Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P = 0.004 and P = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

Pathological Nodal and Vascular Involvement Significantly Impacts the Recurrence Risk in Different Time Frames in Patients With Resectable and Borderline Resectable Pancreatic Cancer: Long-term Conditional Recurrence-free Survival Analysis in the Setting of a Neoadjuvant Treatment Strategy.

OBJECTIVE: To investigate the long-term dynamics of recurrence risk and the significance of prognostic variables using conditional recurrence-free survival (C-RFS) analysis in neoadjuvant treatment (NAT) for resectable (R) and borderline resectable (BR) pancreatic cancer (PC). BACKGROUND: C-RFS analysis assesses the probability of achieving additional RFS according to the RFS already accrued. METHODS: Patients with NAT and subsequent resection for R/BRPC were enrolled. In the C-RFS analysis, the actual 5-year RFS (5yRFS) rate was calculated separately in the subgroup that had already gained a given amount of RFS. The significance levels of prognostic variables associated with 5yRFS were assessed regarding their time-dependent dynamics in a conditional fashion. RESULTS: Among the total 397 patients, 160 survived for more than 5 years without recurrence after surgery (actual 5yRFS rate: 45%). The probability of 5yRFS incrementally increased based on the RFS already accrued. Pathological nodal and vascular involvement were significant influencers of 5yRFS. The patients with nodal involvement consistently remained at significantly higher risk of recurrence than those without, even after 5yRFS, whereas positivity of vascular involvement was significantly associated with the risk of recurrence only during the early postoperative period and lost its significance after 3yRFS accrued. CONCLUSIONS: In NAT for R/BRPC, the probability of gaining additional RFS increases as a function of RFS already accrued, and the significance of prognostic variables time-dependently evolves in their own patterns during the long-term postoperative period.

DUPAN-II normalisation as a biological indicator during preoperative chemoradiation therapy for resectable and borderline resectable pancreatic cancer.

BACKGROUND: Duke pancreatic mono-clonal antigen type 2 (DUPAN-II) is a famous tumour maker for pancreatic cancer (PC) as well as carbohydrate antigen 19-9 (CA19-9). We evaluated the clinical implications of DUPAN-II levels as a biological indicator for PC during preoperative chemoradiation therapy (CRT). METHODS: This retrospective analysis included data from 221 consecutive patients with resectable and borderline resectable PC at diagnosis who underwent preoperative CRT between 2008 and 2017. We focused on 73 patients with elevated pre-CRT DUPAN-II levels (> 230 U/mL; more than 1.5 times the cut-off value for the normal range). Pre- and post-CRT DUPAN-II levels and the changes in DUPAN-II ratio were measured. RESULTS: Univariate analysis identified normalisation of DUPAN-II levels after CRT as a significant prognostic factor (hazard ratio [HR] = 2.06, confidence interval [CI] = 1.03-4.24, p = 0.042). Total normalisation ratio was 49% (n = 36). Overall survival (OS) in patients with normalised DUPAN-II levels was significantly longer than that in 73 patients with elevated levels (5-year survival, 55% vs. 21%, p = 0.032) and in 60 patients who underwent tumour resection (5-year survival, 59% vs. 26%, p = 0.039). CONCLUSION: Normalisation of DUPAN-II levels during preoperative CRT was a significant prognostic factor and could be an indicator to monitor treatment efficacy and predict patient prognosis.

Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial.

BACKGROUND: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients. METHODS: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period. RESULTS: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%). CONCLUSIONS: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.

The clinical impact of splenic artery ligation on the occurrence of digestive varices after pancreaticoduodenectomy with combined portal vein resection: a retrospective study in two institutes.

