Evidence for early blood-brain barrier breakdown in experimental thiamine deficiency in the mouse

In order to assess the involvement of blood-brain barrier (BBB) breakdown in the pathogenesis of thiamine deficiency encephalopathy, autologous albumin immunohistochemistry was performed in mice which were rendered thiamine-deficient by pyrithiamine, a BBB-permeant antagonist of thiamine. In the presymptomatic animals until day 8 of the treatment, histological lesions were not detected by H&E staining. However, localized staining of albumin was evident, suggesting an extravascular leakage of the endogenous intravascular protein. On day 10 of thiamine deficiency, when neurological signs appeared, both histological lesions and massive albumin extravasation were demonstrated in all the animals. The BBB breakdown was only occasionally observed in the brains of mice treated with oxythiamine, a BBB-impermeant antagonist or in control animals. These results suggest that BBB breakdown is not only a phenomenon secondary to tissue destruction, but it is more directly involved in the pathogenesis of thiamine deficiency encephalopathy.     

Mitral Valve Prolapse in Childhood: The Incidence and Clinical Presentations in Different Age Groups

To elucidate the incidence and natural history of mitral valve prolapse (MVP) during childhood, we investigated a total of 4,238 children (aged from 1 day to 15 years) classified by age into 4 groups: Group 1:1 to 28-day-old full-term normal newborns (n = 108), Group 2: 6 to 18-month-old infants (n = 391), Group 3: 6 to 7-year-old children (n = 2,801), and Group 4: 12 to 15-year-old children (n = 938). The incidence of MVP was determined by videorecorded two-dimensional echocardiography in a double-blind method twice-over. There were 109 cases diagnosed as having MVP. The incidence rates of MVP were as follows: Group 1: 0%, Group 2: 0.25%, Group 3: 2.1% and Group 4: 5.1%. Arrhythmias were detected in 49% (27/55) by Holter ECG, and by exercise stress test in 4.7% (2/43). Eighty-three (77%) of 108 cases in Groups 3 and 4, excluding the 1 case in Group 2, showed no symptoms. Ventricular premature contraction (VPC) was the most common arrhythmia, and was benign in all cases. A mid-systolic click (MSC), late systolic murmur (LSM), MSC + LSM, and a pansystolic murmur were detected in 23.1%, 3.7%, 4.6% and 5.6%, respectively. Symptoms caused by MVP increased and appeared more apparently with age. Further prospective long-term follow-up studies to adulthood are necessary.     

Successful endoscopic clipping and application of fibrin glue for an esophago-mediastinal fistula after an esophagectomy

A 64-year-old man visited our hospital complaining of abdominal discomfort. A 2-cm-long 0-IIc + IIa esophageal superficial carcinoma was detected in the middle third of the thoracic esophagus with endoscopy and esophagography. Computed tomography (CT) did not detect any metastasis. The patient underwent video-assisted thoracic surgery of the esophagus (VATS-E). Anastomotic leakage and a thoracic abscess were detected 16 days after the operation. Repeated thoracic drainages and conservative therapy with enteral nutrition were continued for approximately 1 month, but an esophago-mediastinal fistula and small mediastinal cavity remained. Additional drainage using interventional radiology (IVR) reduced the size of the cavity, but could not cure the esophago-mediastinal fistula, 68 days after the operation. The occurrence of an esophago-respiratory fistula followed by a thoracic abscess is a very serious and frequently fatal complication. We performed endoscopic clipping and filling with fibrin glue and succeeded in closing the fistula. Oral intake was started after training in swallowing, and the patient was discharged from hospital 172 days after the operation. One year after the operation he has no sign of a recurrence of the tumor or fistula. We demonstrated a case in which an esophago-mediastinal fistula was successfully repaired by endoscopic clipping with fibrin glue after an operation.     

