Comparative evaluation of 11C-methionine and 18F-fluorodeoxyglucose positron emission tomography for distinguishing between primary central nervous system lymphoma and isocitrate dehydrogenase-wildtype glioblastoma.

PURPOSE: Distinguishing between primary central nervous system lymphoma (PCNSL) and isocitrate dehydrogenase (IDH)-wildtype glioblastoma is important for therapeutic decision-making. This study aimed to compare the performance of 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for distinguishing between these two major malignant brain tumors. METHODS: We retrospectively conducted qualitative and semiquantitative analyses of pre-treatment MET and FDG PET/computed tomography (CT) images of 22 patients with PCNSL and 64 patients with IDH-wildtype glioblastoma. For semiquantitative analysis, we calculated the tumor-to-normal tissue (T/N) ratio by dividing the maximum standardized uptake value (SUV) for the tumor (T) by the average SUV for the normal tissue (N). For performance evaluation, we employed receiver operating characteristic curve analysis and calculated the areas under the curve (AUC) values. RESULTS: In the qualitative analysis, all PCNSLs and IDH-wildtype glioblastomas were MET-positive, while 95% and 84% of PCNSLs and IDH-wildtype glioblastomas, respectively, were FDG-positive. Eleven patients were excluded from the FDG PET/CT semiquantitative analysis because of hyperglycemia. There was no difference in MET T/N ratio between PCNSL and IDH-wildtype glioblastoma (p = 0.37). FDG T/N ratio was significantly higher in PCNSL than in IDH-wildtype glioblastoma (p < 0.001). The AUC value for distinguishing PCNSL from IDH-wildtype glioblastoma was significantly higher for the FDG T/N ratio (0.871) than for the MET T/N ratio (0.565) (p = 0.0027). CONCLUSION: MET PET could detect both PCNSL and IDH-wildtype glioblastoma, but unlike FDG PET, it could not distinguish between these two major malignant brain tumors.

An exploratory prospective phase II study of preoperative neoadjuvant bevacizumab and temozolomide for newly diagnosed glioblastoma.

PURPOSE: This multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bevacizumab (Bev) for newly diagnosed glioblastoma (GB). METHODS: Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1-5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The safety and efficacy were evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy. RESULTS: Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Median PFS and overall survival were 9.5 months and 16.5 months, respectively. CONCLUSION: Preoperative Bev and TMZ is safe as long as the instructions are followed. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively. TRIAL REGISTRATION NUMBER: UMIN000025579, jRCT1031180233 https://jrct.niph.go.jp/latest-detail/jRCT1031180233 . Registration Date: Jan. 16, 2017.

A Case of Idiopathic Peptic Ulcer Disease Treated Effectively with Trimebutine Maleat.

A 30-year-old man with idiopathic peptic ulcer disease (IPUD) experienced repeated recurrence of ulcerative bleeding despite treatment with lansoprazole and then vonoprazan. Further evaluation suggested that the cause of the ulcer was strong contractile movements of the antrum. This prompted the co-administration of trimebutine maleate (TM) and vonoprazan to relieve the stomach contractions. TM was effective in preventing the recurrence of ulcerative bleeding, and the patient has remained in remission for 4 years. This case highlights the potential efficacy of TM in treating IPUD and the importance of considering hypercontractility as the underlying cause in cases of IPUD.

Regenerative Effect of Umbilical Cord-Derived Mesenchymal Stromal Cells in a Rat Model of Established Limb Ischemia.

BACKGROUND: Although regenerative cell therapy is expected to be an alternative treatment for peripheral artery disease (PAD), many regenerative cell therapies have failed to show sufficient efficacy in clinical trials. Most preclinical studies have used acute ischemia models, despite PAD being a chronic disease. In addition, aging and atherosclerosis decrease the quality of a patient's stem cells. Therefore, using a non-acute ischemic preclinical model and stem cells with high regenerative potency are important for the development of effective regenerative therapy. In this study, we assessed the tissue regenerative potential of umbilical cord-derived mesenchymal stromal cells (UCMSCs), which could potentially be an ideal cell source, in a rat model of established ischemia.Methods and Results: The regenerative capacity of UCMSCs was analyzed in terms of angiogenesis and muscle regeneration. In vitro analysis showed that UCMSCs secrete high amounts of cytokines associated with angiogenesis and muscle regeneration. In vivo experiments in a rat non-acute ischemia model showed significant improvement in blood perfusion after intravenous injection of UCMSCs compared with injection of culture medium or saline. Histological analysis revealed UCMSCs injection enhanced angiogenesis, with an increased number of von Willebrand factor-positive microcapillaries, and improved muscle regeneration. CONCLUSIONS: These results suggest that intravenous administration of UCMSCs may be useful for treating patients with PAD.

