Endovascular treatment for a ruptured lumbar artery aneurysm in a patient with neurofibromatosis type 1.

The present medical case report describes successful endovascular treatment via stent graft and coil packing for a ruptured lumbar artery aneurysm in a 55-year-old woman with neurofibromatosis type 1. Although less common, vasculopathy, such as an aneurysm, stenosis, rupture, and arteriovenous fistula, have been reported and can be a cause of death for patients with this disorder. However, only a few cases of a ruptured lumbar aneurysm have been reported.

Open surgical repair of a giant common hepatic artery pseudoaneurysm that perforated into the duodenum and common bile duct.

This is a case of 60-year-old male patient with a history of heavy alcohol consumption and liver dysfunction who presented with a giant hepatic aneurysm. The incidence of giant hepatic aneurysms exceeding 10 cm in diameter is rare, particularly in the context of pseudoaneurysms. Furthermore, simultaneous perforation into the bile duct and duodenum is highly unusual. This case report elucidates the successful surgical management of a large pseudoaneurysm of the common hepatic artery that concurrently perforated the bile duct and duodenum, without any complications or deterioration of liver function.

Prospective clinical study for claudication after endovascular aneurysm repair involving hypogastric artery embolization.

PURPOSE: This prospective study aimed to assess the prognosis of claudication after endovascular aneurysm repair (EVAR) involving hypogastric artery (HGA) embolization. METHODS: Patients who were scheduled to undergo EVAR involving bilateral or unilateral HGA embolization (BHE or UHE, respectively) between May 2017 and January 2019 were included in this study. Patients underwent the walk test preoperatively, one week postoperatively, and monthly thereafter for six months. The presence of claudication and the maximum walking distance (MWD) were recorded. A near-infrared spectroscopy monitor was placed on the buttocks, and the recovery time (RT) was determined. A walking impairment questionnaire (WIQ) was completed to determine subjective symptoms. RESULTS: Of the 13 patients who completed the protocol, 12 experienced claudication in the 6-min walk test. The MWD was significantly lower at one week postoperatively than preoperatively. The claudication prevalence was significantly higher at five and six months postoperatively after BHE than after UHE. BHE was associated with longer RTs and lower WIQ scores than UHE. CONCLUSIONS: We noted a trend in adverse effects on the gluteal circulation and subjective symptoms ameliorating within six months postoperatively, with more effects being associated with BHE than with UHE. These findings should be used to make decisions concerning management strategies for HGA reconstruction.

[Pharmacological and clinical profile of Onasemnogene Aveparvovec, the first gene therapy for spinal muscular atrophy (SMA)].

Onasemnogene abeparvovec (Zolgensma®; formerly AVXS-101) is a one-time gene therapy designed to address the genetic root cause of spinal muscular atrophy (SMA) by replacing the function of the missing or nonworking SMN1 gene via an adeno-associated AAV9 viral vector. On March 19, 2020, the Japanese Ministry of Health, Labor and Welfare approved onasemnogene abeparvovec for the treatment of SMA patients <2 years of age, including presymptomatic patients with a genetic diagnosis. Patients must be negative for elevated anti-AAV9 antibodies. Onasemnogene abeparvovec is administered through a single intravenous infusion, delivering a new working copy of the SMN gene into a patient's cells. Intravenous administration of onasemnogene abeparvovec to SMA model mice resulted in sustained expression of survival motor neuron (SMN) protein, weight gain, improvement of motor function, and prolongation of survival. Its clinical efficacy and safety have been demonstrated through the Phase I START and Phase III STR1VE-US, STR1VE-EU, and SPR1NT trials, and their long-term extension studies. SMA and presymptomatic patients treated with onasemnogene abeparvovec have achieved rates of survival not observed in the natural history of SMA. Treatment has led to rapid motor function improvement, often within one month of dosing, and developmental milestone achievement, including the ability to sit without support. The most commonly observed adverse effects after treatment were elevated liver enzymes, which often resolved with a course of prednisolone, and vomiting. This review discusses the rationale underlying gene replacement therapy for SMA, and describes the basic science, clinical trial experience, and use of onasemnogene abeparvovec.

