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. Alpha 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 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were 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.

Double-catheter technique for the embolization of recurrent cerebral aneurysms: A single-center experience.

Background: Recurrent cerebral aneurysms have complex shapes and are often technically challenging to treat with a single microcatheter. This study evaluates the clinical characteristics and treatment outcomes of patients who received double-catheter coil embolization for recurrent cerebral aneurysms. Methods: Patients who underwent double-catheter coil embolization at our institution between April 2011 and March 2022 for recurrent aneurysms were included in the study. Baseline characteristics, course to recurrence, details of the procedures, and outcomes after endovascular treatment were retrospectively analyzed based on past medical records. Results: Eight patients with recurrent aneurysms were treated with the double-catheter technique. One patient had a subarachnoid hemorrhage due to a rupture of a recurrent aneurysm and the others had radiological recurrence during follow-up. The initial treatment for the aneurysm was clipping in one case and coiling in seven cases. All the aneurysms were located at bifurcation sites. During retreatment, balloon remodeling technique was used in five cases. Angiographic features immediately after the treatment included complete occlusion in one case, neck remnant in three cases, and dome filling in four cases. There were no procedure-related severe complications, besides preexisting oculomotor nerve palsy due to the mass effect of the aneurysm worsened in one patient. The mean follow-up period after retreatment was 4.3 years. There was one case of recurrence after retreatment in which additional endovascular coiling was necessary. Conclusion: This study demonstrated that the double-catheter technique could be a safe and useful treatment option for patients with recurrent aneurysms at bifurcation sites.

Complete Recanalization in Mechanical Thrombectomy Is Associated with Favorable Functional Outcome for M2 Occlusions.

Objective: There are insufficient coherent reports on mechanical thrombectomy (MT) for occlusion of the second segment of the middle cerebral artery (M2 occlusion) in a real-world clinical setting. We evaluated the efficacy and safety of MT for M2 occlusions and compared the primary thrombectomy strategies (stent retriever, aspiration catheter, and combined technique) to analyze factors predicting good functional outcomes. Methods: We evaluated background factors, preprocedural factors, procedural factors, and procedural time for patients who underwent MT for M2 occlusions from our retrospective cohort. According to the modified Rankin Scale (mRS) score three months after MT, patients were divided into good (mRS ≤2) and poor (mRS ≥3) prognosis groups. Results: A total of 29 patients (median age, 78 years; 11 [37.9%] females) were included in the study. In this cohort, rates of successful reperfusion, thrombolysis in cerebral infarction (TICI) 3, postprocedural hemorrhage (PPH), and symptomatic PPH were 82.8, 34.5, 31.0, and 0%, respectively. Good prognoses were achieved in 13 (45%) cases. A prognostic factor of MT for M2 occlusions is TICI 3 from multivariate analysis (OR, 11.7; 95% CI, 1.003-136; p = 0.0497). There was no statistically significant difference in the functional outcome three months after MT based on the choice of the primary thrombectomy strategy. Conclusion: MT for M2 occlusions is a reliable and relatively safe procedure. The presence of TICI 3 was a prognostic factor in this cohort. Future studies are warranted to investigate the optimal thrombectomy strategy for medium vessel occlusion.

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.

Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): open-label, long-term extension of a phase 2b, randomised, placebo-controlled trial.

