Current status of a helicopter transportation system on remote islands for patients undergoing mechanical thrombectomy.

BACKGROUND: Mechanical thrombectomy (MT) is standard treatment for acute ischemic stroke (AIS) with large-vessel occlusion within 6 h of symptom onset to treatment initiation (OTP). Recent trials have extended the therapeutic time window for MT to within 24 h. However, MT treatment remains low in remote areas. Nagasaki Prefecture, Japan has many inhabited islands with no neurointerventionalists. Our hospital on the mainland is a regional hub for eight island hospitals. We evaluated clinical outcomes of MT for patients with AIS on these islands versus on the mainland. METHODS: During 2014-2019, we reviewed consecutive patients with AIS who received MT at our hospital. Patients comprised the Islands group and Mainland group. Patient characteristics and clinical outcomes were compared between groups. RESULTS: We included 91 patients (Islands group: 15 patients, Mainland group: 76 patients). Seven patients (46.7%) in the Islands group versus 43 (56.6%) in the Mainland group achieved favorable outcomes. Successful recanalization was obtained in 11 patients (73.3%) on the islands and 67 (88.2%) on the mainland. The median OTP time in the Islands was 365 min. In both the Islands and Mainland groups, the OTP time and successful recanalization were associated with functional outcome. The modified Rankin Scale (mRS) score at 90 days ≤2 was obtained in two patients and mRS = 3 in four patients among eight patients with OTP time >6 h. CONCLUSIONS: Few patients with AIS on remote islands have received MT. Although patients who underwent MT on the islands had longer OTP, the clinical outcomes were acceptable. OTP time on remote islands must be shortened, as this is related to functional outcome. In some cases with successful recanalization, a favorable outcome can still be obtained even after 6 h. Even if OTP exceeds 6 h, it is desirable to appropriately select patients and actively perform MT.

Efficacy of the Drip and Ship Method in 24-h Helicopter Transportation and Teleradiology for Isolated Islands.

Our hospital, located on the mainland, serves as a hub center for nine hospitals on the remote islands of Nagasaki Prefecture, Japan. There are no stroke specialists on these islands. We can transfer emergency patients from these islands to our hospital at any time, using a teleradiology system and three types of helicopter transport. We examined the efficacy of the drip and ship (DS) method for treating patients with acute ischemic stroke (AIS) on these islands, in comparison with patients on the mainland. From 2010 to 2017, we reviewed 98 consecutive patients with AIS who received intravenous recombinant tissue plasminogen activator (IV rt-PA) in our hospital or were transported to our hospital after IV rt-PA. Patients were divided into the Islands group (received IV rt-PA on the islands, DS; 31 cases) and the Mainland group (67 cases). The median transport distance from the islands was 112 km. The rate of patients achieving favorable outcomes was 54.8% in the Islands group and 64.2% in the Mainland group, with no significant differences. Multivariate analysis revealed that patients living on isolated islands did not have increased risks of unfavorable outcomes. Endovascular therapy (EVT), as part of the drip, ship, and retrieve method, was performed in 22.6% of patients in the Islands group and EVT in 38.8% of those in the Mainland group. The DS method seems feasible and safe for patients living on isolated islands with the use of 24-h helicopter transportation and teleradiology.

The activated conformation of integrin ß7 is a novel multiple myeloma-specific target for CAR T cell therapy.

Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin ß7 molecules. The MMG49 epitope, in the N-terminal region of the ß7 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin ß7 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin ß7+ lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.

Rapid Recanalization Using TrevoProVue through a 4.2 Fr Catheter without a Guiding Catheter via Transbrachial Approach: A Case Report.

Mechanical thrombectomy with a stent retriever has been reported to achieve high rates of successful recanalization, and reduce disability and mortality in patients with acute ischemic stroke (AIS) due to proximal vessel occlusion. However, in a few cases, the treatment is difficult due to artery tortuosity or other factors. The authors present a case of a 94-year-old man presenting with acute right middle cerebral artery occlusion. We attempted to treat using a stent retriever via transfemoral approach, but failed to advance the guiding catheter into the right internal carotid artery due to femoral artery tortuosity and a type III arch. By changing approaches from transfemoral to transbrachial and by using TrevoProVue through a 4.2 Fr Simmons-type catheter without a guiding catheter, we were able to achieve rapid recanalization in only 26 minutes from brachial artery puncture to reperfusion. In conclusion, rapid reperfusion in an AIS patient was successfully achieved by combining a stent retriever with a 4.2 Fr catheter (without a guiding catheter) and a transbrachial approach (as opposed to a transfemoral approach). When the transfemoral approach is not feasible, we recommend consideration of this strategy as an alternative.