Engineered clustered myoblast cell injection augments angiogenesis and muscle regeneration in peripheral artery disease.

The low survival rate of administered cells due to ischemic and inflammatory environments limits the efficacy of the current regenerative cell therapy in peripheral artery disease (PAD). This study aimed to develop a new method to enhance the efficacy of cell therapy in PAD using cell sheet technology. Clustered cells (CCs) from myoblast cell sheets obtained from C57/BL6 mice were administered into ischemic mouse muscles 7 days after induction of ischemia (defined as day 0). Control groups were administered with single myoblast cells (SCs) or saline. Cell survival, blood perfusion of the limb, angiogenesis, muscle regeneration, and inflammation status were evaluated. The survival of administered cells was markedly improved in CCs compared with SCs at days 7 and 28. CCs showed significantly improved blood perfusion, augmented angiogenesis with increased density of CD31+/α-smooth muscle actin+ arterioles, and accelerated muscle regeneration, along with the upregulation of associated genes. Additionally, inflammation status was well regulated by CCs administration. CCs administration increased the number of macrophages and then induced polarization into an anti-inflammatory phenotype (CD11c-/CD206+), along with the increased expression of genes associated with anti-inflammatory cytokines. Our findings suggest clinical potential of rescuing severely damaged limbs in PAD using CCs.

Perioperative Clinical Course Variables Associated with Length of Hospital Stay after Primary Intracranial Meningioma Resection.

The relationship between perioperative clinical course variables and postoperative length of hospital stay (LOS) in patients undergoing primary intracranial meningioma resection has not been fully elucidated. We therefore aimed to identify the perioperative clinical course variables that predict postoperative LOS in such patients. We retrospectively collected data concerning demographics, tumor characteristics, and perioperative clinical course variables in 76 patients who underwent primary intracranial meningioma resection between January 2010 and December 2019, and tested for associations with postoperative LOS. Univariate analyses showed that younger age, fewer days to postoperative initiation of standing/walking, preoperative independence in activities of daily living (ADL), and ADL independence one week after surgery were associated with shorter postoperative LOS. Multiple regression analyses with these factors identified that days to stand/walk initiation and ADL independence one week after surgery were associated with postoperative LOS. Based on these results, we conclude that rehabilitation programs that promote early mobilization and the early acquisition of independence may reduce postoperative LOS in patients who undergo primary intracranial meningioma resection.

Role of Bypass with Preoperatively Diagnosed Small Caliber Veins in Chronic Limb-Threatening Ischemia.

