months). Based on a previous report, bone mineral density changes less than 2% was categorized as the osteopenic group (n = 30), and the others were assigned to the unchanged group (n = 27). Bone mineral density was measured at the lumbar spine using dual-energy X-ray absorptiometry. A representative ovarian reserve marker, endogenous estradiol levels, and follicle-stimulating hormone levels were measured over time and were compared between the osteopenic and unchanged groups. RESULT: Duration of dienogest intake was 59.5 months (osteopenic group) versus 57.5 months (unchanged group). These patients experienced ovarian surgeries in a similar frequency, but the ovarian reserve in osteopenic group was impaired as suggested by the decline of endogenous estradiol level during intake of dienogest compared to that of unchanged group (p = 0.0146). Endogenous follicle-stimulating hormone level between osteopenic group and unchanged group did not reach statistically significant difference, although the osteopenic group showed relatively higher level. CONCLUSION: This study might suggest that decreased ovarian reserve as judged by endogenous estradiol level is a factor that negatively affect bone mineral density, and measurement of endogenous estradiol level during intake of dienogest could have a predictive meaning of future decreased bone mineral density level.

Association of treatment-achieved HbA1c with incidence of coronary artery disease and severe eye disease in diabetes patients.

AIM: To examine the association between treatment-achieved HbA1c values and incidence of both coronary artery disease (CAD) and severe eye disease with different diabetes treatments. METHODS: Associations of treatment-achieved HbA1c were investigated in various treatment groups [diet only; insulin; sulphonylurea (SU) alone; SU with glinides; and antihyperglycaemic agents other than glinides, SU or insulin] taken from a nationwide claims database of 14,633 Japanese diabetes patients. Cox's regression analysis examined risks over a 5.1-year follow-up. RESULTS: A significant linear trend was associated with HbA1c levels and CAD events in the diet-only group, and CAD risks were significantly higher in insulin and SU groups with HbA1c ≤ 7.0% and > 8.0% than in the diet-only group with HbA1c ≤ 7.0%. In contrast to CAD, a linear association was observed regardless of treatment modality between achieved HbA1c levels and risk of severe diabetic eye disease, but with no significant difference in eye disease risk between groups with HbA1c ≤ 7.0% and 7.1-8.0% in those treated with either SU alone, SU with glinides, or insulin. CONCLUSION: These findings suggest that the relationship between treatment-achieved HbA1c and incidence of both CAD and severe diabetic eye disease differed according to treatment, based on a large-scale real-life database. More research is now needed to confirm these findings and to further investigate the underlying mechanisms.

Anatomy of the smooth muscle structure in the female anorectal anterior wall: convergence and anterior extension of the internal anal sphincter and longitudinal muscle.

AIM: The anatomy of the region between the vagina and anal canal plays an essential role when performing a proctectomy for low-lying tumours. However, the anatomical characteristics of this area remain unclear. The purpose of the present study was to clarify the configuration, and both lateral and inferior extensions, of the muscle bundles in the anorectal anterior wall in females. METHODS: Using cadaveric specimens, macroscopic anatomical and histological evaluations were conducted at the anatomy department of our institute. Macroscopic anatomical specimens were obtained from six female cadavers. Histological specimens were obtained from eight female cadavers. RESULTS: The smooth muscle fibres of the internal anal sphincter and longitudinal muscle extended anteriorly in the anorectal anterior wall of females and the muscle bundles showed a convergent structure. The anterior extending smooth muscle fibres merged into the vaginal smooth muscle layer, distributed subcutaneously in the vaginal vestibule and perineum and spread to cover the anterior surface of the external anal sphincter and the levator ani muscle. Relatively sparse space was observed in the region anterolateral to the rectum on histological analysis. CONCLUSION: Smooth muscle fibres of the rectum and vagina are intermingled in the median plane, and there is relatively sparse space in the region anterolateral to the rectum. Therefore, when detaching the anorectal canal from the vagina during proctectomy, an approach from both the lateral sides should be used.

Network meta-analysis of the relative efficacy of bariatric surgeries for diabetes remission.