[A Rare Case of Ruptured/Unruptured Miniature Aneurysms Originating from the Infundibular Dilatation of the Callosomarginal Artery, Branching from the Infracallosal(A2)Segment of the Azygos Anterior Cerebral Artery].

We report the first case of two de novo miniature aneurysms(ruptured/unruptured)emerging from the infundibular dilatation(ID)of the callosomarginal artery, which branches from the infracallosal(A2)segment of the azygos anterior cerebral artery(AACA), in a 36-year-old woman. The patient had previously been diagnosed with a miniature, unruptured aneurysm, occurring in the A2 segment of the AACA, detected by CT angiography(CTA)at another hospital two years ago, and had been followed up with MR angiography(MRA)every 6 months. Three months after the final check-up with MRA, which did not indicate a significant change in the aneurysm, the patient presented with subarachnoid hemorrhage. Subsequent CTA and digital subtraction angiograms revealed that the right callosomarginal artery, originating from the apex of the aneurysmal bulge, had a maximal diameter of 3mm, indicating an ID of the artery. Additionally, two miniature bleb-like aneurysms emerged from the ID, projecting in opposite directions:one projecting to the right-posterior/superior direction and the other to the left-anterior/inferior direction. Both aneurysms were successfully clipped via a right pterional approach with partial resection of the gyrus rectus, and the right-projecting aneurysm was confirmed to be ruptured during surgery. In the current report, we review previously reported cases of AACA with aneurysms, and discuss their clinical characteristics, and the possible mechanisms underlying the formation of the ID and de novo aneurysms in this extremely rare case.

[A Rare Case of Ruptured Internal Carotid-Posterior Communicating Artery Aneurysm Associated with Contralateral Delayed Oculomotor Nerve Palsy].

A 55-year-old man presented with difficulty breathing, chest pain, and disturbance of consciousness, and was transferred to our hospital. Initial whole body CT revealed a diffuse subarachnoid hemorrhage(SAH)with severe pulmonary edema that was considered neurogenic in origin. He received controlled ventilation under sedation and conservative care for the SAH. One day after the onset of the SAH, his left pupil suddenly became dilated to 6mm, with no reaction to light. Head CT showed no new bleeding. Subsequent CT angiogram revealed a right internal carotid-posterior communicating artery aneurysm(IC-PC AN)with a posterior-lateral projection; however, no vessel abnormality was observed in the left anterior or posterior circulations. The aneurysm was successfully treated with coil embolization. We reviewed reported cases of isolated oculomotor nerve palsy(ONP), without direct compression by ruptured aneurysms, and found that only 11 cases exist, including our case. Interestingly, six of them were associated with anterior communicating artery aneurysms. A mass effect, chemical stimulation, and a jet stream of blood were proposed as the mechanisms of this rare type of ONP, in addition to the specific neurovascular relationships between the oculomotor nerve and the posterior cerebral/posterior communicating/superior cerebellar arteries, with abnormal nerve contact or compression. Though rare, ruptured IC-PC ANs could cause contralateral ONP; other types of ruptured aneurysms may also lead to indirect effects on nervous structures without direct compression. This type of rare presentation of ruptured aneurysms should be considered, especially in cases of multiple aneurysms, such as IC-PC ANs.

18F-FDG PET/CT Volumetric Parameters are Associated with Tumor Grade and Metastasis in Pancreatic Neuroendocrine Tumors in von Hippel-Lindau Disease.