BACKGROUND: In chronic limb-threatening ischemia (CLTI), although recent studies suggested that limbs classified as a higher Wound, Ischemia, foot Infection (WIfI) stage would benefit more from bypass surgery than endovascular therapy (EVT), graft unavailability is a major limitation for bypass. However, such graft unavailability is not clearly defined. This study aimed to assess whether bypass with veins judged as small by preoperative ultrasound is acceptable to achieve wound healing. METHODS: Ninety-five limbs classified as WIfI stage 3/4 that underwent infrainguinal bypass with veins were enrolled and divided into two groups based on the preoperative inner diameter of veins. Those with a diameter <2.5 mm were classified as small caliber grafts (SMGs, n=28) and those with a diameter ≥2.5 mm as sufficient caliber grafts (SUGs, n=67), and wound-related outcomes were evaluated. Wound healing rate (WHR) was analyzed in all cohort, and wound recurrence-free rate (WRF) and wound recurrence-free amputation-free survival rate (WRAFS) were calculated for limbs that achieved wound healing. A propensity score matched analysis was also performed to minimize the background difference, and 21 matched pairs were included for the analysis. RESULTS: Although the primary patency rate was significantly worse in SMGs (1-year patency, Crude model: 82.1% in SUGs and 51.0% in SMGs, P=0.0003; matched model: 77.7% in SUGs and 41.6% in SMGs, P = 0.005), the secondary patency rate was maintained in the equivalent level (1-year patency, Crude model: 81.8% in SUGs and 83.1% in SMGs, P=0.26; matched model: 77.7% in SUGs and 78.4% in SMGs, P = 0.24). One-year WHR was equivalent between the groups in both crude and matched models (Crude model: 87.0% in SUGs and 83.8% in SMGs, P=0.13; matched model: 66.3% in SUGs and 61.4% in SMGs, P = 0.65). One-year WRF and WRAFS were also equivalent (Crude model: WRF, 95.9% in SUGs and 100% in SMGs, P = 0.71; WRAFS, 87.2% in SUGs and 88.0% in SMGs, P = 0.78. Matched model: WRF, 100% in SUGs and 100% in SMGs, P = 0.85; WRAFS, 92.9% in SUGs and 78.6% in SMGs, P = 0.38). CONCLUSIONS: Although bypass with small caliber veins showed an inferior primary patency rate, WHR and WRF were equally good if grafts are maintained patent. Bypass with small caliber vein grafts would be an important option to achieve wound healing.

Predictive Model for Postoperative Ambulatory Function after Lower Extremity Bypass in Chronic Limb-Threatening Ischemia.

BACKGROUND: In chronic limb-threatening ischemia, maintenance or recovery of ambulatory function is an important goal of treatment. This study aimed to develop a predictive model for ambulatory ability 1 year after bypass based on preoperative risk factors, including the Wound, Ischemia, and foot Infection (WIfI) classification. METHODS: We analyzed 146 patients with chronic limb-threatening ischemia (154 limbs) who underwent bypass to below the knee arteries. The patients were classified into 2 groups based on ambulatory status 1 year postoperatively: postoperative ambulation (99 patients, 104 limbs) and postoperative nonambulation (47 patients, 50 limbs). Various factors associated with postoperative ambulation were analyzed and a predictive model of postoperative ambulation was developed. RESULTS: Multivariate logistic regression analysis detected preoperative nonambulatory status, functional nonindependence in daily living, older age, WIfI wound grade 3, chronic obstructive pulmonary disease, and hemodialysis as independent risk factors for postoperative nonambulation. The predictive scoring model (scores ranging from -5.0 to 4.4) comprising these risk factors discriminated the postoperative ambulatory status well: the probabilities of postoperative ambulatory ability were ≥85% in those with a score ≤-2, 50% in those with a score of zero, and ≤15% in those with a score ≥2. The area under the receiver operating characteristic curve was 0.898, indicating good performance of the model. CONCLUSIONS: Preoperative nonambulatory status, functional nonindependence, advanced age, high WIfI wound grade, chronic obstructive pulmonary disease, and hemodialysis were important predictors of postoperative nonambulatory status. The predictive model will help us identify patients who will benefit from bypass surgery.

[Points to Note about Neuropsychological Impairment in the Acute Management of Traumatic Brain Injury].

Neuropsychological impairment after traumatic brain injury(TBI)is occasionally difficult to diagnose and called "invisible or hidden impairment," especially when physical impairment is mild. Patients and their family do not recognize the impairment during hospitalization and even after discharge. However, they manifest many problems when they return to real life and society. Here, we have presented the characteristics and tips to diagnose neuropsychological impairment after TBI that are important for clinical neurosurgeons working at acute care hospitals. They are as follows: 1)In the emergency room, accurate evaluation of the consciousness state is the first step. 2)In the acute phase after TBI, do not mix up acute symptomatic seizure and post-traumatic epilepsy. 3)Soon after stabilization of the general condition, detailed radiological examinations should be performed to detect organic brain damages with MRI including DWI, FLAIR, T2*, and SWI. 4)At discharge, it is necessary to provide information about neuropsychological impairment to the patients and their family members. Neurosurgeons should diagnose and treat the patients with accurate understanding of neuropsychological impairment in the acute management of TBI.