BACKGROUND: Bariatric surgery leads to a higher remission rate for type 2 diabetes mellitus than non-surgical treatment. However, it remains unsolved which surgical procedure is the most efficacious. This network meta-analysis aimed to rank surgical procedures in terms of diabetes remission. METHODS AND FINDINGS: We electronically searched for randomized controlled trials in which at least one surgical treatment was included among multiple arms and the diabetes remission rate was included in study outcomes. A random-effects network meta-analysis was performed within a frequentist framework. The hierarchy of treatments was expressed as the surface under the cumulative ranking curve value. Results of the analysis of 25 eligible randomized controlled trials that covered non-surgical treatments and eight surgical procedures (biliopancreatic diversion [BPD], BPD with duodenal switch, Roux-en Y gastric bypass, mini gastric bypass [mini-GBP], laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, greater curvature plication and duodenal-jejunal bypass) showed that BPD and mini-GBP had the highest surface under the cumulative ranking curve values among the eight surgical treatments. CONCLUSION: Current network meta-analysis indicated that BPD or mini-GBP achieved higher diabetes remission rates than the other procedures. However, the result needs to be interpreted with caution considering that these procedures were in the minority of bariatric surgeries.

Failure to rescue the elderly: a superior quality metric for trauma centers.

BACKGROUND: Trauma centers require reliable metrics to better compare the quality of care delivered. We compared mortality after a reported complication, termed failure to rescue (FTR), and FTR in the elderly (age >65 years) (FTRE) to determine which is a superior metric to assess quality of care delivered by trauma centers. METHODS: This was a retrospective review of the National Trauma Databank (NTDB) research data sets 2010 and 2011. Patients ≥16 years admitted to centers reporting ≥80% of AIS and/or ≥ 20% of comorbidities with > 200 subjects in the NTDB were selected. Centers were classified based on the rate of FTR and FTRE (<5 vs. 5-14 vs. ≥15%). The primary outcome was adjusted mortality for each group of trauma centers based on FTR and FTRE classifications. RESULTS: The overall mean ± SD FTR rate was 7.2 ± 5.2% and FTRE was 10.4 ± 7.9%. The adjusted odds ratio (AOR) for mortality was not different when centers with FTR <5% were compared to those with FTR of 5-14 or ≥15%. In contrast, a stepwise increase in FTRE predicted a significantly higher mortality when centers with FTRE 5% were compared to those with 5-14% (AOR: 1.05, p = 0.031) and ≥15% (AOR: 1.13, p < 0.001). Similarly, stepwise increase in FTRE predicted higher adjusted mortality for severely and critically injured patients, whereas FTR did not. CONCLUSIONS AND RELEVANCE: Higher FTRE predicts increased adjusted mortality better than FTR after trauma and should, therefore, be considered an important metric when comparing quality care delivered by trauma centers.

Relationships between bone mass and dietary/lifestyle habits in Japanese women at 3-4 months postpartum.

OBJECTIVES: The relationships between calcaneal bone mass and dietary/lifestyle habits in women at 3-4 months postpartum were examined in the context of osteoporosis prevention. STUDY DESIGN: Cross-sectional survey. METHODS: We measured bone mass using calcaneal ultrasound in mothers who brought their 3- to 4-month-old babies to healthcare centers in Japan for health examination and administered a self-report questionnaire on physical characteristics and dietary/lifestyle habits to those who agreed to participate in the survey. Valid data were available for 1220 women (valid response rate, 97.5%). RESULTS: Based on their stiffness score, a measure of bone mass, 70.9% (n = 865) of the participants were classified as 'no apparent abnormality (stiffness score ≥78.8)' (low-risk group), 18.2% (n = 222) as 'guidance required (≥70.1-<78.8)' (intermediate-risk group), and 10.9% (n = 133) as 'complete examination required (<70.1)' (high-risk group), according to the criteria for osteoporosis screening test results. The percentage of individuals with a history of fracture was higher in the guidance required/complete examination required than in the no apparent abnormality group (P = 0.016). The analysis of relationships between the consumption frequency of certain foods, such as calcium-rich foodstuffs, and bone mass found that women who reported lower frequencies of milk and dark-colored (beta-carotene rich) vegetables for breakfast consumption had a significantly lower bone mass than those who consumed these foods more often. Furthermore, the guidance required/complete examination required group had a significantly lower calcium intake than the no apparent abnormality group (P = 0.022). CONCLUSIONS: These results indicate the need to provide postpartum women with dietary education programs to promote healthy eating habits, such as increased consumption of calcium-rich foods, and prevent osteoporosis.

A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer.

Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration: NCT01207011 (ClinicalTrials.gov).

Predictors of inhalation burn injury using fire site information.

Inhalation burn injury (IBI) is a risk factor for mortality in burn patients. However, it is difficult to diagnose IBI using traditional physical examination alone, especially in prehospital settings. Therefore, facial burn patients are usually treated for suspected IBI. In the present study, we investigated whether fire site information could predict IBI as an alternative to traditional physical examination. This retrospective single-centre analysis involved 27 facial burn patients with suspected IBI who were admitted between 2014 and 2016. The patients were divided into two groups (IBI and non-IBI) according to bronchoscopy findings. Fire site information was compared between the two groups. The IBI (n = 13) and non-IBI (n = 14) groups were compared. Domestic fire was more frequent in the IBI group (69% vs. 29%, P = 0.035). The IBI group included one patient with carboxyhemoglobin ≥10% on admission. Prehospitalization fire site information, particularly domestic fires, might predict IBI in facial burn patients..