Comparison of Edoxaban and Warfarin for the Treatment of Cancer-Associated Venous Thromboembolism　- A Retrospective Observational Study.

BACKGROUND: Because anticoagulant drugs for ambulatory patients with cancer-associated venous thromboembolism (CAT) are limited to warfarin and direct oral anticoagulants (DOACs) in Japan, it is important to assess the outcomes of both drugs.Methods and Results:We retrospectively assessed the outcomes of CAT patients who were treated with warfarin or edoxaban between 2011 and 2017. The assessment was limited to the duration of anticoagulant administration. CAT patients who did not receive anticoagulation therapy were also compared with the warfarin and edoxaban groups. We enrolled 111 CAT patients treated with warfarin (n=58, mean age 62.6 years, mean time in therapeutic range [TTR] % 61.1) or edoxaban (n=53, mean age 64.6 years). Although venous thromboembolism (VTE) recurred in 2 warfarin-treated patients, the 2 treatment groups were not significantly different (P=0.18). Bleeding during anticoagulation therapy occurred in 6 warfarin-treated patients (2 with major bleeding) and in 5 edoxaban-treated patients (no major bleeding) (P=1.0). The non-anticoagulation group (n=37) showed a high recurrence rate (P<0.01) compared with the anticoagulant group. CONCLUSIONS: This study showed that warfarin and edoxaban are equally effective in preventing VTE recurrence and bleeding. However, warfarin control in CAT patients presented some difficulties. This study also demonstrated the efficacy of anticoagulant drugs, compared with no anticoagulation, for CAT patients to prevent VTE recurrence.

Midaortic Syndrome due to Takayasu Arteritis in a Child with Acute Decompensated Cardiac Failure Managed by an Emergency Axillo-External Iliac Artery Bypass: A Follow-Up Case Report of Long-Term Outcomes.

Midaortic syndrome (MAS) is characterized by a diffuse narrowing of the distal thoracic or abdominal aorta and is concomitant with various etiologies. The common symptoms of MAS include severe hypertension or arterial insufficiency distal to the stenosis. This includes lower extremity claudication and heart failure due to afterload mismatch. We present the case of an 8-year-old girl who developed acute decompensated cardiac, respiratory, and renal failures because of the occlusion of the descending aorta secondary to Takayasu arteritis (TA). Although thoracoabdominal-aortic bypass is usually performed for patients with MAS, the procedure was considered too invasive, given the patient's condition. Therefore, we performed an emergency axillo-external iliac artery bypass for revascularization. Subsequently, organ failure improved and she was discharged. At postoperative 10 years, an asymptomatic pseudoaneurysm was detected at the distal anastomosis, for which revision surgery was performed. Overall, the long-term prognosis was satisfactory, suggesting that this procedure is less invasive and effective for treatment of MAS due to TA, in emergencies.

T-448, a specific inhibitor of LSD1 enzyme activity, improves learning function without causing thrombocytopenia in mice.

Dysregulation of histone H3 lysine 4 (H3K4) methylation has been implicated in the pathogenesis of several neurodevelopmental disorders. Targeting lysine-specific demethylase 1 (LSD1), an H3K4 demethylase, is therefore a promising approach to treat these disorders. However, LSD1 forms complexes with cofactors including growth factor independent 1B (GFI1B), a critical regulator of hematopoietic differentiation. Known tranylcypromine-based irreversible LSD1 inhibitors bind to coenzyme flavin adenine dinucleotide (FAD) and disrupt the LSD1-GFI1B complex, which is associated with hematotoxicity such as thrombocytopenia, representing a major hurdle in the development of LSD1 inhibitors as therapeutic agents. To discover LSD1 inhibitors with potent epigenetic modulation and lower risk of hematotoxicity, we screened small molecules that enhance H3K4 methylation by the inhibition of LSD1 enzyme activity in primary cultured rat neurons but have little impact on LSD1-GFI1B complex in human TF-1a erythroblasts. Here we report the discovery of a specific inhibitor of LSD1 enzyme activity, T-448 (3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide fumarate). T-448 has minimal impact on the LSD1-GFI1B complex and a superior hematological safety profile in mice via the generation of a compact formyl-FAD adduct. T-448 increased brain H3K4 methylation and partially restored learning function in mice with NMDA receptor hypofunction. T-448-type LSD1 inhibitors with improved safety profiles may provide unique therapeutic approaches for central nervous system disorders associated with epigenetic dysregulation.

Oral Steroid Use and Abdominal Aortic Aneurysm Expansion　- Positive Association.

BACKGROUND: The maximum axial diameter (MAD) of a fusiform abdominal aortic aneurysm (AAA) is an indicator of the risk of expansion or rupture. Apart from smoking and MAD itself, few expansion risk factors have been reported. In this study, we investigated expansion risk factors for AAA.Methods and Results:This retrospective cohort study included 176 patients who attended Tohoku University Hospital with infrarenal fusiform AAA. AAA expansion rate was determined on multidetector computed tomography, and the correlations between expansion rate and the clinical data were analyzed. The median expansion rate was 2.405 mm/year. On univariate analysis, a significant positive correlation with expansion rate was observed for the initial MAD (P<0.001) and significant negative correlations for oral angiotensin receptor blocker usage (P=0.025), height (P=0.005), body weight (P=0.017), total cholesterol (P=0.007), low-density lipoprotein cholesterol (P=0.004), and HbA1c (P=0.037). On logistic regression analysis, significant positive associations with expansion rate were observed for initial MAD (P<0.001) and oral steroid usage (P=0.029) and a negative association for height (P=0.041). CONCLUSIONS: Oral steroid usage is an important risk factor for AAA expansion, independent of other risk factors of atherosclerosis and MAD.

Inclusion bodies of aggregated hemosiderins in liver macrophages.

Hemosiderin formation is a structural indication of iron overload. We investigated further adaptations of the liver to excess iron. Five patients with livers showing iron-rich inclusions larger than 2 µm were selected from our database. The clinical features of patients and structures of the inclusions were compared with those of 2 controls with mild iron overload. All patients had severe iron overload with more than 5000 ng/mL of serum ferritin. Etiologies were variable, from hemochromatosis to iatrogenic iron overload. Their histological stages were either portal fibrosis or cirrhosis. Inclusion bodies were ultra-structurally visualized as aggregated hemosiderins in the periportal macrophages. X-ray analysis always identified, in addition to a large amount of iron complexes including oxygen and phosphorus, a small amount of copper and sulfur in the mosaic matrixes of inclusions. There were no inclusions in the control livers. Inclusion bodies, when the liver is loaded with excess iron, may appear in the macrophages as isolated organella of aggregated hemosiderins. Trace amounts of copper-sulfur complexes were always identified in the mosaic matrices of the inclusions, suggesting cuproprotein induction against excess iron. In conclusion, inclusion formation in macrophages may be an adaptation of the liver loaded with excess iron.

Histological Analysis of a New Route after Subintimal Crural Angioplasty.

BACKGROUND: Subintimal angioplasty is an alternative approach in treating critical limb ischemia with crural artery disease. However, route or location of the newly created channel is not understood. CASE PRESENTATION: A 68-year-old man was referred to our hospital with ischemic gangrene of the right big toe. We performed endovascular treatment because he was a poor candidate for bypass surgery. The posterior tibial artery was treated using subintimal angioplasty, although it resulted in early occlusion. We decided that he was not able to receive any further limb salvage treatment and performed amputation below the knee 7 days after treatment. The specimen from the origin of posterior tibial artery to plantar artery bifurcation was resected and the formalin-fixed vessel was cut into 39 segments. Histological analysis showed that the newly formed lumen was comparatively well dilated and created in the media by tearing internal elastic lamina in almost the whole of its length. The severely poor runoff vessels below the ankle were thought to be a main cause of early occlusion. CONCLUSIONS: The newly formed lumen by subintimal crural angioplasty could be well dilated and created in the media.

Efficacy of iliac inflow repair in patients with concomitant iliac and superficial femoral artery occlusive disease.

BACKGROUND: In multilevel arterial disease, whether complete revascularization or staged runoff repair should be performed remains controversial. The aim of this study was to evaluate the efficacy of iliac inflow repair and to identify clinical conditions that are associated with the need for runoff repair in concomitant iliac and superficial femoral artery (SFA) occlusive disease. METHODS: Patients undergoing inflow repair for complicated flow-limiting iliac lesions with diffuse SFA disease between 2007 and 2013 were retrospectively reviewed. Patients with poor response to inflow repair underwent infrainguinal revascularization (IIR). RESULTS: The 29 ischemic limbs examined in this study represent 26 different patients (22 males; mean age, 77 ± 8 years). Indications for inflow repair were Rutherford Classifications III (31%), IV (31%), V (31%), and VI (7%). Severity of the complicated SFA disease was either TASC (TransAtlantic Inter-Society Consensus) type C (14%) or type D (86%). Overall, freedom from IIR was 90% after 30 days and 83% after 1 year. Patients having claudication, rest pain, and shallow ischemic ulcers experienced the relief of symptoms, whereas patients with deep gangrene that needed minor amputation required IIR more frequently (p < 0.01). Anatomical risk factors for poor response to inflow repair were poor quality of the deep femoral artery (p < 0.01) and the flow-limiting popliteal artery (p = 0.02), and poor below-knee runoff (≤ 1 vessel, p < 0.01). CONCLUSION: Iliac inflow repair can reverse the symptoms in patients with multilevel arterial occlusive disease that are not associated with gangrenous toes.

Natural History and Chronological Growth Rate of Renal Artery Aneurysms.

Objective: Renal artery aneurysm (RAA) is an uncommon disease, the natural course of which is still not well known. The objective of this study is to define factors that affect the growth rate of RAAs. Materials and Methods: We retrospectively reviewed 32 aneurysms in 26 patients at our institute between January 2010 and March 2016. Basal demographics, comorbidities, reason for diagnosis, and details of the aneurysms and interventions were recorded. The chronological changes in the diameter of the RAA using multiplanar reconstructions of computed tomography images were measured and analyzed. Results: The baseline mean diameter was 20.1±8.4 mm (range: 9.9-41). The mean follow-up period was 3.13±2.1 y (range: 0.5-7.1). The median growth rate was 0.35 mm/y (interquartile range: 0.05, 0.62). The growth rate was slower when the initial diameter was <20 mm than when it was >20 mm (p=0.036). Also, whole-completed calcification was a significant factor for slower growth (p=0.016). We performed ex-vivo surgery in two cases and coil packing with stenting in one. No ruptures occurred during the study period. Conclusion: Our results suggest that cases with an RAA diameter <20 mm do not require intervention. The interval period can be longer in whole-completed calcification types.

A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells.

Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here, we describe the antileukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroid leukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells. Mechanistically, T-3775440 disrupted the interaction between LSD1 and growth factor-independent 1B (GFI1B), a transcription factor critical for the differentiation processes of erythroid and megakaryocytic lineage cells. Knockdown of LSD1 and GFI1B recapitulated T-3775440-induced transdifferentiation and cell growth suppression, highlighting the significance of LSD1-GFI1B axis inhibition with regard to the anti-AML effects of T-3775440. Moreover, T-3775440 exhibited significant antitumor efficacy in AEL and AMKL xenograft models. Our findings provide a rationale for evaluating LSD1 inhibitors as potential treatments and indicate a novel mechanism of action against AML, particularly AEL and AMKL. Mol Cancer Ther; 16(2); 273-84. ©2016 AACR.

Surgical resection and inferior vena cava reconstruction for treatment of the malignant tumor: technical success and outcomes.

OBJECTIVE: The purpose of this study was to review patients who underwent inferior vena cava (IVC) resection with concomitant malignant tumor resection and to consider the operative procedures and the outcomes. MATERIALS AND METHODS: Between 2000 and 2012, 41 patients underwent resection of malignant tumors concomitant with surgical resection of the IVC at our institute. The records of these patients were retrospectively reviewed. RESULTS: Primary tumor resections included nephrectomy, hepatectomy, retroperitoneal tumor extirpation, lymph node dissection, and pancreaticoduodenectomy. The IVC interventions were partial resection in 23 patients and total resection in 18 patients. Four patients underwent IVC replacement. Operation-related complications included pulmonary embolism, acute myocardial infarction, deep vein thrombosis, leg edema and temporary hemodialysis. There were no operative deaths. The mean follow-up period was 24.9 months (range: 2-98 months). The prognosis depended on the type and stage of the tumor. CONCLUSION: Resection and reconstruction of the IVC can be performed safely if the preoperative evaluations and surgical procedures are performed properly. The IVC resection without reconstruction was permissive if the IVC was completely obstructed preoperatively, but it may also be considered in cases where the IVC is not completely obstructed.

Intraductal papillary mucinous neoplasm originating from a jejunal heterotopic pancreas: report of a case.

We report a rare case of an intraductal papillary mucinous neoplasm (IPMN) originating from a jejunal heterotopic pancreas, found incidentally during surgery. A 75-year-old woman was referred to our department for surgical treatment of an abdominal aortic aneurysm (AAA) and a concurrent oropharyngeal tumor. During surgery to correct the AAA, we found a jejunal tumor incidentally and performed partial resection of the jejunum. Microscopically, the jejunal tumor showed dilated ducts containing intraluminal papillae lined with mucinous epithelium with low-grade cytological and architectural atypia within the pancreatic tissue. Immunohistochemical staining revealed MUC1 (-), MUC2 (-), MUC5AC (+), and MUC6 (-) proteins. To the best of our knowledge, only six cases of IPMN originating from a heterotopic pancreas have been reported in English, and this is the first report of an IPMN originating from a jejunal heterotopic pancreas.

Sudden cardiac arrest immediately after stent graft deployment during treatment of iliac aneurysm with iliocaval fistula.

An 84-year-old woman with heaviness of the right lower extremity had an iliocaval fistula related to a right internal iliac aneurysm. Immediately after deployment of an endovascular device, cardiac arrest occurred because of severely decreased sympathetic activity. After surgery, the patient recovered well and has been followed up with exclusion of the arteriovenous fistula and resolution of the type II endoleak. Endovascular treatment for large arteriovenous fistulas induces rapid closure of the fistula together with restoration of blood supply to the lower extremity. Markedly deactivated sympathetic nerve traffic could result in a critical hemodynamic status in association with endograft deployment.

Extracorporeal shock wave therapy improves the walking ability of patients with peripheral artery disease and intermittent claudication.

BACKGROUND: Despite the recent advances in bypass surgery and catheter interventional therapy for peripheral artery disease (PAD), the long-term outcome of revascularization therapy for infrapopliteal lesions remains unsatisfactory. We have previously demonstrated that low-energy extracorporeal shock wave (SW) therapy effectively induces neovascularization through upregulation of angiogenic factors and improves myocardial ischemia in pigs and humans and in hindlimb ischemia in rabbits. In this study, we thus examined whether our SW therapy also improves the walking ability of patients with PAD and intermittent claudication. METHODS AND RESULTS: We treated 12 patients (19 limbs) in Fontaine II stage (males/females, 10/2; 60-86 years old) with low-energy SW therapy to their ischemic calf muscle 3 times/week for 3 consecutive weeks. After 24 weeks, the pain and distance subscale scores of the walking impairment questionnaire were significantly improved (33±25 vs. 64±26, 27±16 vs. 64±23, respectively, both P<0.01). Maximum walking distance was also significantly improved at 4 weeks (151±37% from baseline, P<0.01) and was maintained at 24 weeks (180±74% from baseline, P<0.01). Moreover, the recovery time of the tissue oxygenation index in the calf muscle during a treadmill test, which reflects local O2 supply, was significantly shortened (295±222s vs. 146±137s, P<0.01). Importantly, no adverse effects were noted. CONCLUSIONS: Non-invasive SW therapy improves the walking ability of PAD patients.

Inflammatory popliteal aneurysm.

A 67-year-old man was referred to our department because of fever, right lower thigh swelling, and redness with pain. Laboratory tests showed slightly elevated leukocytes and markedly elevated C-reactive protein levels. Computed tomography confirmed a popliteal aneurysm with wall thickening, so-called mantle sign. Aneurysmorrhaphy with a reversed autologous saphenous vein reconstruction was performed. Aneurysm sac and perianeurysm tissue cultures were negative for aerobic and anaerobic bacteria. The microscopic appearance of the aneurysm showed thickening of the adventitia and infiltration of inflammatory cells. This report presents, for the first time, findings suggestive of an inflammatory aneurysm of the popliteal artery.

Impaired removal of DNA interstrand cross-link in Nijmegen breakage syndrome and Fanconi anemia, but not in BRCA-defective group.

Human diseases characterized by a high sensitivity to DNA interstrand cross-links (ICL) and predisposition to malignance include Nijmegen breakage syndrome (NBS) and Fanconi anemia (FA), which is further classified to three groups: (1) FA core-complex group; (2) FA-ID complex group; and (3) breast cancer (BRCA)-defective group. The relationships between these four groups and the basic defect in ICL repair remain unclear. To study the details of ICL repair in NBS and FA, a highly sensitive PPB (psoralen-polyethylene oxide-biotin) dot blot assay was developed to provide sensitive quantitative measurements of ICL during the removal process. Studies utilizing this assay demonstrated a decreased rate of ICL removal in cells belonging to the FA core-complex group (e.g. groups A and G) and FA-ID complex group (group D2), while ICL removal was restored to normal levels after these cells were complemented with wt-FANCA, wt-FANCG and wt-FANCD2. Conversely, FA-D1 cells with a defective BRCA2 protein displayed normal ICL removal, although they were compromised with respect to recombination. This normal ICL removal rate in recombination-deficient cells was confirmed by using XRCC3-defective Chinese hamster cells, which are similarly compromised with respect to recombination and are sensitive to mitomycin C. The present study also showed that cells from patients with Nijmegen breakage syndrome were defective in ICL removal, while they were impaired in the recombination. These results indicate an obvious defect of FA and NBS in the ICL repair process, except in the BRCA-defective group, and a separate step of recombination-mediated repair pathway between the BRCA group and NBS.

Role of Smad4 on TGF-beta-induced extracellular matrix stimulation in mesangial cells.

BACKGROUND: The best characterized signaling pathway employed by transforming growth factor-beta (TGF-beta) is the Smad pathway; however, its role in matrix production in mesangial cells is unclear. We focused on Smad4, as Smad4 is essential for the activation of Smad-dependent target genes. METHODS: To investigate the function of Smad4 in extracellular matrix (ECM) production, we generated several stably transfected mesangial cell lines (MMC) that have a deletion in the linker region (Smad4 Delta M4: Delta 275-322) or have a deletion in MH1 of Smad4 (Smad4N4: Delta 1-136). The ECM genes, alpha1 type I collagen (COL1A1), plasminogen activator inhibitor-1 (PAI-1) and fibronectin (FN) were assessed in wild-type mesangial cells and stably transfected Smad4-DN cell lines in the absence and presence of TGF-beta. RESULTS: As compared to wild-type MMC that had a 10.8-fold stimulation of TGF-beta-induced p3TP-Lux activity, MMC stably transfected with Smad4 Delta M4 and Smad4N4 had only a 2.0-fold and 1.3-fold stimulation, respectively, indicating that they had dominant-negative effects on TGF-beta signaling. Basal and TGF-beta-induced COL1A1 expression in Smad4 dominant-negative cells were dramatically reduced to very low levels. The early (2 hours) TGF-beta-induced PAI-1 mRNA expression was inhibited; however, the sustained (24 to 48 hours) TGF-beta-induced expression was not affected in Smad4 dominant-negative cells. For FN, TGF-beta-induced expression was maintained in Smad4-dominant negative cells. CONCLUSION: These results indicate that Smad4 is essential for basal and TGF-beta-induced COL1A1 expression, and contributes to the early, but not sustained TGF-beta-induced PAI-1 expression in mesangial cells. However, TGF-beta-induced FN expression is independent of Smad4. In conclusion, Smad4 has a discriminate effect in mediating specific ECM molecules stimulated by TGF-beta in mesangial cells.