A rare case of BRAF V600E-mutated epithelioid glioblastoma with a sarcomatous component.

Epithelioid glioblastoma is a rare subtype of glioblastoma, but the coexistence of a sarcomatous component is even rarer. An 80-year-old woman was admitted to our hospital with somnolence. Magnetic resonance imaging revealed a cystic lesion with a solid component in the left temporal-parietal lobe. Histopathological examination of the resected tumor revealed three components; namely, typical glioblastoma, sarcomatous and epithelioid components at a ratio of about 5:3:2. All components were immunohistochemically positive for vimentin and mutated BRAF (V600E) and showed focal expression of glial fibrillary acidic protein and cytokeratin AE1/AE3, but they were negative for isocitrate dehydrogenase 1. Genetic analysis revealed that both the sarcomatous and epithelioid components harbored BRAF T1799A (V600E) mutation and homozygous deletion of cyclin-dependent kinase inhibitor 2A/B. We diagnosed this tumor as epithelial glioblastoma with a sarcomatous component. Our results indicate that even when the epithelial component is not dominant, immunohistochemical and genetic investigation of BRAF mutations is useful for the diagnosis of glioblastoma subtypes. In particular, although the prognosis of epithelial glioblastoma is poor, potentially effective targeted therapies for BRAF V600E-mutated tumors are available.

Efficacy of the Decalcification of Heavily Calcified Femoral Bifurcation Lesions Using a Cavitron Ultrasonic Surgical Aspirator.

BACKGROUND: In the current diabetes era, severe calcified femoral bifurcation lesions extending to the external elastic lamina are sometimes experienced and are technically challenging during conventional endarterectomy. We previously reported an alternative method, a decalcification technique with a Cavitron Ultrasonic Surgical Aspirator (CUSA), for calcified lesions. This study aimed to clarify the efficacy of CUSA decalcification technique. METHODS: A total of 26 limbs treated with CUSA decalcification from 2014 to 2017 were enrolled and evaluated hemodynamically with ankle-brachial index (ABI) and morphologically with computed tomography angiography (CTA). ABI was measured every 6 months, and CTA was performed early after surgery and then annually thereafter. Curved planar reformation images and cross-sectional multiplanar reconstruction images obtained by CTA were used to measure the cross-sectional area of the common femoral artery (CFA). Then, the time courses of the ABI and CFA areas were analyzed. RESULTS: The operative indication was claudication in 80.8%, rest pain in 7.7%, and tissue loss in 11.5% of the cases. A concomitant profundaplasty was performed in 34.6% of the cases. One case of an intraoperative arterial wall perforation was experienced as a procedure-related complication. Hemodynamic success rate was 96.2% (preoperative ABI: 0.37 ± 0.28, postoperative ABI: 0.75 ± 0.15, P < 0.0001) and technical success rate was 100.0% (preoperative CFA area: 4.1 ± 5.9 mm2, postoperative CFA area: 46.1 ± 17.0 mm2, P < 0.0001), with clinical improvement achieved in 95.8% of cases. Primary and secondary patency rates of the CFA were 100.0% at 2 years postoperatively, and the reintervention-free rate for the ipsilateral limb was 88.5% at 2 years postoperatively. Over a median follow-up period of 28.0 months (range, 12.3-67.0 months), the restenosis rate of CFA was 7.6%, when restenosis was defined as a >50% decrease in cross-sectional area. CONCLUSIONS: CUSA decalcification is a safe and effective alternative method to treat heavily calcified femoral lesions with a good patency rate and a low restenosis rate.

Lysyl oxidase impacts disease outcomes and correlates with global DNA hypomethylation in esophageal cancer.

