[RECOMMENDATION FOR ITCH ASSESSMENT FROM THE ATOPIC ITCH CONSENSUS MEETING (AICOM)].

BACKGROUND: Itch is the most troublesome symptom of atopic dermatitis, and it is important to assess it appropriately for optimal treatment. We discussed issues regarding itch and the most appropriate methods of assessment at the Atopic Itch Consensus Meeting (AICOM), attended by physicians and researchers with expertise in itch treatment and research. METHODS: The AICOM participants prepared a draft consensus statement that addressed the most appropriate itch assessment methods for age groups <2 years, 2-6 years, 7-14 years, and ≥15 years. Consensus was defined as agreement by ≥80% of the participants. RESULTS: Votes were cast by 20 participants (8 dermatologists, 7 pediatricians, and 5 researchers), and a consensus on the best current methods of itch assessment was reached with 95% agreement. For infants and preschool children, because subjective evaluation is difficult, a checklist for itch assessment was developed for caregivers. CONCLUSION: For itch assessment, we recommend subjective evaluation by the patient using a rating scale. For infants and preschoolers, evaluation should be done by the caregiver using a checklist, combined with objective evaluation (of skin lesions, for example) by a physician. We anticipate that more objective itch assessment indices will be established in the future.

The interaction between the immune system and the peripheral sensory nerves in pruritus.

Pruritus is a skin-specific sensation that is observed in various skin diseases, especially in inflammatory skin diseases such as atopic dermatitis, and is deeply involved in their pathogenesis. Pruritus also adversely affects patients' sleep and mental health, placing a heavy burden on daily life. As such, pruritus control is important to the maintenance of health. The mechanism of pruritus has recently been clarified and the discovery of various pruritus mediators, the identification of specific nerves that transmit pruritus and the accumulation of knowledge on pruritus perception have led to a better understanding of all aspects of pruritus generation, transmission and recognition. In the case of pruritus caused by dermatitis, immune cells infiltrating the skin secrete inflammatory cytokines, which also act on peripheral nerves as pruritus mediators and induce an inflammatory response. Interestingly, there has been accumulating evidence that peripheral nerves are also involved in the inflammation via neuropeptides. In this article, we summarize the findings on pruritus mediators secreted by immune cells and the roles of peripheral nerves in pruritus in terms of their interactions with immunity.

Telomere-binding proteins Taz1 and Rap1 regulate DSB repair and suppress gross chromosomal rearrangements in fission yeast.

Genomic rearrangements (gross chromosomal rearrangements, GCRs) threatens genome integrity and cause cell death or tumor formation. At the terminus of linear chromosomes, a telomere-binding protein complex, called shelterin, ensures chromosome stability by preventing chromosome end-to-end fusions and regulating telomere length homeostasis. As such, shelterin-mediated telomere functions play a pivotal role in suppressing GCR formation. However, it remains unclear whether the shelterin proteins play any direct role in inhibiting GCR at non-telomeric regions. Here, we have established a GCR assay for the first time in fission yeast and measured GCR rates in various mutants. We found that fission yeast cells lacking shelterin components Taz1 or Rap1 (mammalian TRF1/2 or RAP1 homologues, respectively) showed higher GCR rates compared to wild-type, accumulating large chromosome deletions. Genetic dissection of Rap1 revealed that Rap1 contributes to inhibiting GCRs via two independent pathways. The N-terminal BRCT-domain promotes faithful DSB repair, as determined by I-SceI-mediated DSB-induction experiments; moreover, association with Poz1 mediated by the central Poz1-binding domain regulates telomerase accessibility to DSBs, leading to suppression of de novo telomere additions. Our data highlight unappreciated functions of the shelterin components Taz1 and Rap1 in maintaining genome stability, specifically by preventing non-telomeric GCRs.

Severity of constipation related to palonosetron during first-line chemotherapy: a retrospective observational study.