BACKGROUND: Approximately 8-17 % of patients with von Hippel-Lindau (VHL) syndrome develop pancreatic neuroendocrine tumors (PNETs), with 11-20 % developing metastases. Tumor grade is predictive of prognosis. OBJECTIVE: The aim of this study was to determine if preoperative metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were associated with metastatic disease and tumor grade. METHODS: Sixty-two patients with VHL-associated PNETs prospectively underwent 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). MTV, TLG, and maximum standardized uptake value (SUVmax) were measured using a semi-automatic method. Surgically resected PNETs were classified according to 2010 World Health Organization tumor grade classification. MTV, TLG, and SUVmax were analyzed by metastatic disease and tumor grade using the Mann-Whitney test. RESULTS: A total of 88 PNETs were identified by CT and 18F-FDG PET/CT, 10 of which were non-FDG-avid. Histologic grading was available for 20 surgical patients. Patients with metastatic PNETs had a higher TLG (median 25.9 vs. 7.7 mean SUV [SUVmean]*mL; p = 0.0092) compared with patients without metastasis, while patients with grade 2 PNETs had a higher MTV (median 6.9 vs. 2.6 mL; p = 0.034) and TLG (median 41.2 vs. 13.1 SUVmean*mL; p = 0.0035) compared with patients with grade 1 PNETs. No difference in tumor size or SUVmax was observed between the groups. CONCLUSIONS: Patients with metastatic PNETs have a higher TLG compared with patients without metastasis. Grade 2 PNETs have a higher MTV and TLG compared with grade 1 PNETs. Tumor size and SUVmax were not associated with grade. Volumetric parameters on 18F-FDG PET/CT may be useful in detecting higher grade PNETs with a higher malignant potential that may need surgical intervention.

Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma.

PURPOSE: Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC. EXPERIMENTAL DESIGN: A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R. RESULTS: Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell-cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of ß-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo CONCLUSIONS: Our findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC. Clin Cancer Res; 22(14); 3458-66. ©2016 AACR.

Whole Body Metabolic Tumor Volume and Total Lesion Glycolysis Predict Survival in Patients with Adrenocortical Carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare but lethal malignancy with few reliable prognostic markers. FDG-PET metabolic parameters have been shown to predict survival in several cancers. The objective was to determine if metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) could serve as prognostic markers in patients with ACC. METHODS: A total of 30 patients with ACC prospectively underwent 18F-FDG PET/CT prior to treatment. Whole body MTV, TLG, and SUVmax were measured by a semiautomatic method. A median cutoff was used to determine an association with overall survival (OS) from the time of 18F-FDG PET/CT by the Kaplan-Meier method. RESULTS: Patients with high whole body MTV (>87.0 mL),TLG (>229.4 SUVlbm*mL), or SUVmax (>8.9 SUV) had a worse OS compared with those with low whole body MTV (median OS, 24 vs 45.1 months, p < .01), TLG (median OS, 24 vs 40.3 months, p < .005), or SUVmax (median OS, 23.7 vs 35.5 months, p < .02). In patients who had operable disease (n = 23), high whole body MTV (>87.0 mL) and TLG (>229.4 SUVlbm*mL) had a worse OS compared with those with low whole body MTV (median OS, 25.1 vs 45.1 months, p < .05) and TLG (median OS, 25.1 vs 40.3 months, p < .05), but a high SUVmax (>8.9 SUV) was not associated with worse OS (p = .11). CONCLUSIONS: Patients with ACC and a high whole body MTV, TLG, and SUVmax have a worse prognosis and OS. Measurement of whole body MTV and TLG may be helpful for guiding therapy for patients with ACC.

Novel role for molecular transporter importin 9 in posttranscriptional regulation of IFN-ε expression.