Abnormal function of human body enzymes and epigenetic alterations such as DNA methylation have been shown to lead to human carcinogenesis. Lysyl oxidase (LOX) enzyme has attracted attention due to its involvement in tumor progression in various cancers. The purpose of this study was to clarify the clinical importance of LOX expression and its epigenetic regulation in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Using a database of 284 ESCCs, we examined LOX expression and its prognostic characteristics. The functional role of LOX was assessed by in vitro growth, migration, and invasion assays. The relationship between LOX expression, global DNA hypomethylation (ie, LINE-1 methylation), and LOX promoter methylation was evaluated by using mRNA expression arrays and pyrosequencing technology. High LOX expression cases had a significantly shorter overall survival and cancer-specific survival (log-rank, P < .001). The prognostic effect of LOX expression was not significantly modified by other clinical variables. Silencing and enzymatic inhibition of LOX suppressed growth and reduced the invasion and migration ability of ESCC cell lines along with the downregulation of AKT and MMP2. An integrated gene analysis in tissues and cell lines revealed that LOX was the most highly upregulated gene in LINE-1 hypomethylated tumors. In vitro, LOX expression was upregulated following DNA demethylation. LOX promoter methylation was not associated with LOX expression. Conclusively LOX expression was associated with poor prognosis in ESCC and was regulated epigenetically by genome-wide hypomethylation. It could serve as a prognostic biomarker in ESCC patients, and therapeutically targeting LOX could reverse the progression of esophageal cancer.

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab.

Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post-Bev recurrent tumors from 9 patients were included. The expression of programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD-L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD-1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post-Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long-term Bev therapy.

Graft flow predictive equation in distal bypass grafting for critical limb ischemia.

OBJECTIVE: Graft flow (GF) seems to be an important prognostic predictor in distal bypass for critical limb ischemia, but previous studies have failed to clarify the association between GF and the graft prognosis. GF differs significantly among grafts, and each graft seems to have an optimal GF depending on various factors. We hypothesized that comparison between the measured GF (mGF) and optimal estimated GF (eGF) would be important in predicting graft prognosis. Herein, we aimed to develop a GF predictive equation by assessing GF determinants and to validate the equation against a clinical dataset. METHODS: A total of 198 distal bypasses with vein grafts for critical limb ischemia from 2011 to 2016 were enrolled. Of these grafts, 135 normal grafts without any abnormalities on early postoperative ultrasound examination were used to develop and validate the equation. Various anatomic and patient-related factors were analyzed to detect GF determinants with stepwise selection, and the GF predictive equation was developed with multiple linear regression analysis. After developing the equation, all 198 grafts were categorized into two groups according to the equation developed based on data from the 135 normal grafts as follows: optimal flow grafts (OFGs), in which mGF > eGF - 14.6, and suboptimal flow grafts (SFGs), in which mGF < eGF - 14.6. The cutoff value of 14.6 was determined using receiver operating characteristic curves to detect graft abnormalities. By comparing OFGs and SFGs, the efficacy of the equation in predicting bypass abnormalities and graft prognosis was assessed. RESULTS: The GF determinants were runoff, hemodialysis (HD), diabetes mellitus (DM), and graft quality (GQ). The predictive equation was estimated as follows: GF(ml/min)=(32.9×run-off)+(9.9×GQ)-(13.0×DM)-(35.1×HD)+12.1 (R2 = 0.71, coefficient: runoff and GQ, 3 [good], 2 [fair], 1 [poor]; DM and HD, 1 [yes], 0 [no]). In the efficacy assessment of the equation, SFGs showed a significantly higher rate of bypass abnormalities (64.0% vs 12.2%; P < .0001), graft intermediate stenosis (10.7% vs 1.6%; P = .0071), graft critical stenosis (28.0% vs 3.2%; P < .0001), and early graft occlusion (17.3% vs 4.3%; P = .0037) than OFGs and were associated with a higher rate of revision surgery within 2 years after surgery (50.7% vs 34.2%; P = .026). SFGs also showed significantly lower primary patency rates (P < .0001) and secondary patency rates (P = .0005). CONCLUSIONS: GF was well-estimated with runoff, GQ, and the presence of DM and HD. A comparison between mGF and eGF, calculated with the equation, will help to detect bypass abnormalities and determine the necessity of additional intraoperative procedures and, thus, achieve optimal outcomes.