PURPOSE: Palonosetron, a long-acting 5-HT3 receptor antagonist, is an effective antiemetic agent for chemotherapy-induced nausea and vomiting; however, it sometimes causes severe constipation. The aim of the present study was to evaluate the severity of palonosetron-related constipation. METHODS: We retrospectively analyzed the incidence and severity of constipation after intravenous administration of 0.75-mg palonosetron in 150 chemotherapy-naïve patients who received first-line chemotherapy at Saga University Hospital. Constipation was classified into grades 1-5 according to the Common Terminology Criteria for Adverse Events version 5.0. Multiple logistic regression analysis was performed to identify factors associated with palonosetron-related worsening of constipation to grade 2 or higher. RESULTS: Palonosetron significantly increased the incidence and severity of constipation (incidence: before vs. after palonosetron, 35.4% vs. 74.0%, p < 0.0001, and severity: before vs. after palonosetron, 26.7% and 8.7% in grades 1 and 2, respectively, vs. 46.7%, 23.3%, and 4.0% in grades 1, 2, and 3, respectively, p < 0.0001). Despite the use of laxatives, 4.0% of patients had grade 3 constipation requiring manual evacuation. Combination treatment with aprepitant (odds ratio (OR), 10.9; 95% confidence interval (CI), 1.3-90.0; p = 0.026) and older age (OR, 1.25; 95% CI, 1.01-1.57; p = 0.039) were factors associated with the severity of constipation. CONCLUSION: Constipation was more severe in patients receiving combination treatment with aprepitant than in those treated with palonosetron alone. Older age was also associated with increased risk of severe palonosetron-related constipation. Identification of risk factors can help target risk-based laxative therapy.

Diagnostic accuracy of FibroScan-AST score to identify non-alcoholic steatohepatitis with significant activity and fibrosis in Japanese patients with non-alcoholic fatty liver disease: Comparison between M and XL probes.

AIM: Recently, FibroScan-AST (FAST) score was reported to be effective for identifying non-alcoholic steatohepatitis (NASH) with significant activity and fibrosis in non-alcoholic fatty liver disease (NAFLD). The aim of this study was to confirm the diagnostic accuracy of FAST score of Japanese patients and compare the cut-off values and diagnostic accuracy between the FibroScan M and XL probes. METHODS: Eighty-two and 84 patients were included the verification and validation sets, respectively. All patients were diagnosed with NAFLD by biopsy by two central expert pathologists. Liver stiffness measurements and controlled attenuation parameter were carried out, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: No significant difference existed in FAST score between the M and XL probes (0.489 vs. 0.483, P = 0.187). No significant difference existed in the area under the ROC between the two probes (M, 0.7598; XL, 0.7614; P = 0.958). According to the Youden index, the cut-off value using the M probe was 0.57 with 68.2% sensitivity and 78.3% specificity. For the XL probe, the cut-off value was 0.56 with 68.2% sensitivity and 73.3% specificity. To obtain sensitivity and specificity values higher than 90%, cut-off values of 0.35 and 0.66 were chosen for the M probe and 0.32 and 0.63 were chosen for the XL probe. CONCLUSIONS: There was no significant difference in diagnostic accuracy of FAST score between the FibroScan M and XL probes. The FAST score can be used to identify NASH with significant risk in Japanese patients regardless of probe selection.

Association between Pericytes in Intraplaque Neovessels and Magnetic Resonance Angiography Findings.

(1) Background: Pericytes are involved in intraplaque neovascularization of advanced and complicated atherosclerotic lesions. However, the role of pericytes in human carotid plaques is unclear. An unstable carotid plaque that shows high-intensity signals on time-of-flight (TOF) magnetic resonance angiography (MRA) is often a cause of ischemic stroke. The aim of the present study is to examine the relationship between the pericytes in intraplaque neovessels and MRA findings. (2) Methods: A total of 46 patients with 49 carotid artery stenoses who underwent carotid endarterectomy at our hospitals were enrolled. The patients with carotid plaques that were histopathologically evaluated were retrospectively analyzed. Intraplaque hemorrhage was evaluated using glycophorin A staining, and intraplaque neovessels were evaluated using CD34 (Cluster of differentiation) stain as an endothelial cell marker or NG2 (Neuron-glial antigen 2) and CD146 stains as pericyte markers. Additionally, the relationships between the TOF-MRA findings and the carotid plaque pathologies were evaluated. (3) Results: Of the 49 stenoses, 28 had high-intensity signals (TOF-HIS group) and 21 had iso-intensity signals (TOF-IIS group) on TOF-MRA. The density of the CD34-positive neovessels was equivalent in both groups. However, the NG2- and CD146-positive neovessels had significantly higher densities in the TOF-HIS group than in the TOF-IIS group. (4) Conclusion: The presence of a high-intensity signal on TOF-MRA in carotid plaques was associated with intraplaque hemorrhage and few pericytes in intraplaque neovessels. These findings may contribute to the development of new therapeutic strategies focusing on pericytes.