BACKGROUND: The phase 2b Riociguat Safety and Efficacy in Patients with Diffuse Cutaneous Systemic Sclerosis (RISE-SSc) trial investigated riociguat versus placebo in early diffuse cutaneous systemic sclerosis. The long-term extension evaluated safety and exploratory treatment effects for an additional year. METHODS: Patients were enrolled to RISE-SSc between Jan 15, 2015, and Dec 8, 2016. Those who completed the 52-week, randomised, parallel-group, placebo-controlled, double-blind phase were eligible for the long-term extension. Patients originally assigned to riociguat continued therapy (riociguat-riociguat group). Those originally assigned to placebo were switched to riociguat (placebo-riociguat group), adjusted up to 2·5 mg three times daily in a 10-week, double-blind dose-adjustment phase, followed by an open-label phase. Statistical analyses were descriptive. Safety including adverse events and serious adverse events was assessed in the long-term safety analysis set (all patients randomly assigned and treated with study medication in the double-blind phase who continued study medication in the long-term extension). The RISE-SSc trial is registered with ClinicalTrials.gov, NCT02283762. FINDINGS: In total, 87 (72%) of 121 patients in the main RISE-SSc study entered the long-term extension (riociguat-riociguat, n=42; placebo-riociguat, n=45). 65 (75%) of 87 patients were women, 22 (25%) were men, and 62 (71%) were White. Overall, 82 (94%) of 87 patients in the long-term extension had an adverse event; most (66 [76%] of 87) were of mild to moderate severity, with no increase in pulmonary-related serious adverse events in patients with interstitial lung disease. INTERPRETATION: No new safety signals were observed with long-term riociguat in patients with early diffuse cutaneous systemic sclerosis. Study limitations include the absence of a comparator group in this open-label extension study. FUNDING: Bayer and Merck Sharp & Dohme.

Impact of pathological complete response following neoadjuvant chemotherapy (gemcitabine, nab-paclitaxel, S-1) and radiation for borderline resectable pancreatic cancer: a case report and review of literature.

BACKGROUND: Pancreatic cancer (PC) is a highly lethal malignancy, even if surgical resection is possible (median survival: < 30 months). The prognosis of borderline resectable pancreatic cancer (BR-PC) is even worse. There is no clear consensus on the optimal treatment strategy, including pre/postoperative therapy, for BR-PC. We report a patient with BR-PC who achieved clinical partial response with neoadjuvant chemoradiation therapy (NACRT) and underwent curative resection, resulting in pathological complete response (pCR). CASE PRESENTATION: A 71-year-old man with jaundice and liver dysfunction was referred to our department because of a 48-mm hypo-vascular mass in the pancreatic head with obstruction of the pancreatic and bile ducts and infiltration of superior mesenteric vein and portal vein. The lesion was identified as atypical cells which suggested adenocarcinoma by biopsy, and he was administered NACRT: gemcitabine and nab-paclitaxel, following S-1 and intensity modulated radiation therapy. After reduction in the tumor size (clinical partial response), pancreaticoduodenectomy was performed, and pCR achieved. Postoperative adjuvant chemotherapy with S-1 was initially administered and the patient is currently alive with no recurrence as of 2 years after surgery. CONCLUSIONS: NACRT is a potentially useful treatment for BR-PC that may lead to pCR and help improve prognosis.

Risk Factors of Brain Arteriovenous Malformation Embolization as Adjunctive Therapy: Single-Center 10-Year Experience.

OBJECTIVE: In the multimodality treatment of complex brain arteriovenous malformations (AVMs), the role of endovascular embolization is not fully elucidated. To assess the risk of embolization, we retrospectively evaluated the outcomes of endovascular treatment for AVM, focusing on the embolization-related complications. METHODS: The present study included patients with brain AVM who underwent embolization at our hospital between April 2011 and May 2021. Risk factors for peri- and postoperative complications were analyzed. RESULTS: During the study period, 36 AVMs were treated during 58 embolization sessions. The goal of the embolization was preoperative in 24 (67%), pre-radiosurgical in 9 (25%), and palliative in 3 (8%) cases. The overall complication rate was 43% (25 of 58) per session and 36% (13 of 36) per patient. Ischemic and hemorrhagic complications were observed in 14 (24%) and 14 (24%) cases, respectively. n-Butyl cyanoacrylate (n-BCA) embolization was detected as the significant risk for postoperative hemorrhage in the univariate (79% vs. 36%, P = 0.012; Fisher exact test) and the multivariable analysis (odds ratio 4.90, 95% confidence interval 1.08-22.2, P = 0.039). The number of embolized feeder in a single session also tended to be higher in a hemorrhagic complication group (median 3.5 vs. 2.0, P = 0.11; Mann-Whitney U-test). CONCLUSIONS: The risk of embolization in multimodality treatment for complex brain AVM was substantial. n-BCA embolization may carry a higher risk of postoperative hemorrhage. An accumulation of cases is awaited to investigate the effectiveness of minimal target embolization in the future.

Case Report: Spontaneous Postpartum Quadruple Cervicocephalic Arterial Dissection With a Heterozygous COL5A1 Variant of Unknown Significance.

Pregnancy-associated cervicocephalic arterial dissection is rare, and its pathophysiology remains poorly understood. Despite the hypothesized contribution to pathogenesis, connective tissue diseases and genetic factors are rarely identified in clinical cases. We describe a case of postpartum arterial dissection involving all four cervicocephalic arteries resulting in acute cerebral infarction. The patient underwent successful endovascular thrombectomy and angioplasty and recovered fully without sequelae. Genetic screening for connective tissue diseases identified a heterozygous missense COL5A1 variant with unknown clinical significance. Two genetically related family members later developed arterial abnormalities, and one of them tested positive for the same COL5A1 gene variant as our patient, while the other was scheduled for genetic testing. The extensive clinical presentation of our patient and the prevalence of arterial abnormalities in her family warrant further assessment of the association between the identified COL5A1 gene variant and the pathogenesis of arterial dissections.

Anti-polymyositis/Scl antibody-positive overlap syndrome of diffuse cutaneous systemic sclerosis, dermatomyositis, systemic lupus erythematosus, and antiphospholipid syndrome.

A 37-year-old Japanese man with a 3-year history of diffuse cutaneous systemic sclerosis was admitted to our hospital with high fever, arthralgia, myalgia, and muscle weakness. A physical examination revealed facial erythema, Gottron's sign, and mechanic's hands in addition to skin sclerosis. Laboratory data revealed significantly elevated levels of creatine kinase and decreased complement. Anti-RNP, anti-Smith, anti-DNA, anti-ß2 -glycoprotein 1, anti-polymyositis (PM)/Scl75, and anti-PM/Scl100 antibodies were detected. He also had urinary protein, interstitial lung disease, pericarditis, multifocal cerebral infarctions, and leukoencephalopathy. Thus, a diagnosis of overlap syndrome of diffuse cutaneous systemic sclerosis, dermatomyositis, and systemic lupus erythematosus with antiphospholipid syndrome was made. Because of the intractable course, he was treated with multiple immunosuppressive and immunomodulatory drugs, including three rounds of 1000 mg methylprednisolone pulse therapy. This is the first case report of anti-PM/Scl antibody-positive overlap syndrome of three major connective tissue diseases.

Spontaneous regression of a symptomatic developmental venous anomaly with capillary stain.

BACKGROUND: Developmental venous anomalies are considered benign lesions; however, they can become symptomatic. A capillary stain, which is an atypical angiographical feature of developmental venous anomalies, is reported to be relevant to symptomatic developmental venous anomalies. CASE DESCRIPTION: A 20-year-old man with no pertinent medical history had an epileptic seizure. Magnetic resonance imaging showed severe focal oedema and gadolinium contrast enhancement in the right precentral gyrus and inferior frontal gyrus adjacent to the Sylvian fissure, indicating venous congestion; these presentations had not been observed on magnetic resonance imaging 8 months before. Digital subtraction angiography revealed a developmental venous anomaly with capillary stain. After conservative treatment, the brain oedema resolved spontaneously and contrast enhancement of the lesion reduced significantly. CONCLUSION: We report a rare case of a symptomatic developmental venous anomaly with unique radiological characteristics and its natural and clinical evolution. Despite the presence of a capillary stain, our patient exhibited temporary exacerbations and spontaneous regression, suggesting that the capillary stain was associated with a reversible condition. This is the first report to detail the spatiotemporal changes of a developmental venous anomaly with capillary stain through imaging, suggesting that regular follow-up imaging is warranted in the management of patients with developmental venous anomalies.

Coordination of retrotransposons and type I interferon with distinct interferon pathways in dermatomyositis, systemic lupus erythematosus and autoimmune blistering disease.

Type I interferon (IFN) plays a crucial role in innate and adaptive immunity, and aberrant IFN responses are involved in systemic autoimmune diseases, such as systemic lupus erythematosus (SLE) and dermatomyositis (DM). Type I IFNs can be induced by transcribed retrotransposons. The regulation of retrotransposons and type I IFN and the downstream IFN pathways in SLE, DM, and autoimmune blistering disease (AIBD) were investigated. The gene expression levels of retrotransposons, including LINE-1, type I-III IFNs, and IFN-stimulated genes (ISGs) in peripheral blood cells from patients with DM (n = 24), SLE (n = 19), AIBD (n = 14) and healthy controls (HCs, n = 10) were assessed by quantitative polymerase chain reaction. Upregulation of retrotransposons and IFNs was detected in DM patient samples, as is characteristic, compared to HCs; however, ISGs were not uniformly upregulated. In contrast, retrotransposons and IFNs, except for type II IFN, such as IFN-γ, were not upregulated in SLE. In AIBD, only some retrotransposons and type I interferons were upregulated. The DM, SLE, and AIBD samples showed coordinated expression of retrotransposons and type I IFNs and distinct spectra of IFN signaling. A positive correlation between LINE-1 and IFN-ß1 was also detected in human cell lines. These factors may participate in the development of these autoimmune diseases.

Neuroendovascular Training Using Multisource Video-Recording System in a Hybrid Operating Room.

BACKGROUND: Increasing restrictions over trainees' working hours and the recent coronavirus disease 2019 pandemic warrant new educational methods of surgical skills. We assessed a novel video-recording system for neuroendovascular skill education, developed with the installation of a hybrid operating room (OR) at our institution. METHODS: A single-plane angiography unit with a large flat display (FlexVision XL; Philips Medical Systems) was installed in our OR. All media sources in the OR, including live fluoroscopy and ceiling-mounted camcorders, were connected to a video switcher. This video switcher laid up to 8 video images into one big image, which was transferred to the large display and the professional-use Blu-ray recorder. The recording was performed continuously during the procedure. This recording system was evaluated retrospectively with a questionnaire administered to the 5 trainees. RESULTS: Using this system, 68 interventional procedures were recorded. Among the potential merits, the trainees assigned the greatest value to the simultaneous recording of the operator's hand motions and the fluoroscopy images. Among the potential limitations of the system, the prolonged time and the increased volume of the video data bothered the trainees the most. The recorded video looked like a live demonstration. CONCLUSIONS: Our "selfie" video recording system was useful for skill training of neuroendovascular interventions.

Inhibition of skin fibrosis in systemic sclerosis by botulinum toxin B via the suppression of oxidative stress.

Oxidative stress has been reported to play an important role in the pathogenesis of skin fibrosis in systemic sclerosis (SSc). We previously identified that botulinum toxin (BTX) injection suppresses pressure ulcer formation in a cutaneous ischemia-reperfusion injury mouse model by regulation of oxidative stress. However, the therapeutic possibility of BTX administration for preventing skin fibrosis in SSc is unclear. The objective of this study was to investigate the effect of BTX-B on skin fibrosis in a murine model of SSc and determine the underlying mechanism. We found that BTX-B injection significantly reduced dermal thickness and inflammatory cell infiltration in bleomycin-induced skin fibrosis lesion in mice. We also identified that the oxidative stress signal detected through bioluminescence in OKD48 mice after bleomycin injection in the skin was significantly decreased by BTX-B. Additionally, mRNA levels of oxidative stress associated factors (NOX2, HO-1, Trx2) were significantly decreased by BTX-B. Apoptotic cells in the lesional skin of bleomycin-treated mice were significantly reduced by BTX-B. Oxidant-induced intracellular accumulation of reactive oxygen species in SSc fibroblasts was also inhibited by BTX-B. In conclusion, BTX-B might improve bleomycin-induced skin fibrosis via the suppression of oxidative stress and inflammatory cells in the skin. BTX-B injection may have a therapeutic effect on skin fibrosis in SSc.

Survey of actual conditions of erythema marginatum as a prodromal symptom in Japanese patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare but life-threatening condition. HAE types I and II (HAE-1/2) result from C1-inhibitor (C1-INH) deficiency. However, recent genetic analysis has established a new type of HAE with normal C1-INH (HAEnC1-INH). The mutations of factor XII, plasminogen, angiopoietin 1, and kininogen 1 genes may be the cause of HAEnC1-INH. Nevertheless, other causative molecules (HAE-unknown) may be involved. The Japanese therapeutic environment for HAE has been improving owing to the self-subcutaneous injection of icatibant, which was approved for the treatment of acute attack and enables early therapy. Erythema marginatum (EM) is a visible prodromal symptom which occasionally occurs prior to an angioedema attack; hence, recognizing the risk of an acute attack is important for early treatment. However, the detailed characteristics of EM remain unclear. In this study, we first investigated the clinical manifestations of EM in Japanese patients with HAE. METHODS: A 20-point survey was developed and distributed to 40 physicians to gather clinical data on EM from patients with HAE. RESULTS: Data on 68 patients with HAE (58 patients with HAE-1/2 and 10 patients with HAE-unknown) were collected. Of the patients with HAE-1/2, 53.4% experienced EM, whereas 43.1% did not. The forearm was the most frequent area of EM (64.5%), followed by the abdomen (29.0%) and upper arm and precordium (19.3%). Of the HAE-1/2 patients with EM, 41.9% always had angioedema following EM, while 29.0% always had colocalization of EM with angioedema. Moreover, 3.2% showed a correlation between the awareness of EM and severity of an angioedema attack. In 60.9% of HAE-1/2 patients with EM, the interval between the awareness of EM and appearance of angioedema was <3 h. Of the patients with HAE-unknown, 30.0% also experienced EM. CONCLUSION: We confirmed that more than one-half of Japanese patients with HAE-1/2 and one-third of those with HAE-unknown develop EM as the prodromal symptom of an angioedema attack. Physicians should communicate the significance of EM to patients with HAE to prepare them for possible imminent attacks.

Rotational Angiography-Based Gamma Knife Radiosurgery for Brain Arteriovenous Malformations: Preliminary Therapeutic Outcomes of the Novel Method.

BACKGROUND: High-definition vascular imaging is desirable for treatment planning in Gamma Knife radiosurgery (GKRS; Elekta AB) for brain arteriovenous malformations (BAVMs). Currently, rotational angiography (RA) provides the clearest 3-dimensional visualization of niduses with high spatial resolution; however, its efficacy for GKRS has not been clarified. At our institution, RA has been integrated into GKRS (RA-GKRS) for better treatment planning and outcomes since 2015. OBJECTIVE: To evaluate RA-GKRS outcomes of BAVMs and compare them with conventional GKRS (c-GKRS) outcomes. METHODS: We retrospectively analyzed the radiosurgical outcomes of 50 BAVMs treated with RA-GKRS compared with the 306 BAVMs treated with c-GKRS. Considering possible differences in the baseline characteristics, we also created propensity score-matched cohorts and compared the radiosurgical outcomes between them to ensure comparability. RESULTS: The obliteration time was shorter in the RA-GKRS group (cumulative rate, 88% vs 65% at 4 yr [P = .001]). Multivariate Cox proportional hazards analysis demonstrated that the RA-GKRS group (hazard ratio 2.38, 95% CI 1.58-3.60; P = .001) had a better obliteration rate. The cumulative 4-yr post-GKRS hemorrhage rates were 4.0% and 2.6% in the RA-GKRS and c-GKRS groups, respectively (P = .558). There was a trend toward early post-GKRS signal change in the RA-GKRS group compared with the c-GKRS group (cumulative rate, 38% vs 29% at 2 yr; P = .118). Those results were also confirmed in the matched cohort analyses. CONCLUSION: The integration of RA into GKRS is promising and may provide earlier nidus obliteration.