Larger Posterior Revascularization Associated with Reduction of Choroidal Anastomosis in Moyamoya Disease: A Quantitative Angiographic Analysis.

BACKGROUND AND PURPOSE: Choroidal anastomosis, a hemorrhage-prone periventricular collateral manifestation in Moyamoya disease, outflows to the cortex posterior to the central sulcus. The objective of the present study was to test whether the angiographic extent of revascularization posterior to the central sulcus contributes to the postoperative reduction of choroidal anastomosis. MATERIALS AND METHODS: This retrospective cohort study included choroidal anastomosis-positive hemispheres before direct bypass surgery. The postoperative reduction of choroidal anastomosis was determined by a consensus of 2 raters according to the previous research. An imaging software automatically traced the angiographic revascularization area, which was subsequently divided into anterior and posterior parts by an anatomic line corresponding to the central sulcus. Each area was quantitatively measured as a percentage relative to the whole supratentorial area. RESULTS: Postoperative reduction of choroidal anastomosis was achieved in 68 (85.0%) of the 80 included hemispheres. The revascularization area posterior to the central sulcus was significantly larger in the hemispheres with reduction than in those with no reduction (mean, 15.2% [SD, 7.1%] versus 4.2% [SD, 3.4%], P < .001), whereas no significant difference was observed in the revascularization area anterior to the central sulcus. Multivariate analysis revealed that the revascularization area posterior to the central sulcus was the only significant factor associated with reduction (OR, 1.57; 95% CI, 1.21-2.03, for every 1% increase). CONCLUSIONS: The results suggest that a larger revascularization posterior to the central sulcus is associated with postoperative reduction of choroidal anastomosis regardless of the extent of anterior revascularization. It might facilitate optimal selection of the revascularization site for preventing hemorrhage.

Predictors of Poor Functional Status in Adult Fontan Patients Living at Moderate Altitude.

Patients who have undergone Fontan palliation have reduced exercise tolerance measured by maximal oxygen consumption (VO2 max). Declining exercise capacity is associated with increased morbidity and mortality. The impact of hemodynamics and other variables on this population's functional status is not well understood. This study sought to identify variables that predict low VO2 max in Fontan patients living at moderate altitude (5,000-8,000 feet). We performed a retrospective cohort study of 44 adult Fontan patients living at moderate altitude who had undergone cardiopulmonary exercise testing (CPET) and cardiac catheterization. We evaluated hemodynamic parameters measured during catheterization, imaging results, and laboratory studies for correlation with VO2 max measured during CPET. Our study cohort (median age 30 years, 52% female) had exercise impairment with mean VO2 max of 21.6 mL/kg/min. Higher trans-pulmonary gradient (TPG) (p < 0.001) and mean pulmonary artery (PA) pressure (p = 0.013) were predictors of lower maximal and submaximal VO2. Higher BNP values correlated with lower VO2 max (p = 0.01). Platelet count, GGT, albumin, and pulmonary vasodilator therapy did not correlate with VO2 max. None of the studied variables were associated with higher minute ventilation to peak carbon dioxide production (VE/VCO2 slope) or change in VO2 max over time. In conclusion, higher TPG and mean PA pressure predicted lower exercise tolerance amongst our cohort of adult Fontan patients living at moderate altitude. Future studies are needed to determine if these clinical variables represent viable therapeutic targets that could result in improved exercise tolerance and outcomes in patients with Fontan circulation.

Identification of the Bleeding Point in Hemorrhagic Moyamoya Disease Using Fusion Images of Susceptibility-Weighted Imaging and Time-of-Flight MRA.

BACKGROUND AND PURPOSE: The location of intracerebral hemorrhage in Moyamoya disease is a prognostic factor for rebleeding and the degree of preventive effects obtainable with bypass surgery. We evaluated whether the bleeding point and responsible vessel were detectable using fusion images of SWI and time-of-flight MRA performed during chronic-phase hemorrhage. MATERIALS AND METHODS: We retrospectively enrolled 42 patients with hemorrhagic Moyamoya disease (48 hemorrhagic events). Fusion images of SWI and MRA were made using workstations, and we defined the bleeding point as the point at which the signal of an abnormally extended artery on MRA overlapped the hypointense area on SWI. Two independent raters identified the bleeding point, and classified the location and responsible vessels. RESULTS: The bleeding point was detectable at a frequency of 79.2% by rater 1. Agreement for the presence of a bleeding point was high (interrater κ = 0.83; 95% CI, 0.65-1; intrarater κ = 0.86; 95% CI, 0.68-1). The frequency of a periventricular location of the bleeding point was 65.8% by rater 1, and agreement on the location was again high (interrater κ = 0.92; 95% CI, 0.82-1; intrarater κ = 0.85; 95% CI, 0.72-0.99). The choroidal artery was the most frequent responsible vessel (57.9% by rater 1), and agreement on the responsible vessel was high (interrater κ = 0.84; 95% CI, 0.69-1; intrarater κ = 0.90; 95% CI, 0.78-1). CONCLUSIONS: Detection of the bleeding point in hemorrhagic Moyamoya disease using SWI and MRA fusion images offers highly reproducible results.