L'inhalation de fumées (IF) est un facteur de mortalité chez les brûlés. Son diagnostic clinique est difficile, en particulier en préhospitalier, ce qui fait que les brûlés du visage sont souvent traités comme ayant subi une IF. Cette étude s'est penchée sur les données recueillies sur le site de l'incendie pouvant permettre, mieux que l'examen clinique, de poser le diagnostic d'IF. Cette étude monocentrique rétrospective a revu les dossiers de 27 patients avec brûlures faciales admis entre 2014 et 2016, divisés en 2 groupes (IF, 13 patients et non IF, 14 patients) selon les données endoscopiques. Les données de l'incendie ont ensuite été comparées entre ces 2 groupes. L'incendie était plus fréquemment survenu au domicile dans le groupe IF (65% VS 29%, p = 0,035). Un patient IF avait une HbCO > 10% à l'entrée. La survenue de la brûlure pendant un incendie au domicile pourrait être prédictive d'une IF.

High serum dihydrotestosterone examined by ultrasensitive LC-MS/MS as a predictor of benign prostatic hyperplasia or Gleason score 6 cancer in men with prostate-specific antigen levels of 3-10 ng/mL.

There has been no consensus on the role of serum androgen concentrations in prostate cancer detection in men with prostate-specific antigen levels of 3-10 ng/mL. In this study, testosterone and dihydrotestosterone concentrations in blood were examined by a newly developed method using ultrasensitive liquid chromatography with two serially linked mass spectrometers (LC-MS/MS). We investigated the correlation between serum androgen levels and Gleason scores at biopsy. We analyzed data of 157 men with a total prostate-specific antigen range of 3-10 ng/mL who underwent initial systematic prostate needle biopsy for suspected prostate cancer between April 2000 and July 2003. Peripheral blood testosterone and dihydrotestosterone concentrations were determined by LC-MS/MS. Blood levels of testosterone and dihydrotestosterone were compared with pathological findings by multivariate analyses. Median values of prostate-specific antigen and prostate volume measured by ultrasound were 5.7 ng/mL and 31.4 cm3 , respectively. Benign prostatic hyperplasia was diagnosed in 97 patients (61.8%), and prostate cancer was diagnosed in 60 (38.2%) patients, including 31 (19.7%) patients with a Gleason score of 6 and 29 (18.5%) patients with a Gleason score of 7-10. Median values of testosterone and dihydrotestosterone in blood were 3798.7 and 371.7 pg/mL, respectively. There was a strong correlation between serum testosterone and dihydrotestosterone. In multivariate analysis, age, prostate volume, and serum dihydrotestosterone were significant predictors of benign prostatic hyperplasia or prostate cancer with a Gleason score of 6. The area under the receiver operating characteristics curve for age, prostate volume, and serum dihydrotestosterone were 0.67, 0.67, and 0.67, respectively . We confirmed that high dihydrotestosterone blood levels can predict benign prostatic hyperplasia or prostate cancer with a Gleason score of 6 in men with prostate-specific antigen levels of 3-10 ng/mL.

Bone-peg grafting for osteochondritis dissecans of the humeral capitellum.

PURPOSE: To review the outcome of bone-peg grafting for osteochondritis dissecans (OCD) grade II lesions of the humeral capitellum. METHODS: Records of 10 male adolescent baseball players aged 10 to 15 (mean, 12.3) years who underwent bone-peg grafting for OCD grade II lesions of the humeral capitellum of the dominant arm were reviewed. The mean time from symptom onset to presentation was 11 (range, 1-36) months. The mean duration of conservative treatment was 5 (range, 1-25) months. The mean time from symptom onset to surgery was 17 (range, 3-39) months; it was >6 months in 6 patients. The mean size of the lesions was 13x14 mm. Patients were assessed for elbow pain, range of elbow and forearm motion, Timmerman- Andrews elbow score, return to sports activity level, and radiographic evidence of healing, osteoarthritic changes, and radial head hypertrophy. RESULTS: The mean follow-up period was 25 (range, 10-52) months. Postoperatively, elbow pain was absent in 6, mild in 2, and moderate in 2 patients. The mean range of elbow motion changed from 136º to 139° (p=0.80). The mean Timmerman-Andrews elbow score improved from 163 to 189 (p=0.014); it was excellent in 7, good in 2, and fair in one patient. The mean extent of lesion healing was 71% (range, 33-100%). Five patients achieved complete healing after a mean of 5.2 (range, 5-6) months and returned to sports at a competitive level. The other 5 achieved partial healing of 33 to 56% (mean, 41%) that occurred laterally but not medially. Two of them returned to sports at a competitive level: one changed the throwing side and another had radial head hypertrophy. The remaining 3 underwent arthroscopic debridement of the unhealed lesion at 5, 10, and 15 months. One patient developed secondary osteoarthritis and further underwent costal osteochondral autografting 10 months later. None of the 5 patients with partial healing versus 4 of the 5 patients with complete healing underwent surgery within 6 months of symptom onset. All 3 patients with a dot at the interface versus 2 of the 6 patients with a line at the interface between the fragment and the lesion on MRI had complete healing. CONCLUSION: Bone-peg grafting is a viable option for OCD grade II lesions of the humeral capitellum when performed within 6 months of symptom onset and when the interface between the fragment and the lesion appears as a dot (rather than a line) on MRI.

Is the Susceptibility Vessel Sign on 3-Tesla Magnetic Resonance T2*-Weighted Imaging a Useful Tool to Predict Recanalization in Intravenous Tissue Plasminogen Activator?

The aim of this study was to investigate the independent factors associated with the absence of recanalization approximately 24 h after intravenous administration of tissue-type plasminogen activator (IV TPA). The previous studies have been conducted using 1.5-Tesla (T) magnetic resonance imaging (MRI). We studied whether the characteristics of 3-T MRI findings were useful to predict outcome and recanalization after IV tPA. Patients with internal carotid artery (ICA) or middle cerebral artery (MCA) (horizontal portion, M1; Sylvian portion, M2) occlusion and treated by IV tPA were enrolled. We studied whether the presence of susceptibility vessel sign (SVS) at M1 and low clot burden score on T2*-weighted imaging (T2*-CBS) on 3-T MRI were associated with the absence of recanalization. A total of 49 patients were enrolled (27 men; mean age, 73.9 years). MR angiography obtained approximately 24 h after IV tPA revealed recanalization in 21 (42.9 %) patients. Independent factors associated with the absence of recanalization included ICA or proximal M1 occlusion (odds ratio, 69.6; 95 % confidence interval, 5.05-958.8, p = 0.002). In this study, an independent factor associated with the absence of recanalization may be proximal occlusion of the cerebral arteries rather than SVS in the MCA or low T2*-CBS on 3-T MRI.

Insulin-dependent diabetes and serious trauma.

PURPOSE: Trauma patients with diabetes mellitus (DM) represent a unique population as the acute injury and the underlying disease may both cause hyperglycemia that leads to poor outcomes. We investigated how insulin-dependent DM (IDDM) and noninsulin-dependent DM (NIDDM) impact mortality after serious trauma without brain injury. METHODS: The National Trauma Data Bank (NTDB) version 7.0 was queried for all patients with moderate to severe traumatic injury [injury severity score (ISS) >9]. Patients were excluded if missing data, age <10 years, severe brain injury [head abbreviated injury scale (AIS) >3], dead on arrival or any AIS = 6. Logistic regression modeled the association between DM and mortality as well as IDDM, NIDDM and mortality. RESULTS: Overall 166,103 trauma patients without brain injury were analyzed. Mortality was 7.6 and 4.4 % in patients with and without DM, respectively (p < 0.01). Mortality was 9.9 % for patients with IDDM and 6.7 % for NIDDM (p < 0.01). The increased mortality associated with DM was only significantly higher for DM patients in their forties (5.6 vs. 3.3 %, p < 0.01). Regression analyses demonstrated that DM (AOR 1.14, p = 0.04) and IDDM (AOR 1.46, p < 0.01) were predictors of mortality compared to no DM, but NIDDM was not (AOR 1.02, p = 0.83). CONCLUSIONS: While DM was a predictor for higher mortality after serious trauma, this increase was only observed in IDDM and not NIDDM. Our findings suggest IDDM patients who present after serious trauma are unique and attention to their hyperglycemia and related insulin therapy may play a critical role in recovery.

Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study).

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. PATIENTS AND METHODS: In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. RESULT: ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. CONCLUSIONS: Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. REGISTRATION NUMBER: JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).

Thymidylate synthase and methylenetetrahy-drofolate reductase gene polymorphisms and gastric cancer susceptibility in a population of Northern Brazil.

The folate metabolic pathway, which is involved in DNA synthesis and methylation, is associated with individual susceptibility to several diseases, including gastric tumors. In this study, we investigated four polymorphisms [thymidylate synthase enhancer region, single nucleotide polymorphism thymidylate synthase 5' (TS5'), TS3' untranslated region, and methylenetetrahydrofolate reductase (MTHFR) 677C> T] in 2 genes related to the folate pathway, TS and MTHFR, and their possible association with the risk gastric cancer development in a population from Pará state, Brazil. For the TS enhancer region, TS3' untranslated region, and single nucleotide polymorphism TS5' polymorphisms, no significant results were obtained. For the MTHFR 677C>T polymorphism, TT genotype carriers had a higher risk of developing tumors in the antrum (P = 0.19 vs CC and P = 0.02 vs CT) and intestine (odds ratio = 4.18, 95% confidence interval = 0.66-26.41; P = 0.252 vs CC and odds ratio = 2.25, 95% confidence interval = 0.32-15.75; P = 0.725 vs CT). Those carrying at least 1 T allele had an increased risk of lymph node metastasis (odds ratio = 3.00, 95% confidence interval = 0.88-10.12; P = 0.133). Our results suggest that polymorphisms in MTHFR affect the susceptibility to gastric tumors in the Brazilian population and may be a factor causing poor prognosis in such patients.

Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.

BACKGROUND: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation. PATIENTS AND METHODS: Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed [area under the curve (AUC) = 6 and 500 mg/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. RESULTS: All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients). CONCLUSION: This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).

Stroke service: how can we improve and measure outcomes? Consensus summary from a global stroke forum.

The success of acute stroke treatment is first and foremost time-dependent, and the need for improvement in acute stroke management is demonstrated by the fact that only a minority of patients gain access to treatment - in particular, intravenous recombinant tissue plasminogen activator (IV tPA) - within the necessary time window. Standards of acute stroke care vary widely both regionally and nationally; consequently, various healthcare organizations have undertaken initiatives to measure and improve quality of care. To date, most quality measures have been process-based, focusing primarily on metrics of patient care in the acute hospital-based setting (e.g., time to recombinant tPA administration). Therefore, there remains a need for metrics designed to assess how improvements in process translate into patient outcomes. A global forum was convened to share best practice and provide consensus recommendations on core metrics for measuring improvements in access to care and patient outcomes. Recommendations for core metrics of patient outcomes include hospital-based outcomes (e.g., neurological status at 24 h, ambulatory status at discharge) and post-discharge outcomes (e.g., modified Rankin Scale score at 30 and/or 90 days). Recommendations for best practice relating to aspects of people, process, and technology involved in the stroke treatment pathway that may help provide improvements in these core outcome measures are also outlined.

Disruption of the temporally regulated cloaca endodermal ß-catenin signaling causes anorectal malformations.

The cloaca is temporally formed and eventually divided by the urorectal septum (URS) during urogenital and anorectal organ development. Although congenital malformations, such as anorectal malformations (ARMs), are frequently observed during this process, the underlying pathogenic mechanisms remain unclear. ß-Catenin is a critical component of canonical Wnt signaling and is essential for the regulation of cell differentiation and morphogenesis during embryogenesis. The expression of ß-catenin is observed in endodermal epithelia, including URS epithelia. We modulated the ß-catenin gene conditionally in endodermal epithelia by utilizing tamoxifen-inducible Cre driver line (Shh(CreERT2)). Both ß-catenin loss- and gain-of-function (LOF and GOF) mutants displayed abnormal clefts in the perineal region and hypoplastic elongation of the URS. The mutants also displayed reduced cell proliferation in the URS mesenchyme. In addition, the ß-catenin GOF mutants displayed reduced apoptosis and subsequently increased apoptosis in the URS epithelium. This instability possibly resulted in reduced expression levels of differentiation markers, such as keratin 1 and filaggrin, in the perineal epithelia. The expression of bone morphogenetic protein (Bmp) genes, such as Bmp4 and Bmp7, was also ectopically induced in the epithelia of the URS in the ß-catenin GOF mutants. The expression of the Msx2 gene and phosphorylated-Smad1/5/8, possible readouts of Bmp signaling, was also increased in the mutants. Moreover, we introduced an additional mutation for a Bmp receptor gene: BmprIA. The Shh(CreERT2/+); ß-catenin(flox(ex3)/+); BmprIA(flox/-) mutants displayed partial restoration of URS elongation compared with the ß-catenin GOF mutants. These results indicate that some ARM phenotypes in the ß-catenin GOF mutants were caused by abnormal Bmp signaling. The current analysis revealed the close relation of endodermal ß-catenin signaling to the ARM phenotypes. These results are considered to shed light on the pathogenic mechanisms of human ARMs.