Optimal threshold of a control parameter for tomotherapy respiratory tracking: A phantom study.

BACKGROUND: Radixact Synchrony® , a real-time motion tracking and compensating modality, is used for helical tomotherapy. Control parameters are used for the accurate application of irradiation. Radixact Synchrony® uses the potential difference, which is an index of the accuracy of the prediction model of target motion and is represented by a statistical prediction of the 3D distance error. Although there are several reports on Radixact Synchrony® , few have reported the appropriate settings of the potential difference threshold. PURPOSE: This study aims to determine the optimal threshold of the potential difference of Radixact Synchrony® during respiratory tumor-motion-tracking irradiation. METHODS: The relationship among the dosimetric accuracy, motion tracking accuracy, and control parameter was evaluated using a moving platform, a phantom with a basic respiratory model (the fourth power of a sinusoidal wave), and several irregular respiratory model waveforms. The dosimetric accuracy was evaluated by gamma analysis (3%, 1 mm, 10% dose threshold). The tracking accuracy was measured by the distance error of the difference between the tracked and driven positions of the phantom. The largest potential difference for 95% of treatment time was evaluated, and its correlation with the gamma-pass ratio and distance error was investigated. The optimal threshold of the potential difference was determined by receiver operating characteristic (ROC) analysis. RESULTS: A linear correlation was identified between the potential difference and the gamma-pass ratio (R = -0.704). A linear correlation was also identified between the potential difference and distance error (R = 0.827). However, as the potential difference increased, it tended to underestimate the distance error. The ROC analysis revealed that the appropriate cutoff value of the potential difference was 3.05 mm. CONCLUSION: The irradiation accuracy with motion tracking by Radixact Synchrony® could be predicted from the potential difference, and the threshold of the potential difference should be set to ∼3 mm.

Age- and sex-based changes in spike protein antibody status after SARS-CoV-2 vaccination and effect of past-infection in healthcare workers in Osaka.

OBJECTIVE: We aimed to compare the changes in SARS-CoV-2 spike protein antibody titres based on age group and sex using paired blood sampling after vaccination in association with the presence of nucleocapsid protein antibody. METHODS: All participants were healthcare workers at Yao Municipal Hospital in Osaka who voluntarily provided peripheral blood samples (n = 636, men/women 151/485, mean age 45 years). We investigated the serial changes in SARS-CoV-2 spike protein antibody titres at 1 and 7 months after the second vaccination regarding their relationship with sex and age group. At 7 months, we also examined anti-nucleocapsid assays. Antibody titres were shown as logarithmic values and the differences were assessed using a paired or unpaired student's t-test as appropriate. RESULTS: Among participants younger than 30 years, the antibody titres of spike protein were significantly higher in women one (p = 0.005) and seven (p = 0.038) months after vaccination. However, among those aged 30-49 years, the antibody titres were not different between the sexes at either follow-up time point. In contrast, among those aged 50-59 years, between-sex differences in antibody titres were observed only at 7 months, which was associated with a significant reduction in men. A significant negative correlation was observed between the antibody titres for spike protein at both time points in participants with positive nucleocapsid protein antibody at 7 months (r = - 0.467, p = 0.043), although a significant positive correlation was observed in those with negative results (r = 0.645, p < 0.001), CONCLUSIONS: Between-sex differences in SARS-CoV-2 spike protein antibody titres by paired blood sampling at different time points after vaccination depended on age group. The presence of nucleocapsid protein antibody was associated with changes in spike protein antibody titres after vaccination.

First-line pembrolizumab for patients with early relapsing urothelial carcinoma after perioperative chemotherapy: a retrospective analysis of bladder cancer and upper urinary tract cancer.

BACKGROUND: First-line pembrolizumab is available for recurrent disease within 12 months after the receipt of platinum-based perioperative chemotherapy. However, the benefit of first-line pembrolizumab is unclear. This study evaluated the oncological outcome of patients treated with pembrolizumab compared with chemotherapy as first-line therapy for early relapsing disease after the receipt of platinum-based perioperative chemotherapy. METHODS: Data from a multicenter study included 454 patients diagnosed with unresectable or metastatic UC from November 2006 to July 2021. We identified patients with early and non-early relapsing disease. Oncological outcomes were evaluated using progression-free survival, overall survival, and survival with disease control. RESULTS: Fifty-three patients with early relapsing disease and 15 patients with non-early relapsing disease were identified. Of 53 patients with early relapsing disease, 26 (49.1%) were treated with pembrolizumab and 27 (50.9%) were treated with chemotherapy as first-line therapy. Fifteen patients with non-early relapsing disease were treated with chemotherapy. Early relapsing disease was associated with shorter progression-free survival and overall survival than non-early relapsing disease. Pembrolizumab was associated with longer progression-free survival and survival with disease control than chemotherapy in patients with early relapsing disease. There was no significant difference in overall survival between pembrolizumab and chemotherapy, but overall survival plateau with a long tail was observed in pembrolizumab. CONCLUSIONS: First-line pembrolizumab in earlier clinical settings for highly malignant tumors might improve the prognosis of patients with early relapsing disease after the receipt of platinum-based perioperative chemotherapy.

[A Case of Bilateral Trigeminal Neuralgia and the Possible Onset Mechanisms Based on the Operative Findings].

Several cases of bilateral trigeminal neuralgia(TN)have been reported;however, the possible onset mechanism has rarely been discussed. We encountered a case of bilateral TN occurring in two stages. A 64-year-old woman presented with left TN. Magnetic resonance imaging showed the transverse pontine vein adhering to the left trigeminal root and superior cerebellar artery adhering to the right trigeminal root;however, no symptoms were noted. Immediately after microvascular decompression(MVD)on the left side, TN disappeared completely. However, 2 years postoperatively, the patient presented with right TN. The second MVD surgery revealed that the right cerebellar surface severely adhered to the dura mater, particularly under the surface of the tentorium. The arachnoid membrane at the cerebellopontine angle was slightly adhered. The patient was completely free from pain after the second MVD. The intraoperative findings suggested that the brain stem may have shifted and the cerebellopontine cistern may have narrowed because of cerebellar adhesion to the surrounding structures and arachnoid adhesion. We speculate that such structural changes in the posterior fossa after the first operation may have caused the asymptomatic vascular adhesion to change into the symptomatic offending adhesion over time.

Comparison of radiological changes after single- position versus dual- position for lateral interbody fusion and pedicle screw fixation.

BACKGROUND: There have been few comparisons between dual positions, which require a position change, and a single position, which does not require position change, and it is not clear whether there is a difference in indirect decompression achieved by the two procedures. Therefore, the purpose of this study was to compare perioperative and radiographic outcomes following lateral lumbar interbody fusion (LLIF) in two cohorts of patients who underwent surgery in a single position or dual position. METHODS: This study involved 45 patients who underwent indirect decompression at 68 levels, with LLIF and percutaneous pedicle screw (PPS) fixation for lumbar degenerative spondylolisthesis with spinal canal stenosis. Patient demographics and perioperative data were compared between two groups: patients who remained in the lateral decubitus position for pedicle screw fixation (SP group) and those turned to the prone position (DP group). RESULTS: A total of 26 DP and 19 SP patients were analyzed. The operation time was approximately 31 min longer for the DP group (129.7 ± 36.0 min) than for the SP group (98.4 ± 41.3 min, P < 0.01). We also evaluated the pre- and postoperative image measurements, there was no significant difference for lumbar lordosis, segmental disc angle, slipping length, and disc height between the groups. The CSA of the dural sac (DP group, from 55.3 to 78.4 mm2; SP group, from 54.7 to 77.2 mm2) and central canal diameter (DP group, from 5.9 to 7.9 mm; SP group, from 5.6 to 7.7 mm) was significantly larger after surgery in both groups. However, there were no statistically significant differences between the two groups (P = 0.684). CONCLUSIONS: SP surgery could reduce the average surgery time by about 31 min. We found that the effect of indirect decompression by SP-PPS fixation following LLIF was considered to be a useful technique with no difference in dural sac enlargement or disc angle obtained compared with DP-PPS fixation.

The correlation analysis between sagittal alignment and cross-sectional area of paraspinal muscle in patients with lumbar spinal stenosis and degenerative spondylolisthesis.

BACKGROUND: The relationship between spinal alignment and skeletal muscle mass (SMM) has attracted attention in recent years. Sagittal alignment is known to deteriorate with age, but it is not known whether this is related to paraspinal muscles. Therefore, the purpose of this study is to elucidate the role of the multifidus (MF) and psoas major (PS) muscles in maintaining global spinal alignment in patients with lumbar spinal stenosis (LSS) and/or degenerative spondylolisthesis (DS), and to analyze whether each muscles' cross-sectional area (CSA) correlates with whole-body SMM using bioimpedance analysis (BIA). METHODS: We retrospectively evaluated 140 patients who were hospitalized for surgery to treat LSS and/or DS. Spinal alignment, CSA of spinal muscles, and body composition parameters were measured from full-length standing whole-spine radiography, MRI, and BIA before surgery. The following standard measurements were obtained from radiographs: sagittal balance (C7-SVA), cervical lordosis (CL; C2-C7), lumbar lordosis (LL; L1-S1), thoracic kyphosis (TK; T5-T12), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). RESULTS: The average PS CSA (AveCSA) was highest at L4-L5, whereas MF AveCSA was highest at L5-S1. Paraspinal muscle CSAs were greater in males than in females. There was no statistically significant difference between the left and right CSA for either MF or PS. Correlation coefficient showed strong correlations between the PS AveCSA (L4-L5) and whole body SMM (r = 0.739). Correlation coefficient analysis also showed weak correlation between SMM and PT (r = - 0.184). Furthermore, PS AveCSA (L4-L5) correlated with the PT (r = - 0.183) and age (r = - 0.156), while PT correlated with the whole body SMM (r = - 0.184) but not with age. CONCLUSIONS: Whole body SMM showed correlation with PS AvCSA (L4-L5) and with PT among the spinal parameters, which was the same result in MF AvCSA (L4-L5). These findings suggest that the posterior inclination of the pelvis may be correlated with paraspinal muscle area rather than age.

Relationships between thermal dose parameters and the efficacy of definitive chemoradiotherapy plus regional hyperthermia in the treatment of locally advanced cervical cancer: data from a multicentre randomised clinical trial.

PURPOSE: To evaluate the contribution of the thermal dose parameters during regional hyperthermia (HT) treatment to the clinical outcomes in patients with cervical carcinoma (CC) who received chemoradiotherapy (CRT) plus HT. MATERIALS AND METHODS: Data from a multicentre randomised clinical trial of concurrent CRT + HT vs. CRT alone were used to evaluate the efficacy and safety of this combination therapy in the CC patients. The intrarectal temperatures of patients undergoing HT were recorded. The complete thermal data of 47 (92%) of the 51 patients in the CRT + HT group were available for the thermal analysis. Thus, 47 patients who received CRT + HT were included in the present study. RESULTS: Among the patients who received CRT + HT, a higher CEM43T90 (≥1 min) value (a thermal dose parameter) was significantly associated with better local relapse-free survival in both univariate (p = 0.024) and multivariate (p = 0.0097) analyses. The disease-free survival of the patients with higher CEM43T90 (≥1 min) values tended to be better in comparison to patients with lower CEM43T90 (<1 min) value (p = 0.071). A complete response tended to be associated with the CEM43T90 (p = 0.056). Disease-free survival, local relapse-free survival and complete response rate for patients with higher CEM43T90 (≥1) were significantly better than those for patients with CRT alone (p = 0.036, p = 0.036 and p = 0.048). CONCLUSIONS: Dose-effect relationships between thermal dose parameters and clinical outcomes were confirmed in the CC patients treated with a combination of CRT + HT. This study also confirmed that HT with lower CEM43T90 is insufficient to achieve a significant hyperthermic sensitisation to CRT.

Prevalence of diffuse idiopathic skeletal hyperostosis (DISH) assessed with whole-spine computed tomography in 1479 subjects.

BACKGROUND: Computed tomography (CT) analyses have reported that the prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in Japan is 8.7-27.1%. However, these data were obtained using chest-abdominal CT, and no evaluations of sagittal, coronal, and axial images using whole-spine CT have been reported. The aim of this study was to investigate the prevalence and characteristic of DISH by whole spinal CT. METHODS: Participants were patients who had experienced trauma who had undergone whole-spine CT scanning based on the initial clinical practice guidelines for trauma in our institute from April 2015 to February 2018. The subjects were > 20 years old and 1479 were included in the analysis. The presence and distribution of DISH and clinical parameters such as age and sex were reviewed retrospectively according to the location of DISH. RESULTS: The overall prevalence of DISH was 19.5% (n = 289). Subjects with DISH were older than those without. DISH was located in the thoracic spine in 65.1% and thoracolumbar spine in 24.2% of patients. More than 80% of ligamentous ossifications associated with DISH occurred at T8 (n = 255, 88%), T9 (n = 262, 91%), and T10 (n = 247, 85%). Most of the ossification occurred to the right anterior of the vertebral body, and there were few ossifications in the areas in contact with the artery and vein. CONCLUSIONS: The prevalence of DISH based on whole-spine CT was 19.5%. Ossification was noted more often at T8, T9, and T10, and to the right anterior of the vertebral body. It is for the first time report that we have studied the location of ossification in detail using the axial images of whole spine CT. We hope this study will enhance the understanding of the characteristics of DISH.

Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis.

Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.

Prognostic Impact of Intra-abdominal/Pelvic Inflammation After Radical Surgery for Locally Recurrent Rectal Cancer.

BACKGROUND: The influence of postoperative infectious complications, such as anastomotic leakage, on survival has been reported for various cancers, including colorectal cancer. However, it remains unclear whether intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer is relevant to its prognosis. OBJECTIVE: The purpose of this study was to evaluate factors associated with survival after radical surgery for locally recurrent rectal cancer. DESIGN: The prospectively collected data of patients were retrospectively evaluated. SETTINGS: This study was conducted at a single-institution tertiary care cancer center. PATIENTS: Between 1983 and 2012, patients who underwent radical surgery for locally recurrent rectal cancer with curative intent at the National Cancer Center Hospital were reviewed. MAIN OUTCOME MEASURES: Factors associated with overall and relapse-free survival were evaluated. RESULTS: During the study period, a total of 180 patients were eligible for analyses. Median blood loss and operation time for locally recurrent rectal cancer were 2022 mL and 634 minutes. Five-year overall and 3-year relapse-free survival rates were 38.6% and 26.7%. Age (p = 0.002), initial tumor stage (p = 0.03), pain associated with locally recurrent rectal cancer (p = 0.03), CEA level (p = 0.004), resection margin (p < 0.001), intra-abdominal/pelvic inflammation (p < 0.001), and surgery period (p = 0.045) were independent prognostic factors associated with overall survival, whereas CEA level (p = 0.01), resection margin (p = 0.002), and intra-abdominal/pelvic inflammation (p = 0.001) were associated with relapse-free survival. Intra-abdominal/pelvic inflammation was observed in 45 patients (25.0%). A large amount of perioperative blood loss was the only factor associated with the occurrence of intra-abdominal/pelvic inflammation (p = 0.007). LIMITATIONS: This study was limited by its retrospective nature and heterogeneous population. CONCLUSIONS: Intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer is associated with poor prognosis. See Video Abstract at http://journals.lww.com/dcrjournal/Pages/videogallery.aspx.

Prognostic impact of hospital volume on familial adenomatous polyposis: a nationwide multicenter study.

PURPOSE: Many studies have shown that hospital volume is significantly associated with short- and long-term outcomes in various diseases, including cancer. However, there have been no reports discussing the relationship between hospital volume and familial adenomatous polyposis (FAP). This study aimed to clarify whether hospital volume affects short- and long-term outcomes in FAP patients. METHODS: We established a retrospectively collected database of FAP patients who underwent initial surgical treatment at 23 Japanese institutions during 2000-2012. Factors associated with short- and long-term outcomes were analyzed. RESULTS: The study cohort included 303 FAP patients. These patients were classified into tertile categories according to hospital volume: low (n = 31), middle (n = 72), and high volume (n = 200). The proportion of only adenoma/stage 0 was comparable among tertile categories. The adoption of operative procedure significantly differed among tertile categories; specifically, high-volume institutions preferred handsewn ileal pouch-anal anastomosis without diverting ileostomy (P < 0.001 and < 0.001, respectively). Nevertheless, the frequency of complications with Clavien-Dindo classification grade ≥ 3 was not significantly different among tertile categories. Functional results were acceptable in every category. Wexner scores were significantly lower in high-volume compared to low-volume institutions (P = 0.02). Multivariate analyses showed that UICC stage and hospital volume were significantly associated with overall survival (P = 0.04 and 0.03, respectively). CONCLUSIONS: Hospital volume was significantly associated with short- and long-term outcomes in FAP patients.

Clinical impact of JOABPEQ mental health scores in patients with low back pain: Analysis using the neuropathic pain screening tool painDETECT.

BACKGROUND: In patients with low back pain (LBP) who combine psychosocial factors with clinical findings of pain, there is a possibility that the psychosocial factors modify the pain. In the current study, we investigated the relationship between the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) mental health score and the characteristics of LBP. METHODS: Of 650 patients with LBP, 319 were excluded, leaving 331 patients included in this study. All patients between the ages of 20 and 79 were asked to complete a set of questionnaires including the Japanese version of the painDETECT (PDQ-J), Numeric Rating Scale (NRS), the JOABPEQ, and the Short Form 36 (SF-36). Based on their JOABPEQ mental health scores, the patients were divided into two groups: those with JOABPEQ mental health score of <50 were classified as low score group, and those scoring ≥50 were classified as the high score group. To identify any differences between the two groups, age, sex, PDQ-J score, NRS score, duration of symptoms, percentage of pain components, percentage of lower limb symptoms and self-reported general health were compared. RESULTS: 196 patients (59.2%) were classified into the low score group, and 135 (40.8%) into the high score group. The mean PDQ-J and NRS scores and percentage of LBP patients with neuropathic pain and lower limb symptoms were higher in the low score group. We also evaluated the relationship between lower limb symptoms and JOABPEQ mental health scores in 331 LBP patients. The results show that a significantly greater number of LBP patients in the low mental score group had lower limb symptoms compared to the high mental score group. CONCLUSION: We found that psychological factors may modify pain intensity and may lead to an exaggerated or histrionic presentation of the pain, or neuropathic LBP may be exacerbating psychological factors.

[A Case of Intravesical Foreign Body by Erosion of Surgical Mesh Used for an Inguinal Hernia Repair].

We report our experience with a case in which eroded mesh used for inguinal hernia repair migrated into the bladder. An 84-year-old man underwent surgery for colorectal cancer at the age of 40, and radical surgery for a right inguinal hernia at the age of 83. At his initial visit, he reported macroscopic hematuria. Cystoscopy revealed a yellowish-brown foreign body on the right bladder wall, and computed tomography showed the presence of emphysema in association with the foreign body. Based on a presumptive diagnosis of vesical calculi, transurethral lithotripsy was performed. However, the foreign body was strongly adherent to the bladder wall ; when lithotripsy was attempted, the calcified surface of the foreign body detached, and the exposed surface showed a mesh-like structure. Transurethral extraction was judged impossible ; therefore, laparotomy was performed at a later date to remove the foreign body, with en bloc resection including some of the bladder. The foreign body consisted of a surgical mesh that had been used for inguinal hernia repair. With the spread of surgery using surgical mesh, we should be careful about complications.

Working Environment Factors Associated with Regular Dental Attendance.

The aim of this study was to identify factors in the working environment associated with regular dental attendance. Thirty-three general practitioners provided data on 488 patients who underwent dental maintenance between 2003 and 2015. The age of the patients ranged from 40 to 65 years. Appointment adherence, employment format, overtime work, night work, and subjective evaluation of work were investigated. Multiple logistic regression analysis was performed to identify factors associated with regular dental attendance. Among all participants, 296 (60.7%) were female, 320 (65.6%) worked full-time, 193 (39.5%) worked overtime, and 34 (7.0%) worked nights. The results of the analysis revealed that only night work was a significant factor after adjusting for sex, age, and employment format (odds ratio, 0.220; 95% confidence interval, 0.088-0.550). The results of this study suggest that night work disturbs regular dental attendance.

Number of Non-vital Teeth as Indicator of Tooth Loss during 10-year Maintenance: A Retrospective Study.

The purpose of this study was to investigate whether number of non-vital teeth was an indicator of tooth loss during maintenance. Thirty-three general practitioners provided data on 321 patients undergoing maintenance over 10 years. The number of present teeth (PT), smoking status, level of bone loss, number of non-vital teeth, and reason for tooth loss during that period were investigated. Multiple logistic regression was performed to identify whether the number of non-vital teeth was associated with tooth loss. The average number of lost teeth was 1.07±1.82; that of PT at baseline was 24.4±3.9; and that of non-vital teeth at baseline was 5.4±4.5. Multiple logistic regression revealed a significant association between >8 non-vital teeth and tooth loss during maintenance (odds ratio [OR]: 2.40; 95% confidence interval [CI]: 1.18-4.87). It also demonstrated relationships between >8 non-vital teeth and root fracture or caries (OR: 3.90; 95%CI: 1.68-9.03 or OR: 2.85, 95%CI: 1.14-7.10, respectively). The number of non-vital teeth was associated with tooth loss during maintenance. The results suggest that patients with many non-vital teeth before commencement of maintenance are particularly at risk of tooth loss due to root fracture or caries. Therefore, the number of non-vital teeth offers a useful indicator of potential tooth loss.

A Novel Natural Product-Derived Compound, Vestaine A1, Exerts both Pro-Angiogenic and Anti-Permeability Activity via a Different Pathway from VEGF.

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is a key molecule in the regulation of both angiogenesis and vascular permeability. However, it is known that overproduction of VEGF induces abnormal blood vessel formation and these vessels cause several disease pathologies, such as diabetic retinopathy. The purpose of this study was to find novel vasoactive compounds which have different properties from VEGF. METHODS/RESULTS: We screened a natural product library using a co-culture angiogenic assay of endothelial cells and fibroblasts. By focusing on morphological changes of endothelial cells, we isolated the novel compounds vestaine A1 and vestaine B1 from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 63697. Vestaine A1 enhanced tube formation of endothelial cells in Matrigel and suppressed cell death induced by serum deprivation. Vestaine A1 activated both MEK1/2 and PI-3 kinase pathways independently of the VEGF pathway in a dose- and time-dependent fashion. Finally, vestaine A1 potently suppressed VEGF-induced vascular permeability both in vitro and in vivo. CONCLUSION: Vestaine A1 has the potential to exhibit both pro-angiogenic and anti-permeability properties, and would therefore be useful for therapeutic treatment for abnormal vascular permeability-related diseases.

Feasibility of Routine Application of Gadoxetic Acid-Enhanced MRI in Combination with Diffusion-Weighted MRI for the Preoperative Evaluation of Colorectal Liver Metastases.

BACKGROUND: Gadoxetic acid-enhanced magnetic resonance imaging (MRI) in combination with diffusion-weighted MRI (Gd-EOB-MRI/DWI) has become popular for evaluating colorectal liver metastases (CRLM). This retrospective observational study aimed to determine whether this procedure should be indicated prior to hepatectomy in all patients with CRLM. METHODS: A retrospective survey of relevant data of patients who had undergone hepatectomy for CRLM from 2008 to 2014 was performed. The rates of detection by contrast-enhanced computed tomography (CE-CT) and Gd-EOB-MRI/DWI were evaluated. In addition, relapse-free and overall survivals after primary hepatectomy were compared between patients who had undergone only CE-CT versus those who had undergone both CE-CT and Gd-EOB-MRI/DWI. RESULTS: In all, 419 pathologically confirmed CRLM were resected in 202 hepatectomies in 177 patients. The sensitivity of detection of CRLM was 77 % for CE-CT and 93 % for Gd-EOB-MRI/DWI (P < 0.01). The sensitivity of detection of 1-5, 6-10, and 11-15 mm CRLM by CE-CT was 9.6 % (5/52), 47 % (26/55), and 76 % (57/75), respectively, whereas that by Gd-EOB-MRI/DWI was 54 % (28/52), 91 % (50/55), and 99 % (74/75), respectively; these differences are significant (P < 0.01 for all three groups). Relapse-free (P = 0.99) and overall survival (P = 0.79) did not differ significantly between 37 patients evaluated preoperatively by only CE-CT and 168 patients evaluated by both CE-CT and Gd-EOB-MRI/DWI. CONCLUSION: Gd-EOB-MRI/DWI detects small CRLM (≤15 mm) with higher sensitivity than CE-CT. However, whether Gd-EOB-MRI/DWI should be a routine component of preoperative evaluation remains unclear in terms of survival benefit.

Mismatch repair deficiency in Lynch syndrome-associated colorectal adenomas is more prevalent in older patients.

AIMS: The aim of this study was to examine the expression of mismatch repair (MMR) proteins in Lynch syndrome (LS)-associated colorectal adenomas and to evaluate their relationship with clinicopathological variables and potential utility in LS screening. METHODS AND RESULTS: We performed immunohistochemistry for MLH1, PMS2, MSH2 and MSH6 in 134 adenomas obtained from 26 genetically confirmed LS patients. MMR deficiency, as determined by loss of any MMR protein, was observed in 113 adenomas (84%). All the MMR-deficient adenomas exhibited homogeneous loss of MMR proteins, which reflected underlying germline mutations. MMR deficiency was more frequent in adenomas obtained from older patients (aged ≥60 years; 81 of 86, 94%), with larger tumour size (>5 mm; 71 of 73, 97%) and with high-grade dysplasia (50 of 51, 98%). Multivariate analyses indicated that increased age and larger tumour size were associated independently with MMR deficiency. CONCLUSIONS: This study shows that MMR deficiency is associated significantly with increased age, in addition to two previously reported factors-larger size and high-grade dysplasia. When adenomas are analysed during LS screening, high sensitivity is expected if the adenomas are associated with any of these three factors.

A multicentre randomised clinical trial of chemoradiotherapy plus hyperthermia versus chemoradiotherapy alone in patients with locally advanced cervical cancer.

PURPOSE: To evaluate the effectiveness of whole-pelvic hyperthermia (HT) added to standard chemoradiotherapy (CRT) in locally advanced cervical cancer (CC), by investigating the clinical response and survival of patients treated with cisplatin-based CRT vs. CRT with HT (CRT + HT). MATERIALS AND METHODS: This study was conducted at five hospitals in Japan between September 2001 and March 2015 in patients with the International Federation of Gynecology and Obstetrics stage IB (bulky)-IVA CC undergoing definitive CRT. After giving a written informed consent, patients were randomly allocated to two treatment groups: CRT and CRT + HT group. Overall survival (OS), disease-free survival (DFS), local relapse-free survival (LRFS), complete response (CR) rate and tolerability were evaluated. RESULTS: In total, 101 patients were treated. Patient characteristics, total dose of cisplatin and radiotherapy were similar for both groups. Although not statistically significant, the 5-year OS, DFS and LRFS in the CRT + HT group (77.8%, 70.8% and 80.1%, respectively) were better than those in the CRT group (64.8%, 60.6% and 71.0%, respectively). CR was significantly more likely to be achieved in patients in the CRT + HT group than in the CRT group (88% vs. 77.6%; adjusted odds ratio, 3.993; 95% confidence interval, 1.018-15.67; p = .047). CRT + HT was well tolerated and caused no additional acute or long-term toxicity compared with CRT alone. CONCLUSIONS: HT combined with CRT improved the CR rate of CRT in patients with locally advanced CC, however, could not improve survival outcomes. Further studies in larger samples are warranted.

The antioxidant N-acetyl cysteine suppresses lidocaine-induced intracellular reactive oxygen species production and cell death in neuronal SH-SY5Y cells.

BACKGROUND: The local anesthetic lidocaine can affect intra- and extra-cellular signaling pathways in both neuronal and non-neuronal cells, resulting in long-term modulation of biological functions, including cell growth and death. Indeed, lidocaine was shown to induce necrosis and apoptosis in vitro. While several studies have suggested that lidocaine-induced apoptosis is mitochondrial pathway-dependent, it remains unclear whether reactive oxygen species (ROS) are involved in this process and whether the observed cell death can be prevented by antioxidant treatment. METHODS: The effects of lidocaine and antioxidants on cell viability and death were evaluated using SH-SY5Y cells, HeLa cells, and HeLa cell derivatives. Cell viability was examined via MTS/PES ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt]/phenazine ethosulfate) assay. Meanwhile, cell apoptosis and necrosis were evaluated using a cell death detection assay with Annexin V-FITC and PI staining, as well as by assaying for caspase-3/7 and caspase-9 activity, and by measuring the release of lactate dehydrogenase, respectively. Mitochondrial transmembrane potential (ΔΨm) was assessed using the fluorescent probe tetramethylrhodamine ethyl ester. RESULTS: Lidocaine treatment resulted in suppression of the mitochondrial electron transport chain and subsequent attenuation of mitochondrial membrane potential, as well as enhanced ROS production, activation of caspase-3/7 and caspase-9, and induction of apoptosis and necrosis in SH-SY5Y cells in a dose- and time-dependent manner. Likewise, the anesthetics mepivacaine and bupivacaine also induced apoptosis in SH-SY5Y cells. Notably, the antioxidants N-acetyl cysteine (NAC) and Trolox successfully scavenged the mitochondria-derived ROS and suppressed local lidocaine-induced cell death. CONCLUSIONS: Our findings demonstrate that the local anesthetics lidocaine, mepivacaine, and bupivacaine inhibited the activity of mitochondria and induced apoptosis and necrosis in a dose-dependent manner. Furthermore, they demonstrate that treatment with the antioxidants NAC, Trolox, and GGA resulted in preservation of mitochondrial voltage and inhibition of apoptosis via suppression of caspase activation.