Where do we aspire to publish? A position paper on scientific communication in biochemistry and molecular biology

The scientific publication landscape is changing quickly, with an enormous increase in options and models. Articles can be published in a complex variety of journals that differ in their presentation format (online-only or in-print), editorial organizations that maintain them (commercial and/or society-based), editorial handling (academic or professional editors), editorial board composition (academic or professional), payment options to cover editorial costs (open access or pay-to-read), indexation, visibility, branding, and other aspects. Additionally, online submissions of non-revised versions of manuscripts prior to seeking publication in a peer-reviewed journal (a practice known as pre-printing) are a growing trend in biological sciences. In this changing landscape, researchers in biochemistry and molecular biology must re-think their priorities in terms of scientific output dissemination. The evaluation processes and institutional funding for scientific publications should also be revised accordingly. This article presents the results of discussions within the Department of Biochemistry, University of São Paulo, on this subject.

Addition of Amide Proton Transfer Imaging to FDG-PET/CT Improves Diagnostic Accuracy in Glioma Grading: A Preliminary Study Using the Continuous Net Reclassification Analysis.

BACKGROUND AND PURPOSE: Amide proton transfer imaging has been successfully applied to brain tumors, however, the relationships between amide proton transfer and other quantitative imaging values have yet to be investigated. The aim was to examine the additive value of amide proton transfer imaging alongside [18F] FDG-PET and DWI for preoperative grading of gliomas. MATERIALS AND METHODS: Forty-nine patients with newly diagnosed gliomas were included in this retrospective study. All patients had undergone MR imaging, including DWI and amide proton transfer imaging on 3T scanners, and [18F] FDG-PET. Logistic regression analyses were conducted to examine the relationship between each imaging parameter and the presence of high-grade (grade III and/or IV) glioma. These parameters included the tumor-to-normal ratio of FDG uptake, minimum ADC, mean amide proton transfer value, and their combinations. In each model, the overall discriminative power for the detection of high-grade glioma was assessed with receiver operating characteristic curve analysis. Additive information from minimum ADC and mean amide proton transfer was also evaluated by continuous net reclassification improvement. P < .05 was considered significant. RESULTS: Tumor-to-normal ratio, minimum ADC, and mean amide proton transfer demonstrated comparable diagnostic accuracy in differentiating high-grade from low-grade gliomas. When mean amide proton transfer was combined with the tumor-to-normal ratio, the continuous net reclassification improvement was 0.64 (95% CI, 0.036-1.24; P = .04) for diagnosing high-grade glioma and 0.95 (95% CI, 0.39-1.52; P = .001) for diagnosing glioblastoma. When minimum ADC was combined with the tumor-to-normal ratio, the continuous net reclassification improvement was 0.43 (95% CI, -0.17-1.04; P = .16) for diagnosing high-grade glioma, and 1.36 (95% CI, 0.79-1.92; P < .001) for diagnosing glioblastoma. CONCLUSIONS: Addition of amide proton transfer imaging to FDG-PET/CT may improve the ability to differentiate high-grade from low-grade gliomas.

Sialadenoma papilliferum in the buccal mucosa detected on 18F-fluorodeoxyglucose-positron emission tomography.

An incidental discovery of an accumulation of 18F-fluorodeoxyglucose (FDG) in the oral cavity of patients with malignant tumours on FDG positron emission tomography (PET) can pose a problem regarding the differential diagnosis of metastatic lesions. Large accumulations can often be found even when tumours in the salivary or thyroid gland are benign, so FDG-PET is limited in its ability to differentiate between benign and malignant disease. This report describes a rare case of sialadenoma papilliferum in the buccal mucosa that was discovered incidentally on FDG-PET in a patient with multiple metastases to bone after an operation for rectal cancer.

Therapeutic vaccination based on side population cells transduced by the granulocyte-macrophage colony-stimulating factor gene elicits potent antitumor immunity.