PURPOSE: Pancreaticoduodenectomy (PD) concomitant with portal vein resection (PVR) often develops into digestive varices with an occurrence rate of 30-50%, and the variceal bleeding is sometimes untreatable and results in fatality. Against this issue, splenic artery (SpA) ligation during PD-PVR is emerging as an easy and effective prophylactic surgical option. The aim of this study was to investigate the significance of SpA ligation in the development of digestive varices in patients undergoing PD-PVR. METHOD: We retrospectively investigated 97 patients with PDAC who received PD-PVR in two hospitals. Vascular reconstruction of the splenic vein (SpV) was not performed in either hospital. We assessed the occurrence rate of digestive varices in these patients in association with the performance of SpA ligation. RESULTS: The occurrence rate of digestive varices was 23%. SpA ligation was the only significant decreasing factor for the development of digestive varices (odds ratio 0.3, p = 0.035). Although SpV resection was not a significant risk factor for the development of digestive varices in all patients, SpV resection was a significant risk factor for the development of digestive varices in patients without SpA ligation, as demonstrated in previous reports. SpA ligation did not increase surgical complications or impair pancreatic function. CONCLUSION: PD-PVR surgery was accompanied by a 23% incidence of digestive varices, and SpA ligation significantly decreased the development of digestive varices without causing clinically significant complications. TRIAL REGISTRATION: No. 18196 (Osaka International Cancer Institute) and no. 19006 (National Hospital Organization Osaka National Hospital).

A predictive score for identification of rupture site in subarachnoid haemorrhage with multiple intracranial aneurysm.

PURPOSE: The rigid method of identifying the rupture site in cases of subarachnoid haemorrhage (SAH) with multiple intracranial aneurysms (MIAs) is still unclear. Here we present a reliable method by using a combination of six predictors. MATERIALS AND METHODS: Concerning the 48 SAH patients with MIAs who visited the Showa General Hospital during the period from January 2005 to March 2016, several predictors of rupture site such as the aneurysm-related morphologic features (size, aspect ratio, shape, bleb), aneurysm location, and the distribution of SAH were investigated. Compared with other coexisting aneurysms in each predictor, each aneurysm was categorized into 'suspicion' or 'non-suspicion', and we analyzed the association between 'suspicion' and rupture. RESULTS: In the first analysis, all variables were associated with rupture and included in the multivariate logistic regression analysis. The presence of bleb (OR, 20.7; CI, 2.3-186; p = .007) and the aneurysm location (OR, 23.5; CI, 5.2-106; p < .001) were significantly associated with rupture in multivariate logistic regression analysis. Based on the results, a predictive score for rupture was created and calculated for each aneurysm, and the aneurysm with highest predictive score in each patient was categorized into 'suspicion'. 'Suspicion' in the predictive score was significantly associated with rupture (OR, 412.5; CI, 52.2-16384; p < .001). The sensitivity (0.90), specificity (0.98) and the accuracy (0.94) of identifying the rupture site by the predictive score were quite satisfactory. CONCLUSION: Our results suggest that the predictive score may be an excellent parameter to identify the rupture site in cases of SAH with MIAs.

Clinical course of Japanese patients with early systemic sclerosis: A multicenter, prospective, observational study.

OBJECTIVES: To investigate the clinical course of Japanese patients with early diffuse cutaneous systemic sclerosis (dcSSc) and early SSc with interstitial lung disease (ILD). METHODS: We prospectively analyzed the clinical features of 207 Japanese patients with early dcSSc (n = 150) and limited cutaneous SSc (lcSSc) with ILD (n = 57) in 10 medical centers every year for 7 consecutive years. RESULTS: Mean modified Rodnan total skin thickness score (mRSS) was 18.3 and 67.4% of the cohort had ILD. Most patients started immunosuppressive therapy and vasodilators during 7 years (83.4% and 87.9%, respectively). Mean value of mRSS of total patients was significantly reduced from the initial registration after the first year. However, other parameters for physical function associated with skin sclerosis including fist closure, hand extension, and oral aperture were not so ameliorated during the study period. Health Assessment Questionnaire-disability index and serum KL-6 levels were constant throughout the course. Percent vital capacity and the presence of ILD, clinically suspected pulmonary arterial hypertension, and digital ulcers were gradually exacerbated during the period. CONCLUSION: In Japanese early dcSSc patients and SSc patients with ILD, mRSS was continuously reduced during 7 years of follow-up, but there was little improvement of physical disability and organ involvement.

Initial predictors of skin thickness progression in patients with diffuse cutaneous systemic sclerosis: Results from a multicentre prospective cohort in Japan.

OBJECTIVE: To identify initial parameters that predict worsening of skin thickening in patients with diffuse cutaneous systemic sclerosis (dcSSc) using a multicentre, prospective, observational cohort in Japan. METHODS: A total of 171 patients with dcSSc were selected from a prospective cohort database based on the following criteria: dcSSc, modified Rodnan total skin thickness score (mRSS) ≥7, disease duration <60 months, and valid mRSS data at one year. Worsening of skin thickness was defined as an increase in mRSS ≥3 points and an increase ≥25% from baseline to one year. Initial demographic and clinical parameters useful for predicting the progression of skin thickness were identified using univariate and multivariable analysis, and prediction models of skin thickening progression were built based on combinations of independent predictive parameters. RESULTS: Only 23 patients (13.5%) experienced worsening mRSSs at one year. Short disease duration, low mRSS, absence of nailfold bleeding, arthritis, and a high erythrocyte sedimentation rate at diagnosis were identified as predictors of subsequent worsening of the mRSS even after adjusting for the treatment. Assessment of the best predictive model revealed that patients with a disease duration ≤12 months and mRSS ≤19 had a risk of mRSS worsening within one year, with a sensitivity of 73.9% and specificity of 81.1%. CONCLUSION: Identification of predictors of subsequent worsening of skin thickness in dcSSc patients is useful for identifying patients who require intensive treatment with potential disease-modifying agents and for improving clinical trial design by characterizing eligible progressors in the Japanese population.

Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial.

OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.

Clinical implications of the serum CA19-9 level in "biological borderline resectability" and "biological downstaging" in the setting of preoperative chemoradiation therapy for pancreatic cancer.

BACKGROUND: Biological factors are emphasized in borderline resectable pancreatic cancer (BRPC), and CA19-9 is an important factor for biological borderline resectability (b-BR). The aim of this study was to investigate the cut-off value of CA19-9 for biological borderline resectability and "biological downstaging" in chemoradiation therapy (CRT) for pancreatic cancer (PC). METHODS: A total of 407 patients with anatomically resectable PC (a-R) and BRPC (a-BR) received preoperative gemcitabine-based CRT. The b-BR was determined, according to the CA19-9 value prior to preoperative CRT (pre-CA19-9), as the subgroup of a-R cases in which the survival was comparable with that in a-BR cases. "Biological downstaging" was determined based on prognostic analyses regarding the CA19-9 value after preoperative CRT (post-CA19-9) in association with the survival of R cases (a-R cases without the b-BR factor). RESULTS: The 5-year survival of a-R patients with pre-CA19-9 > 120 U/mL was comparable with that of a-BR patients (44% vs 34%, p = 0.082). The survival of b-BR patients with post-CRT CA19-9 ≤ 37 U/mL (normalized) was comparably favorable with that of R patients (56% vs 65%, p = 0.369). The incidence of distant recurrence was higher in b-BR patients without post-CA19-9 normalization than in those with post-CA19-9 normalization (70% vs 50%, p = 0.003), while the incidence of local recurrence was comparable between these two groups (12% vs 13%, p = 0.986). CONCLUSIONS: Biological BRPC was determined to be an anatomically resectable disease with pre-CA19-9 > 120 U/mL, and post-CA19-9 normalization indicated "biological downstaging" in b-BR in the preoperative CRT strategy.

Protective effect of dimethyl fumarate for the development of pressure ulcers after cutaneous ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) is associated with various pathogenic conditions, and there has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non-blanchable erythema. Several studies demonstrated that oxidative stress is a key player in I/R injury, and the inhibition of oxidative stress may be capable of protecting tissue damage after I/R injury in various organs including skin. Dimethyl fumarate (DMF) approved by the Food and Drug Administration is Nrf2 activator, and recent studies revealed the antioxidative and anti-inflammatory effects of DMF on I/R injury in animal models. Our objective was to assess the effects of oral administration of DMF on the development of PUs after cutaneous I/R injury in mice. We found that DMF administration significantly decreased the size of PUs after cutaneous I/R. Cutaneous I/R-induced oxidative stress was also significantly inhibited by DMF in OKD48 mice, in which oxidative stress can be visually assessed. In addition, DMF treatment decreased hypoxic area, the numbers of apoptotic cells, and vascular loss in I/R area. DMF treatment suppressed the infiltration of MPO+ neutrophils and the production of proinflammatory cytokines in I/R site after cutaneous I/R injury. in vitro experiments, DMF treatment suppressed the production of reactive oxygen species in pericyte-like cells. These results suggest that DMF treatment might prevent the formation of PUs induced by cutaneous I/R injury via suppressing oxidative stress and subsequent inflammation. DMF treatment during the early phase of decubitus ulcers might protect against further progression.

Prevalence and clinical characteristics of overactive bladder in systemic sclerosis.

Objectives: Overactive bladder (OAB) is a clinical diagnosis defined with the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence. Objective was to evaluate the demographic and clinical characteristics of Japanese systemic sclerosis (SSc) patients with OAB.Methods: OAB was diagnosed by OAB symptom score (OABSS) in 104 Japanese SSc patients (93 women and 11 men). Differential diseases of OAB were conducted by urologists.Results: The prevalence of OAB in SSc patients was 27.9% (29/104). SSc patients with OAB were characterized by old age, a long history of morbidity (15.4 vs. 11.2 years, p < .01), high anti-centromere antibody positive rate (75.9 vs. 44%, p < .05), high incidence of gastroesophageal reflux disease (93.1 vs. 73.3%, p < .05), low anti-SS-A antibody positive rate (6.9 vs. 26.8%, p < .05), and low incidence of internal lung disease (17.9 vs. 45.7%, p < .05) compared to SSc patients without OAB.Conclusion: This is the first study that evaluated the prevalence and clinical features of OAB in Japanese SSc patients. Since SSc patients might be prone to develop OAB, it was thought that OAB should be noted as one of the complications of SSc patients.

Nail squamous cell carcinoma: A hidden high-risk human papillomavirus reservoir for sexually transmitted infections.

Human papillomavirus (HPV) causes cervical cancer, anal cancer, vulvar cancer, vaginal cancer, penile cancer, and oropharyngeal cancer. Squamous cell carcinoma (SCC) in the genital region in particular is recognized to be caused by HPV infection, and intraepithelial lesions of the penis and vulva are termed penile intraepithelial neoplasia and vulvar intraepithelial neoplasia, respectively. Although SCC of the nail apparatus is recognized as being associated with high-risk HPVs, it is not well-known in general medicine, and its analysis has been insufficient. In this article, we reviewed 136 cases of HPV-associated nail SCC and SCC in situ and delineated their clinical characteristics. We found that half of the cases were high-risk HPV-associated. Almost all of the types were high-risk α-HPVs. This disease had a male dominance and left hand digit 3 and right hand digits 1-3 were typically affected. In this review, 24% of the cases of nail SCC had a history of other HPV-associated diseases, suggesting the possibility of genitodigital transmission. We propose that nail SCC is a hidden high-risk HPV-associated reservoir and should be recognized as a sexually transmitted infection.

Short- and long-term outcomes of choledochojejunostomy during pancreaticoduodenectomy and total pancreatectomy: interrupted suture versus continuous suture.

PURPOSE: Choledochojejunostomy can be performed with either interrupted sutures (IS) or continuous sutures (CS). No reports have compared the short- or long-term patient outcomes resulting from these two methods. METHODS: A total of 228 consecutive patients who underwent pancreaticoduodenectomy or total pancreatectomy were prospectively enrolled in this study. All patients were alternately (by turns) assigned to the IS and CS groups. Among those patients, 161 patients who received regular postoperative follow-up for more than 2 years were eligible for analysis (IS group, n = 81; CS group, n = 80). A comparative analysis was performed between these groups regarding short-term (e.g., anastomotic leakage) and long-term complications (e.g., anastomotic stricture), time required to complete the anastomosis, and cost. RESULTS: The incidence of anastomotic leakage and anastomotic stricture was comparable between the IS and CS groups (1.2% vs. 1.2%, p = 0.993; 8.6% vs. 6.2%, p = 0.563). The groups did not differ regarding the incidence of any short- or long-term complications. The time required to complete the anastomosis in the IS group was 27.0 ± 6.6 min, compared with 16.2 ± 5.0 min in the CS group (p < 0.001). The cost was $144.7 ± 34.6 in the IS group vs. $11.7 in the CS group (p < 0.001). CONCLUSIONS: The IS and CS groups did not differ regarding short- and long-term outcomes. The anastomosis was completed in significantly less time in the CS group. The CS method was also superior in terms of cost.

Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

Efficacy of Botulinum Toxin B Injection for Raynaud's Phenomenon and Digital Ulcers in Patients with Systemic Sclerosis.

The efficacy and safety of botulinum toxin B (BTX-B) for treatment of Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis was assessed. A total of 45 patients with systemic sclerosis who had Raynaud's phenomenon were blinded and divided randomly into 4 groups: a no-treatment control group, and 3 treatment groups, using 250, 1,000 or 2,000 international units (U) of BTX-B injections in the hand with more severe symptoms. Four weeks after injection, pain/numbness visual analogue scale scores and Raynaud's score in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group and the group treated with 250 U BTX-B. These beneficial effects were sustained until 16 weeks after the single injection. At 4 weeks after injection skin temperature recovery in the group treated with 2,000 U BTX-B was significantly improved. The numbers of digital ulcers in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group. In conclusion, 1,000 and 2,000 U BTX-B injections significantly suppressed the activity of Raynaud's phenomenon and digital ulcers in patients with SSc without serious adverse events.

Cutaneous collagenous vasculopathy: Report of first Japanese case and review of the literature.

Cutaneous collagenous vasculopathy (CCV) is a rare acquired idiopathic microangiopathy characterised by the progressive development of diffuse asymptomatic telangiectasias over the skin. Histologically, the presence of a thick hyaline collagenous wall around the affected capillaries, comprising the accumulation of collagen type IV, is noted. We herein report the case of a 17-year-old Japanese boy with symmetrical patches of diffuse telangiectasias on the bilateral extremities that persisted for 10 months. A histological examination revealed dilated capillaries in the papillary dermis surrounded by thick perivascular deposition of hyaline-like materials, which stained positive for periodic acid-Schiff and collagen type IV. We additionally performed a review of 26 CCV patients previously reported in the English literature and summarised the clinical and histological features of generalised telangiectatic disorders, such as CCV, generalised essential telangiectasia and hereditary haemorrhagic telangiectasia. To establish an accurate diagnosis, it is important for dermatologists to recognise the clinical and histological characteristics of CCV and the importance of the histological analysis.

Novel intraoperative use of the "Tensipresser" to assess factors predictive of pancreatic fistula after pancreaticoduodenectomy.

PURPOSES: Pancreatic fistula (PF) is a challenging complication of pancreaticoduodenectomy (PD). 'Soft pancreas' is reported as a risk factor for PF; however, palpation by the surgeon is not an objective method of evaluating pancreatic texture. We conducted this study to investigate whether a texture analyzer called a "Tensipresser" can be used to quantify pancreatic tissue hardness and predict the development of postoperative PF. METHODS: We assessed pancreatic texture in 85 patients who underwent PD. After surgeons assessed the texture of the pancreas subjectively, the physical properties were measured on the pancreatic margin intraoperatively, by the two-bite method using the "Tensipresser". The incidence and severity of PF were based on the definitions of the International Study Group on Pancreatic Fistula. RESULTS: Symptomatic PF (grade B and C) developed in 16% of the patients. Patients were divided into two groups based on the Tensipresser measurement: those with a soft and fragile pancreas with hardness < 2070 gw/cm2 and cohesiveness < 0.65 (SF group); and all other patients (non-SF group). In the univariate and multivariate analysis, a small pancreatic duct diameter (<4 mm), no conduction of preoperative chemoradiation therapy, and inclusion in the SF group were significant predictors of PF. CONCLUSION: The Tensipresser can evaluate pancreatic texture objectively, helping to define intraoperatively, those at risk of the development of PF.

Preoperative Gemcitabine-based Chemoradiation Therapy for Borderline Resectable Pancreatic Cancer: Impact of Venous and Arterial Involvement Status on Surgical Outcome and Pattern of Recurrence.

OBJECTIVE: To evaluate the outcome of preoperative gemcitabine-based chemoradiation therapy (CRT) for borderline resectable pancreatic cancer (BRPC), focusing on the associations among the tumor-vascular relationship, surgical outcomes, and pattern of recurrence. SUMMARY BACKGROUND DATA: Among the various multimodal treatment strategies for pancreatic cancer, preoperative CRT and subsequent surgery is 1 promising strategy for BRPC. METHODS: A total of 184 patients with BRPC received preoperative CRT. BRPC was classified as follows, based on radiographic findings before the initiation of preoperative CRT: BR-V, a tumor involving the portal-superior mesenteric vein without arterial involvement; and BR-A, a tumor with the involvement of a relevant major artery. We assessed the association of these 2 subgroups with the following parameters: (1) resection rate, (2) survival, and (3) pattern of recurrence. RESULTS: The resection rate of BR-V cases (84%) was significantly higher than that of BR-A cases (57%) (P < 0.001). The 5-year survival rates of the resected BR-V and BR-A cases were 51% and 25%, respectively (P = 0.003). The 5-year cumulative incidence of distant recurrence was significantly higher in the BR-A cases compared with the BR-V cases (67% vs 54%, P = 0.006); however, the 5-year cumulative incidence of local recurrence was not significantly different between the groups. CONCLUSIONS: In BRPC, arterial involvement was associated with impaired outcome regarding resection rate and survival, possibly due to the difference in the underlying pathophysiology between BR-V and the advanced nature of BR-A as a systemic disease.

Prognostic significance of ß2-adrenergic receptor expression in malignant melanoma.

Recent studies cite ß2-adrenergic receptor (ß2AR) antagonists as novel therapeutic agents for melanoma, as they may reduce the disease progression. The ß2AR has shown to be expressed in malignant melanoma. However, it remains unclear whether the ß2AR expression has a clinical and pathological significance in patients with cutaneous malignant melanoma. We herein conducted a clinicopathological study to investigate the protein expression of ß2AR in malignant melanoma of the skin and its prognostic significance. One hundred thirty-three patients with surgically resected cutaneous malignant melanoma were evaluated. Tumor sections were stained by immunohistochemistry for ß2AR, Ki-67, the microvessel density (MVD) determined by CD34, and p53. ß2AR was highly expressed in 44.4 % (59 out of 133) of the patients. The expression of ß2AR was significantly associated with the tumor thickness, ulceration, T factor, N factor, disease stage, tumor size, cell proliferation (Ki-67), and MVD (CD34). Using Spearman's rank test, the ß2AR expression was correlated with Ki-67 (r = 0.278; 95 % CI, 0.108 to 0.432; P = 0.001), CD34 (r = 0.445; 95 %CI, 0.293 to 0.575; P < 0.001), and the tumor size (r = 0.226; 95 % CI, 0.053 to 0.386; P = 0.008). Using a univariate analysis, the tumor thickness, ulceration, disease stage, ß2AR, Ki-67, and CD34 had a significant relationship with the overall and progression-free survivals. A multivariable analysis confirmed that ß2AR was an independent prognostic factor for predicting a poor overall survival (HR 1.730; 95 % CI 1.221-2.515) and progression-free survival (HR 1.576; 95 % CI 1.176-2.143) of malignant melanoma of the skin. ß2AR can serve as a promising prognostic factor for predicting a worse outcome after surgical treatment and may play an important role in the development and aggressiveness of malignant melanoma.