IFN-ε is a unique type I IFN whose constitutive expression in lung, brain, small intestine, and reproductive tissues is only partially understood. Our previous observation that posttranscriptional events participate in the regulation of IFN-ε mRNA expression led us to investigate whether the 5' and/or 3' untranslated regions (UTR) have regulatory functions. Surprisingly, we found that full-length IFN-ε 5'UTR markedly suppressed mRNA expression under basal conditions. Analysis of the secondary structure of this region predicted formation of two stable stem-loop structures, loops 1 and 2. Studies using luciferase constructs harboring various stretches of IFN-ε 5'UTR and mutant constructs in which the conformation of loop structures was disrupted showed that loop 1 is essential for regulation of mRNA expression. Incubation of HeLa cell extracts with agarose-bound RNAs harboring IFN-ε loop structures identified importin 9 (IPO9), a molecular transporter and chaperone, as a candidate that associates with these regions of the 5'UTR. IPO9 overexpression decreased, and IPO9 silencing increased basal IFN-ε expression. Our studies uncover a previously undescribed function for IPO9 as a specific, and negative, posttranscriptional regulator of IFN-ε expression, and they identify key roles for IFN-ε stem-loop structure 1 in this process. IPO9-mediated effects on 5'UTRs appear to extend to additional mRNAs, including hypoxia-inducible factor-1α, that can form specific loop structures.

Identification of chromosome 3q28 and ALPK1 as susceptibility loci for chronic kidney disease in Japanese individuals by a genome-wide association study.

BACKGROUND: Although genome-wide association studies (GWASs) have implicated several genes in the predisposition to chronic kidney disease (CKD) in Caucasian or African American populations, the genes that confer susceptibility to CKD in Asian populations remain to be identified definitively. We performed a GWAS to identify genetic variants that confer susceptibility to CKD in Japanese individuals. METHODS: 3851 Japanese individuals from three independent subject panels were examined. Subject panels A, B, and C comprised 252, 910, and 190 individuals with CKD and 249, 838, and 1412 controls, respectively. A GWAS for CKD was performed in subject panel A. RESULTS: Five single nucleotide polymorphisms (SNPs) at chromosome 3q28, ALPK1, FAM78B, and UMODL1 were significantly (false discovery rate<0.05) associated with CKD by the GWAS. The relation of these five SNPs and of an additional 22 SNPs at these loci to CKD was examined in subject panel B, revealing that rs9846911 at 3q28 was significantly associated with CKD in all individuals and that rs2074381 and rs2074380 in ALPK1 were associated with CKD in individuals with diabetes mellitus. These three SNPs were further examined in subject panel C, revealing that rs2074381 and rs2074380 were significantly associated with CKD. For subject panels B and C combined, rs9846911 was significantly associated with CKD in all individuals and rs2074381 and rs2074380 were associated with CKD in diabetic individuals. CONCLUSIONS: Chromosome 3q28 may be a susceptibility locus for CKD in Japanese individuals, and ALPK1 may be a susceptibility gene for CKD in such individuals with diabetes mellitus.

High expression of KIBRA in low atypical protein kinase C-expressing gastric cancer correlates with lymphatic invasion and poor prognosis.

Overexpression of atypical protein kinase Cλ/ι (aPKCλ/ι), a regulator of cell polarity, is frequently associated with the poor prognoses of several cancers, including gastric cancer. Recent studies revealed a molecular link between aPKC and KIBRA, an upstream regulator of tumor suppressor Hippo pathway that regulates cell proliferation and apoptosis. Further, KIBRA directly inhibits the kinase activity of aPKC to regulate epithelial cell polarity. These observations suggest that the KIBRA-aPKC connection plays a role in cancer progression; however, clinical significance of the correlation between these factors remains unclear. Here we examined the correlation between KIBRA/aPKCλ/ι expression, as detected by immunohistochemistry, and clinicopathological outcomes in 164 gastric cancer patients using Fisher's exact test and Kaplan-Meier log-rank test. We found an intimate correlation between the expression level of KIBRA and aPKCλ/ι (P = 0.012). Furthermore, high expression of KIBRA is correlated with lymphatic (P = 0.046) and venous invasion (P = 0.039). The expression level of KIBRA by itself did not correlate with the prognosis; however, high expression of KIBRA in low aPKCλ/ι-expressing gastric cancer correlated with disease-specific (P = 0.037) and relapse-free survival (P = 0.041) by Kaplan-Meier with log-rank test and higher lymphatic invasion cases by Fisher's exact test (P = 0.042). Furthermore, overexpression of the aPKC-binding region of KIBRA disrupted tight junctions in epithelial cells. These results suggest that high expression of KIBRA in low aPKC-expressing cells causes massive loss of aPKC activity, leading to loss of polarity and invasiveness of gastric cancer cells.