Variable indoleamine 2,3-dioxygenase expression in acral/mucosal melanoma and its possible link to immunotherapy.

Immune checkpoint inhibitors have improved the prognosis of advanced melanoma. Although anti-programmed death ligand-1 (PD-L1) is a well-studied biomarker for response to anti-programmed death-1 PD-1 therapy in melanoma, its clinical relevance remains unclear. It has been established that the high expression of indoleamine 2,3-dioxygenase (IDO) is correlated to a response to anti-CTLA-4 treatment in melanoma. However, it is still unknown whether the IDO expression is associated with response to anti-PD-1 therapy in advanced melanoma. In addition, acral and mucosal melanomas, which comprise a great proportion of all melanomas in Asians, are genetically different subtypes from cutaneous melanomas; however, they have not been independently analyzed due to their low frequency in Western countries. To evaluate the association of IDO and PD-L1 expression with response to anti-PD-1 antibody in acral and mucosal melanoma patients, we analyzed 32 Japanese patients with acral and mucosal melanomas treated with anti-PD-1 antibody from the perspective of IDO and PD-L1 expression levels by immunohistochemistry (IHC). Multivariate Cox regression models showed that the low expression of IDO in tumors was associated with poor progression-free survival (HR = 0.33, 95% CI = 0.13-0.81, P = 0.016), whereas PD-L1 expression on tumors was not associated with progression-free survival. Significantly lower expression of IDO in tumors was found in non-responders compared to responders. Assessment of the IDO expression could be useful for the identification of suitable candidates for anti-PD-1 therapy among acral and mucosal melanomas patients. Further validation study is needed to estimate the clinical utility of our findings.

Usefulness of Intraoperative Cone Beam CT Images on Video-assisted Thoracic Surgery.

For the resection of pulmonary ground glass opacity (GGO) or non-palpable nodule on video-assisted thoracic surgery (VATS), preoperative computed tomography (CT)-guided VATS marker pricking is usually performed. Recently, air embolisms after VATS marker pricking have been reported to be serious problems. The purpose of this study was to evaluate the usefulness of intraoperative cone beam CT images on VATS to avoid preoperative VATS marker pricking. The CT number of the both GGO and nodule indicate the range from -200 to -800 HU in general. We evaluated the detection ability of the lesion in seven elements and the simulated lungs. The result indicated that there was a linear equation of "y=1.0599×-2.1492" and the degree of correlation was "R2=0.9826" for the relationship between CT number and W number [voxel number in cone beam computed tomography (CBCT)]. Evaluation of low contrast resolution has been performed. The contrast noise ratios were 2.86 on CBCT and 1.50 on multi detector-row computed tomography (MDCT), while the relative contrast ratios were same both on CBCT and MDCT (0.19) as the lowest CT number (-700 HU). In clinical situation, four types of pulmonary lesions (pure GGO, mixed GGO, solid nodule, and cyst) were detected on MDCT, and intraoperative CBCT could identify all lesions as same configuration as on MDCT. The contrast noise ratio (CNR) and relative contrast ratio (RCR) could not admit the significant difference. In conclusion, the intraoperative CBCT can be used as a non-invasive image navigator for VATS, and the preoperative CT-guided VATS marker pricking can be avoided.

Magnetic Resonance (MR) Imaging Assessment for Glossopharyngeal Neuralgia: Value of Three-Dimensional T2-Reversed MR Imaging (3D-T2R) in Conjunction with Other Modes of 3D MR Imaging.