Intake of Japanese and Chinese teas reduces risk of Parkinson's disease

Studies that have addressed the association between the intake of coffee or caffeine and Parkinson's disease (PD) were conducted mainly in Western countries. Little is known about this relationship in an Asian population. Therefore, we performed an assessment of the association of the intake of coffee, other caffeine-containing beverages, and caffeine with the risk of PD in Japan. The study involved 249 PD cases and 368 control subjects. Information on dietary factors was obtained through a self-administered diet history questionnaire. Adjustment was made for sex, age, region of residence, educational level, pack-years of smoking, body mass index, the dietary glycemic index, and intake of cholesterol, vitamin E, β-carotene, vitamin B(6,) alcohol, and iron. Intake of coffee, black tea, and Japanese and Chinese teas was significantly inversely associated with the risk of PD: the adjusted odds ratios in comparison of the highest with the lowest quartile were 0.52, 0.58, and 0.59, respectively (95% confidence intervals = 0.30-0.90, 0.35-0.97, and 0.35-0.995, respectively). A clear inverse dose-response relationship between total caffeine intake and PD risk was observed. We confirmed that the intake of coffee and caffeine reduced the risk of PD. Furthermore, this is the first study to show a significant inverse relationship between the intake of Japanese and Chinese teas and the risk of PD.     

Neoadjuvant chemotherapy followed by surgery as standard treatment for stage II + III thoracic esophageal squamous cell carcinoma in Japan

In Japan, the overall 5-year survival rates after surgery alone for thoracic esophageal squamous cell carcinoma are 88% in patients with stage I and 52% in patients with stage II + III disease. Because of the poor outcome of stage II + III patients, multimodality approaches based on chemotherapy or chemoradiotherapy have been evaluated as adjuvant therapy. Neoadjuvant chemoradiotherapy has mainly been evaluated in the USA, while adjuvant chemotherapy for systemic effects has mainly been evaluated in Japan. In 2003, the results of a randomized study (Japan Clinical Oncology Group [JCOG] 9204) comparing surgery alone with postoperative chemotherapy with cisplatin and fluorouracil were reported, confirming that adjuvant chemotherapy prevents relapse in patients with esophageal cancer after surgery. In 2008, another study (JCOG 9907) comparing postoperative and preoperative chemotherapy was reported, and those results showed that preoperative chemotherapy induced downstaging and R0 reduction and improved overall survival without additional serious adverse events. Preoperative chemotherapy with cisplatin and fluorouracil followed by surgery can be regarded as the standard treatment for stage II + III thoracic esophageal squamous cell carcinoma in Japan.     

A patient with anti-aquaporin 4 antibody presenting hypersomnolence as the initial symptom and symmetrical hypothalamic lesions

Here we report a case with positive serum anti-aquaporin 4 (AQP4) antibody who presented with hypersomnolence, symmetrical hypothalamic lesions and a reduced CSF orexin (hypocretin) level without optic nerve and spinal cord lesions on MRI. All of the symptoms, MRI finding and CSF orexin level improved simultaneously after steroid therapy. AQP4 is a member of the AQP superfamily which is strongly expressed in the hypothalamus where orexin (hypocretin)-containing neurons are primarily concentrated. Although there have been only a few reports similar to our case, the present case suggests a close relationship between the positive serum anti-AQP4 antibody and symmetrical hypothalamic lesions with hypersomnolence and without optic /spinal lesion, which is improved by steroid treatment.     

Dynamic changes of mitochondrial fusion and fission proteins after transient cerebral ischemia in mice

With fusion or fission, mitochondria alter their morphology in response to various physiological and pathological stimuli, resulting in elongated, tubular, interconnected, or fragmented forms. Immunohistochemistry and Western blot analysis were performed at 2 days, 7 days, 14 days, and 28 days after 90 min of transient middle cerebral artery occlusion (tMCAO) in mice. This study showed that mitochondrial fission protein dynamin-related protein 1 (Drp1) and fusion protein optic atrophy 1 (Opa1) were both upregulated in the ischemic penumbra, with the peak at 2 days after tMCAO, whereas phosphorylated-Drp1 (P-Drp1) progressively increased with a peak at 14 days after tMCAO. Double-immunofluorescence analysis showed many Drp1/cytochrome c oxidase subunit l (COX1) double-positive cells and Opa1/COX1 double-positive cells in the ischemic penumbra and also showed some double-positive cells with Drp1/terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) and Opa1/TUNEL in the ischemic penumbra. In contrast, both Drp1 and Opa1 showed progressive decreases until 2 days after tMCAO in the ischemic core because of necrotic brain damage. The present study suggests that there was a continuous mitochondrial fission and fusion during these periods in the ischemic penumbra after tMCAO, probably in an effort toward mitophagy and cellular survival.     