Among cancer immunotherapies, granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccine (GVAX) therapies appear promising and have been shown to be safe and effective in multiple clinical trials. However, the antitumor efficacies of GVAX therapy alone are in some cases limited. Here we showed that GVAX therapy targeting cancer stem cells (CSCs) substantially suppressed tumor development in syngeneic immunocompetent mice recapitulating normal immune systems. CSCs were isolated as side population (SP) cells from 4T1 murine breast carcinoma cell line and transduced with GM-CSF gene delivered by non-transmissible Sendai virus (4T1-SP/GM). Impaired tumorigenicity of subcutaneously injected 4T1-SP/GM depended on CD8+ T cells in concert with CD4+ T cells and natural killer cells. Mice therapeutically vaccinated with irradiated 4T1-SP/GM cells had markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with those treated with irradiated cells of non-transduced 4T1-SP cells or non-SP (4T1-NSP/GM) cells. Tumor suppression was accompanied by the robust accumulation of mature dendritic cells at vaccination sites and T-helper type 1-skewed systemic cellular immunity. Our results suggested that CSC cell-based GVAX immunotherapy might be clinically useful for inducing potent tumor-specific antitumor immunity.

Pathological changes of adipose tissue in secondary lymphoedema.

BACKGROUND: The pathophysiology of lymphoedema is poorly understood. Current treatment options include compression therapy, resection, liposuction and lymphatic microsurgery, but determining the optimal treatment approach for each patient remains challenging. OBJECTIVES: We characterized skin and adipose tissue alterations in the setting of secondary lymphoedema. METHODS: Morphological and histopathological evaluations were conducted for 70 specimens collected from 26 female patients with lower-extremity secondary lymphoedema following surgical intervention for gynaecological cancers. Indocyanine green lymphography was performed for each patient to assess lymphoedema severity. RESULTS: Macroscopic and ultrasound findings revealed that lymphoedema adipose tissue had larger lobules of adipose tissue, with these lobules surrounded by thick collagen fibres and interstitial lymphatic fluid. In lymphoedema specimens, adipocytes displayed hypertrophic changes and more collagen fibre deposits when examined using electron microscopy, whole-mount staining and immunohistochemistry. The number of capillary lymphatic channels was also found to be increased in the dermis of lymphoedema limbs. Crown-like structures (dead adipocytes surrounded by M1 macrophages) were less frequently seen in lymphoedema samples. Flow cytometry revealed that, among the cellular components of adipose tissue, adipose-derived stem/stromal cells and M2 macrophages were decreased in number in lymphoedema adipose tissue compared with normal controls. CONCLUSIONS: These findings suggest that long-term lymphatic volume overload can induce chronic tissue inflammation, progressive fibrosis, impaired homeostasis, altered remodelling of adipose tissue, impaired regenerative capacity and immunological dysfunction. Further elucidation of the pathophysiological mechanisms underlying lymphoedema will lead to more reliable therapeutic strategies.

Longitudinal and long-term effects of radiotherapy on swallowing function after tongue reconstruction.

OBJECTIVE: This study evaluated the longitudinal and long-term effects of radiotherapy on swallowing function after tongue reconstruction. METHODS: The study comprised 16 patients who had: undergone glossectomy and tongue reconstruction with free flap transfer, received adjuvant radiotherapy, and survived without recurrence for at least 1 year. Swallowing function, as indicated by tolerance of oral intake, was evaluated before radiotherapy, at radiotherapy completion, and at 6 and 12 months after radiotherapy completion. RESULTS: Before radiotherapy, all patients could tolerate oral intake. At radiotherapy completion, only three patients could consume all nutrition orally. However, swallowing function improved over time, and by 12 months after radiotherapy completion it had returned nearly to that before radiotherapy. CONCLUSION: Acute dysphagia due to radiotherapy after tongue reconstruction is severe, but can improve gradually. Multidisciplinary support of patients during percutaneous endoscopic gastrostomy dependence is important to improve long-term functional outcomes.

FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma.

Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.

Differentiation between primary central nervous system lymphoma and glioblastoma: a comparative study of parameters derived from dynamic susceptibility contrast-enhanced perfusion-weighted MRI.

AIM: To evaluate the diagnostic performance of parameters derived from dynamic susceptibility contrast-enhanced perfusion-weighted magnetic resonance imaging, including first-pass slope ratio (FSR), which is potentially easier to derive than the other proposed parameters in this study, for differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma. MATERIALS AND METHODS: Twenty-eight patients (10 PCNSLs and 18 glioblastomas) were analysed. Six perfusion parameters - corrected cerebral blood volume ratio (cCBVR), uncorrected CBV ratio (uCBVR), FSR, leakage coefficient (K2), percentage of signal-intensity recovery measured at the end of the first-pass (PSRend), and PSR measured using mean signal-intensity after the first-pass (PSRmean) - were derived from enhancing areas selected semi-automatically. Comparisons of cCBVR and uCBVR and of PSRend and PSRmean were conducted. The differences between PCNSL and glioblastoma were compared for the six parameters, and their diagnostic performance was evaluated by receiver operating characteristic curve analysis. RESULTS: For both tumours, cCBVR was significantly higher than uCBVR, and PSRend was significantly lower than PSRmean. PCNSL demonstrated lower cCBVR, uCBVR and FSR, and higher K2, PSRend and PSRmean compared with glioblastoma (p=0.0044 or less). On receiver operating characteristic curve analysis, the areas under the curve were 0.822 for cCBVR, 0.944 for uCBVR, 0.917 for FSR, 0.917 for K2, 0.933 for PSRend, and 0.894 for PSRmean. No significant difference was observed among the parameters, except cCBVR, which was significantly inferior to uCBVR. CONCLUSIONS: PCNSL can be differentiated from glioblastoma with high diagnostic value using any of the parameters, except cCBVR. FSR demonstrates high differential performance comparable to the other parameters.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy.

Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

Salvage supracricoid laryngectomy after failed radiotherapy and partial laryngectomy.

BACKGROUND: A case of salvage supracricoid laryngectomy with cricohyoidoepiglottopexy after failed radiation therapy and vertical partial laryngectomy had successful oncological and functional outcomes. This is the first reported application of salvage supracricoid laryngectomy with cricohyoidoepiglottopexy after the failure of two major treatments. CASE REPORT: A 65-year-old man was referred for salvage supracricoid laryngectomy with cricohyoidoepiglottopexy. The right recurrent hemilarynx was successfully resected. After pexis, the right lobe of the thyroid gland was repositioned to overlap and reinforce the pexis gap and fill the devoid portion of the strap muscular closure. Multiple scattered foci (recurrent tumour-node-metastasis stage T2) were identified around the arytenoid cartilage and beneath the musculocutaneous flap. Four years after supracricoid laryngectomy with cricohyoidoepiglottopexy, the patient's recovery was following a favourable course and he had satisfactory laryngeal function. CONCLUSION: Appropriate case selection and proficient surgical skills were essential for a successful outcome. Head and neck surgeons should not be afraid to adopt functional preservation open surgical procedures in well-selected and well-motivated patients. A requirement for more challenging surgical procedures and meticulous rehabilitation processes should not exclude appropriate treatments from a surgeon's repertoire.

Immediate soft-tissue reconstruction using a rectus abdominis myocutaneous flap following wide resection of malignant bone tumours of the pelvis.

Resection of malignant bony tumours of the pelvis creates large bone and soft-tissue defects, and is frequently associated with complications such as wound dehiscence and deep infection. We present the results of six patients in whom a rectus abdominis myocutaneous (RAM) flap was used following resection of a malignant tumour of the pelvis. Bony reconstruction was performed using a constrained hip tumour prosthesis in three patients, vascularised fibular graft in two and frozen autograft in one. At a mean follow-up of 63 months (16 to 115), no patients had a problem with the wound. Immediate reconstruction using a RAM flap may be used after resection of a malignant tumour of the pelvis to provide an adequate volume of tissue to eliminate the dead space, cover the exposed bone or implants with well-vascularised soft tissue and to reduce the risk of complications.

Multimodal endoscopic treatment for delayed severe esophageal stricture caused by incomplete stent removal.

The usefulness of a covered self-expandable metallic stent for benign esophageal stricture and perforation was well established. In case of benign disease, early stent removal was recommended within 6-8 weeks after placement. A case with severe esophageal stricture caused by incomplete stent removal 7 years after stent placement for spontaneous esophageal rupture was reported. Residual stent fragments could be removed by step-by-step multimodal endoscopic treatment, producing satisfactory luminal diameter of the esophagus. In particular, stent trimming with argon plasma coagulation was safe and effective strategy. The endoscopic stent removal is minimally invasive and should be attempted before surgical intervention; however, it is most important to ensure early stent removal before tissue ingrowth or overgrowth can develop.

A novel measurement and delivery system for synchronizing oxygen gas flow with blood flow during cardiopulmonary bypass.

Monitoring the blood pump and the oxygen gas flow meter are important maneuvers at the initiation of cardiopulmonary bypass (CPB). We present a novel system, designed to improve safety in the heart-lung machine by linking the control of blood flow and the oxygen gas flow meter. This system uses a mass flow controller to provide and control oxygen flow based on the ventilation-perfusion (V/Q) ratio, using the electronic signal of the blood flow. We tested the system, in vitro and in vivo, and examined the resulting level of blood oxygenation. When extracorporeal circulation was initiated, the oxygen flow was instantly linked to the circulating blood flow, providing an adequate V/Q ratio; the partial pressure of oxygen in the blood was maintained at a normal level. Although we have yet to confirm the safety of this system in clinical trials, the new safety assist device can automatically supply oxygen to the oxygenator at the beginning of CPB.