BACKGROUND: To retrospectively examine the usefulness of gray-scale reversal imaging of T2-weighted images (3D-T2R) in conjunction with other modes of 3D MRI for preoperative assessments in patients with glossopharyngeal neuralgia (GPN) due to neurovascular compression. MATERIAL/METHODS: Imaging findings on 3D-T2R, constructive interference in steady state (CISS), and MRA were analyzed with reference to operative charts in 10 patients with GPN. RESULTS: Offending vessels were associated with the posterior inferior cerebellar artery (PICA) in 9 of 10 patients (90%). Eight of the 10 patients (80%) had offending vessels located at the supraolivary fossette. Of those eight patients, six (75%) had a shift of the ipsilateral vertebral artery to the affected side. Five (42%) and seven (48%) contact points were associated with the root entry/exit zone and the peripheral nerve system segment, respectively. In six of nine contact points (67%), 3D-T2R demonstrated the pathomorphological features at the contact points better than CISS. CONCLUSIONS: The offending vessels were mostly associated with posterior inferior cerebellar arteries, were frequently located at the supraolivary fossette, and had attachments at the root entry/exit zone and at the peripheral segment of the glossopharyngeal nerve, which was well demonstrated on 3D-T2R.

Escherichia coli-derived recombinant human bone morphogenetic protein-2 combined with bone marrow-derived mesenchymal stromal cells improves bone regeneration in canine segmental ulnar defects.

BACKGROUND: Large bone defects in canines usually require assistance to achieve healing. Implantation of osteoinductive factors can promote bone healing, while transplantation of osteoprogenitor cells can enhance bone regeneration. We hypothesized that implantation of an osteoinductive factor, recombinant human bone morphogenetic protein-2 (rhBMP-2), combined with osteoprogenitor cells, bone marrow-derived mesenchymal stromal cells (BMSCs), would synergistically promote bone healing. In this study, we examined the combined effects of Escherichia coli-derived rhBMP-2 and BMSCs on bone healing after implantation into canine ulnar defects. RESULTS: Critical-sized osteoperiosteal segmental defects (2.5 cm) were created in the ulnae of healthy female beagle dogs, and implanted with combinations of E. coli-derived rhBMP-2 (560 or 140 µg) and autologous BMSCs (10(7), 10(5), or 0 cells). In the present study,18 forelimbs of nine healthy purpose-bred female beagles were used. All six treatment groups contained three forelimbs, and the animals were euthanized after 12 weeks. The control groups (560 and 140 µg/0 cells) were cited from our previous study to reduce the number of experimental animals. Radiographically, the regenerated bone width was significantly increased in the 560 or 140 µg with 10(7) and 10(5) cells groups compared with the 0 cells groups. By quantitative CT, the bone mineral density was higher in the 560 µg with 10(7) and 10(5) cells groups, while non-uniformity of the bone mineral density was improved in the 560 µg with 10(7) and 10(5) cells groups and 140 µg/10(7) cells group. Mechanically, the maximum loads at failure were significantly higher in the 560 µg with 10(7) and 10(5) cells groups. Histologically, the regenerated bone was well-developed and contained osteocyte-like cells marrow cavities, and vessels. However, the osteoclasts and osteoblasts were hardly observed. The osteocyte-like cell numbers were significantly higher in the 560 µg with 10(7) and 10(5) cells and 140 µg with 10(7) and 10(5) cells groups. CONCLUSIONS: Implantation of E. coli-derived rhBMP-2 and BMSCs led to significantly enhanced bone formation, with improved bone mineral density and reduced non-uniformity of the regenerated bone. Combined implantation of rhBMP-2 and BMSCs may be useful for promotion of bone healing in critical-sized defects in canines.

Diffusion weighted images of metastatic as compared with nonmetastatic axillary lymph nodes in patients with newly diagnosed breast cancer.

BACKGROUND: To investigate the ability of diffusion weighted images (DWI) to differentiate between metastatic and nonmetastatic axillary lymph nodes (LNs) in patients with newly diagnosed breast cancer. METHODS: From January 2010 to February 2012, DWI was performed at b values of 0 and 800 for 16 metastatic LNs from 16 patients with breast cancer, and 20 nonmetastatic LNs from 20 women without breast cancer. The metastatic LNs were proven by ultrasound (US) guided core biopsy and the same LNs were identified on MRI by comparing the US images with MR images. Nonmetastatic LNs were verified by the stability in size and shape for at least 2 years on MRI. The apparent diffusion coefficient (ADC) value of the metastatic and nonmetastatic axillary LNs was compared. Receiver-operating-characteristics (ROC) analysis was performed to evaluate the diagnostic performance of the ADC value in differentiating between metastatic and nonmetastatic axillary LNs. RESULTS: The mean ADC value was 0.746 × 10(-3) for metastatic LNs and 1.033 × 10(-3) for nonmetastatic LNs (P < 0.001). The area under the ROC curve was 0.884. The sensitivity and specificity for differentiating metastatic from nonmetastatic axillary LNs using a cutoff ADC value of 0.852 were 85% and 81%, respectively. CONCLUSION: There is a statistically significant difference between the ADC values of pathologically proven metastatic LNs and nonmetastatic LNs. DWI and ADC values are a useful tool for differentiating metastatic from nonmetastatic axillary LNs.

Arterial spin-labeling MR imaging of cerebral hemorrhages.

INTRODUCTION: The purpose of this study is to identify the characteristics of brain perfusion measured by arterial spin-labeling magnetic resonance imaging (ASL-MRI) in cerebral hemorrhages. METHODS: Brain blood flow values (CBF-ASL values) for cerebral and cerebellar hemispheres and segmented cerebral regions were measured by ASL-MRI in 19 putaminal hemorrhage patients and 20 thalamic hemorrhage patients in acute or subacute stages. We assessed the lateralities of CBF-ASL values and the relationships between CBF-ASL values and other imaging findings and clinical manifestations. RESULTS: Both the 19 putaminal hemorrhage patients and the 20 thalamic hemorrhage patients had significantly low CBF-ASL values of the contralateral cerebellum in subacute stage, suggesting that ASL-MRI might delineate crossed cerebellar diaschisis (CCD). Ipsilateral low CBF-ASL values were observed in frontal lobes and thalami with a putaminal hemorrhage and lentiform nuclei, temporal lobes, and parietal lobes with a thalamic hemorrhage, suggesting that ASL-MRI showed the ipsilateral cerebral diaschisis (ICD). In the putaminal hemorrhage patients, the hematoma volume negatively affected both the bilateral cerebellar and cerebral hemispheric CBF-ASL values. In the thalamic hemorrhage patients, a concomitant intraventricular hemorrhage caused low cerebral hemispheric CBF-ASL values. CONCLUSION: The use of ASL-MRI is sensitive to the perfusion abnormalities and could thus be helpful to estimate functional abnormalities in cerebral hemorrhage patients.

A reoperation of thrombosed On-X valve detected by multidetector-row computed tomography.

A 62-year-old female patient underwent mitral valve replacement with a 31/33-mm On-X valve for ischemic mitral valve regurgitation. Three months later, transthoracic echocardiography incidentally showed a blocked leaflet with 6 mmHg of mean pressure gradient and 2.4 cm(2) of mitral valve orifice area. Transesophageal echocardiography could not detect thrombus. Electrocardiographically gated multidetector-row computed tomography (MDCT) clearly demonstrated a blocked leaflet in the close position and thrombus (2 cm in length, 0.4 cm(2) in area) attached onto the atrial aspect of the leaflet. These findings observed by MDCT were confirmed at reoperation. MDCT was useful diagnostic method for visualizing prosthetic valve thrombosis.

Effect of antifibrinolytic therapy with tranexamic acid on abdominal aortic aneurysm shrinkage after endovascular repair.

OBJECTIVE: The long-term outcomes of endovascular abdominal aortic aneurysm repair (EVAR) remain to be determined, but patients with aneurysm shrinkage after EVAR appear to have a good prognosis. We previously observed that antiplatelet therapy is a risk factor for lack of aneurysm shrinkage, a finding suggesting that coagulation and fibrinolysis play roles in shrinkage. We therefore studied the effect of antifibrinolytic therapy with tranexamic acid (TXA) on aneurysm shrinkage after EVAR. METHODS: From May 2007 to May 2012, EVAR was performed in 187 patients, 165 of whom had an enhanced computed tomographic evaluation 6 months after their procedure. Six of the 165 patients were excluded from the study because they had a type Ia endoleak or coil embolization to treat a type II endoleak ≤ 6 months after EVAR. Of the remaining 159 patients, 110 underwent EVAR before we started to use TXA in our centers. TXA therapy (1500 mg/d for 6 months) began in January 2011, and 48 patients completed the treatment regimen. Patients not treated with TXA were compared with those given TXA. Analyses to identify risk factors for lack of aneurysm shrinkage were performed. RESULTS: No patient had a thromboembolic event. There were no significant differences between the no-TXA and TXA groups in demographics, aneurysm characteristics, prosthesis implanted, type II endoleak occurrence during EVAR or 1 or 6 months afterward, or aneurysm shrinkage at 1 month. However, at 6 months after EVAR, the TXA group had significantly greater aneurysm shrinkage (P = .035) and a significantly higher percentage of patients with >4 mm in shrinkage (P = .010). Multiple regression analysis showed aneurysm diameter, type II endoleak 6 months after EVAR, and TXA treatment were independently associated with aneurysm shrinkage or lack of shrinkage. CONCLUSIONS: Antifibrinolytic therapy with TXA was associated with aneurysm shrinkage after EVAR. Studies to identify the dosage of TXA that is optimally safe and effective in this application, as well as investigations of the best timing and route (parenteral vs oral) for TXA administration, are warranted.

Assessment of aggressiveness of rectal cancer using 3-T MRI: correlation between the apparent diffusion coefficient as a potential imaging biomarker and histologic prognostic factors.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) permits non-invasive assessment of tumor characteristics. PURPOSE: To assess the value of DW-MRI as a potential non-invasive marker of tumor aggressiveness in rectal cancer by analyzing the relationship between tumoral apparent diffusion coefficient (ADC) values of MRI and histopathologic prognostic parameters that are not affected by preoperative chemoradiation therapy. MATERIAL AND METHODS: Forty patients with rectal cancer were assessed with primary staging 3-T MRI, including DWI, before undergoing surgical therapy. In all patients, surgery was performed without neoadjuvant therapy. Mean tumor ADC was measured and compared between subgroups based on pretreatment carcinoembryonic antigen (CEA) levels, MRI parameters (e.g. postoperative local recurrence), and histopathologic parameters, including A (invasive distance: A1, T-stage; A2, mesorectal fascia [MRF] status), B (differentiation grade: B1, poorly differentiated; B2, moderately differentiated; B3, well differentiated), C (others: C1, N-stage; C2, lymphangiovascular invasion). RESULTS: Mean tumor ADCs were different when comparing groups stratified by histologic differentiation grades (P=0.0192). There was no significant difference in mean ADCs when stratifying patients according to CEA levels, T-stage, N-stage, MRF status, presence of lymphangiovascular invasion, or the presence of local recurrence. CONCLUSION: Significant correlations were found between mean ADC values and differentiation grade. ADC may be useful as an imaging biomarker of tumor aggressiveness, but it cannot serve as an independent biomarker of advanced rectal cancer.

Mid-term results of 17-mm St. Jude Medical Regent prosthetic valves in elder patients with small aortic annuli: comparison with 19-mm bioprosthetic valves.

This study was designed to compare the mid-term outcomes after aortic valve replacement (AVR) between 17-mm mechanical heart valves (MV) and 19-mm bioprosthetic valves (BV) in elderly patients with small aortic annuli. Between 2000 and 2011, 127 consecutive patients (mean age 79 years; 87 % female) underwent AVR for aortic valve stenosis with a small aortic annulus. 19-mm BV (n = 67) was implanted. When the 19-mm BV did not fit the annulus, 17-mm St. Jude Medical Regent prosthetic mechanical valve (n = 60) was used instead of an aortic root-enlargement procedure. The follow-up rate was 94.0 % in the BV group, and 98.5 % in the MV group. No significant differences in survival rate and valve-related complications were found between the 2 groups. In-hospital mortality rates were 1.5 % (n = 1) in the BV group and 5.0 % (n = 3) in the MV group. Late mortality rates were 3.9 % per patient-years (p-y; n = 8) in the BV group, and 6.0 % per p-y (n = 10) in the MV group. Five-year Kaplan-Meier survival rates were 62 % in the BV group, and 72 % in the MV group (log-rank P = 0.280). Freedom from major adverse valve-related stroke and cerebral bleeding events was 92.5 and 98.5 % in the BV group, and 94.7 and 100 % in the MV group. AVR using 17-mm MV in elder patients with small aortic annuli provided equivalent mid-term clinical results to that with 19-mm BV.