Esophageal stenosis and the Glasgow Prognostic Score as independent factors of poor prognosis for patients with locally advanced unresectable esophageal cancer treated with chemoradiotherapy (exploratory analysis of JCOG0303)

Background

The aim of this study was to investigate the possible prognostic factors and predictive accuracy of the Glasgow Prognostic Score (GPS) for patients with unresectable locally advanced esophageal squamous cell carcinoma (LAESCC) treated with chemoradiotherapy.

Methods

One hundred forty-two patients were enrolled in JCOG0303 and assigned to the standard cisplatin and 5-fluorouracil (PF)-radiotherapy (RT) group or the low-dose PF-RT group. One hundred thirty-one patients with sufficient data were included in this analysis. A Cox regression model was used to analyze the prognostic factors of patients with unresectable LAESCC treated with PF-RT. The GPS was classified based on the baseline C-reactive protein (CRP) and serum albumin levels. Patients with CRP ≤1.0 mg/dL and albumin ≥3.5 g/dL were classified as GPS0. If only CRP was increased or only albumin was decreased, the patients were classified as GPS1, and the patients with CRP >1.0 mg/dL and albumin <3.5 g/dL were classified as GPS2.

Results

The patients’ backgrounds were as follows: median age (range), 62 (37–75); male/female, 119/12; ECOG PS 0/1/2, 64/65/2; and clinical stage (UICC 5th) IIB/III/IVA/IVB, 3/75/22/31. Multivariable analyses indicated only esophageal stenosis as a common factor for poor prognosis. In addition, overall survival tended to decrease according to the GPS subgroups (median survival time (months): GPS0/GPS1/GPS2 16.1/14.9/8.7).

Conclusions

Esophageal stenosis was identified as a candidate stratification factor for randomized trials of unresectable LAESCC patients. Furthermore, GPS represents a prognostic factor for LAESCC patients treated with chemoradiotherapy.

Clinical Trial Information

UMIN000000861.

     

Results of a nation-wide retrospective study of lymphadenectomy for esophagogastric junction carcinoma

Background

Esophagogastric junction (EGJ) carcinoma has attracted considerable attention because of the marked increase in its incidence globally. However, the optimal extent of esophagogastric resection for this tumor entity remains highly controversial.

Methods

This was a questionnaire-based national retrospective study undertaken in an attempt to define the optimal extent of lymph node dissection for EGJ cancer. Data from patients with EGJ carcinoma, less than 40 mm in diameter, who underwent R0 resection between January 2001 and December 2010 were reviewed.

Results

Clinical records of 2807 patients without preoperative therapy were included in the analysis. There are distinct disparities in terms of the nodal dissection rate according to histology and the predominant tumor location. Nodal metastases frequently involved the abdominal nodes, especially those at the right and left cardia, lesser curvature and along the left gastric artery. Nodes along the distal portion of the stomach were much less often metastatic, and their dissection seemed unlikely to be beneficial. Lower mediastinal node dissection might contribute to improving survival for patients with esophagus-predominant EGJ cancer. However, due to low dissection rates for nodes of the middle and upper mediastinum, no conclusive result was obtained regarding the optimal extent of nodal dissection in this region.

Conclusions

Complete nodal clearance along the distal portion of the stomach offers marginal survival benefits for patients with EGJ cancers less than 4 cm in diameter. The optimal extent of esophageal resection and the benefits of mediastinal node dissection remain issues to be addressed in managing patients with esophagus-predominant EGJ cancers.