Effectiveness and Safety of Ultrasound Guided Lower Extremity Nerve Blockade in Infragenicular Bypass Grafting for High Risk Patients With Chronic Limb Threatening Ischaemia.

OBJECTIVES: Surgical revascularisation to accomplish limb salvage remains preferable in some patients with chronic limb threatening ischaemia (CLTI). The aim of this study was to evaluate the effectiveness and safety of ultrasound guided lower extremity nerve blockade (UGNB) in infragenicular bypass surgery (IGBS). METHODS: This was a single centre, retrospective clinical study. Fifty-nine patients with CLTI (67 limbs) who underwent IGBS under UGNB (femoral and sciatic nerve blockade) at Asahikawa Medical University between January 2012 and December 2017 were compared with patients with CLTI (137 limbs) who underwent IGBS under general anaesthesia (GA) over the same period. Propensity score matching based on pre-operative comorbidities was used to minimise background differences of the two groups. RESULTS: Fifty-six pairs of CLTIs were matched and analysed (55% dialysis dependent). Procedure duration was similar between the two groups, but intraoperative catecholamine index and intravenous fluid volume were lower with UGNB compared with GA (2.9 ± 4.6 vs. 5.9 ± 6.5; p < .01 and 1831 ± 990 vs. 2335 ± 931 mL; p < .01, respectively). The mean arterial blood pressure during induction of anaesthesia was significantly decreased with GA. Post-operatively, the time period to resume a clear liquid and solid food diet was significantly shorter with UGNB (P<0.01 for both outcome measures). Intravenous fluid volume was significanlty lower, while cardiac complications and delirium, based on the NEECHAM confusion scale, occurred significantly less often with UGNB than GA. These significant differences show advantages of UGNB compared to GA. No mortality or major amputations were observed in either group. Early graft thrombosis was observed in five limbs (8.9%) with UGNB and in four limbs with GA (7.1%) (p = .73). CONCLUSIONS: UGNB has advantages for intra- and post-operative management and could be a useful method to prevent peri-operative complications for high risk patients with CLTI. To ensure the effectiveness of UGNB for IGBS for future indications, a randomised study is required.

Nrf2 promotes oesophageal cancer cell proliferation via metabolic reprogramming and detoxification of reactive oxygen species.

Cancer cells consume a large amount of energy and maintain high levels of anabolism to promote cell proliferation via metabolic reprogramming. Nuclear factor erythroid 2-related factor 2 (Nrf2; NFE2L2) is a master transcription regulator of stress responses and promotes metabolic reprogramming to support cell proliferation in various types of cancer. As oesophageal cancer is one of the most aggressive gastrointestinal cancers, we aimed to clarify the effect of Nrf2 on metabolic reprogramming in oesophageal cancer. The relationship between Nrf2 expression and clinical outcome was evaluated using a database comprising 201 oesophageal cancers. Using in vitro assays and metabolome analysis, we examined the mechanism by which Nrf2 affects malignant phenotype. High-level immunohistochemical expression of Nrf2 was significantly associated with poor recurrence-free survival (HR = 2.67, p = 0.0004) and overall survival (HR = 2.90, p < 0.0001) in oesophageal cancer patients. In an in vitro assay with siRNA in TE-11 cells, which showed high Nrf2 expression, Nrf2 depletion significantly decreased cell growth and enhanced G1 cell cycle arrest and apoptosis. In addition, reactive oxygen species (ROS) were not removed by detoxification via the Nrf2 pathway, with concomitant induction of the p38 mitogen-activated protein kinase pathway. The metabolome analysis showed that Nrf2 strongly promoted metabolic reprogramming to glutathione metabolism, which synthesizes the essential fuels for cancer progression. Furthermore, metabolome analysis using oesophageal cancer specimens confirmed that samples displaying high Nrf2 expression promoted glutathione synthesis. Metabolic reprogramming to glutathione metabolism, and ROS detoxification by activation of Nrf2, enhanced cancer progression and led to a poor clinical outcome in oesophageal cancer patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression.

RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knockout mice in a C57BL/6 N background by using the CRISPR-Cas9 system. Although intestinal organoids from Rnf43 knockout mice did not show continuous growth in the absence of R-spondin, an azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice. These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Laser speckle flowgraphy can also be used to show dynamic changes in the blood flow of the skin of the foot after surgical revascularization.

OBJECTIVES: Laser speckle flowgraphy is a new method that enables the rapid evaluation of foot blood flow without contact with the skin. We used laser speckle flowgraphy to evaluate foot blood flow in peripheral arterial disease patients before and after surgical revascularization. MATERIALS AND METHODS: A prospective single-center study. Thirty-one patients with 33 limbs that underwent surgical revascularization for peripheral arterial disease were included. Pre- and postoperative foot blood flows were measured on the plantar surface via laser speckle flowgraphy and skin perfusion pressure. The laser speckle flowgraphy device was used to visualize the blood flow distribution of the target skin and processed the pulse wave velocity of synchronized heart beats. The mean blood flow, which was expressed as the area of the pulse wave as the beat strength of skin perfusion on laser speckle flowgraphy converted into a numerical value, was assessed as dynamic changes following surgery. Beat strength of skin perfusion was also investigated in non-peripheral arterial disease controls (23 patients/46 limbs). RESULTS: The suitability of beat strength of skin perfusion in non-peripheral arterial disease controls was achieved; the beat strength of skin perfusion value was significantly higher in every area of interest in non-peripheral arterial disease controls compared to that in peripheral arterial disease limbs at the preoperative stage (105.8 ± 8.2 vs. 26.3 ± 8.2; P < 0.01). Although the pulse wave before surgery was visually flat in peripheral arterial disease patients, the pulse wave was remarkably and immediately improved through surgical revascularization. Beat strength of skin perfusion showed a dynamic change in foot blood flow (26.3 ± 8.2 at preoperation, 98.5 ± 6.7 immediately after surgery, 107.6 ± 5.7 at seven days after surgery, P < 0.01 for each compared to preoperation) that correlated with an improvement in skin perfusion pressure. CONCLUSIONS: Laser speckle flowgraphy is a noninvasive, contact-free modality that is easy to implement, and beat strength of skin perfusion is a useful indicator of foot circulation during the perioperative period. Further analysis with a larger number of cases is necessary to establish appropriate clinical use.

Histidine-rich Glycoprotein Could Be an Early Predictor of Vasospasm after Aneurysmal Subarachnoid Hemorrhage.

Cerebral vasospasm (CVS) is a major contributor to the high morbidity and mortality of aneurysmal subarachnoid hemorrhage (aSAH) patients. We measured histidine-rich glycoprotein (HRG), a new biomarker of aSAH, in cerebrospinal fluid (CSF) to investigate whether HRG might be an early predictor of CVS. A total of seven controls and 14 aSAH patients (8 males, 6 females aged 53.4±15.4 years) were enrolled, and serial CSF and serum samples were taken. We allocated these samples to three phases (T1-T3) and measured HRG, interleukin (IL)-6, fibrinopeptide A (FpA), and 8-hydroxy-2'-deoxyguanosine (8OHdG) in the CSF, and the HRG in serum. We also examined the release of HRG in rat blood incubated in artificial CSF. In contrast to the other biomarkers examined, the change in the CSF HRG concentration was significantly different between the nonspasm and spasm groups (p<0.01). The rat blood/CSF model revealed a time course similar to that of the human CSF samples in the non-spasm group. HRG thus appears to have the potential to become an early predictor of CVS. In addition, the interaction of HRG with IL-6, FpA, and 8OHdG may form the pathology of CVS.

Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1ß from activated macrophages leads to poor prognosis in pancreatic cancer.

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15-PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15-PGDH suppression in PDAC. Here, we showed that interleukin-1ß (IL-1ß), a pro-inflammatory cytokine, downregulates 15-PGDH expression in PDAC cells, and that IL-1ß expression was inversely correlated with 15-PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL-1ß and reduced 15-PGDH expression in PDAC cells. Furthermore, the number of CD163-positive tumor-associated macrophages was shown to be inversely correlated with 15-PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15-PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL-1ß derived from TAMs suppresses 15-PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients.