Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer

Vascular endothelial growth factor receptor 2 (VEGFR2) is an essential factor in tumor angiogenesis and in the growth of pancreatic cancer. Immunotherapy using epitope peptide for VEGFR2 (VEGFR2‐169) that we identified previously is expected to improve the clinical outcome. Therefore, a phase I clinical trial combining of VEGFR2‐169 with gemcitabine was conducted for patients with advanced pancreatic cancer. Patients with metastatic and unresectable pancreatic cancer were eligible for the trial. Gemcitabine was administered at a dose of 1000 mg/m² on days 1, 8, and 15 in a 28‐day cycle. The VEGFR2‐169 peptide was subcutaneously injected weekly in a dose‐escalation manner (doses of 0.5, 1, and 2 mg/body, six patients/one cohort). Safety and immunological parameters were assessed. No severe adverse effect of grade 4 or higher was observed. Of the 18 patients who completed at least one course of the treatment, 15 (83%) developed immunological reactions at the injection sites. Specific cytotoxic T lymphocytes (CTL) reacting to the VEGFR2‐169 peptide were induced in 11 (61%) of the 18 patients. The disease control rate was 67%, and the median overall survival time was 8.7 months. This combination therapy for pancreatic cancer patients was tolerable at all doses. Peptide‐specific CTL could be induced by the VEGFR2‐169 peptide vaccine at a high rate, even in combination with gemcitabine. From an immunological point of view, the optimal dose for further clinical trials might be 2 mg/body or higher. This trial was registered with ClinicalTrial.gov (no. NCT 00622622). (Cancer Sci 2009)     

Feasibility of early ambulation three hours after transfemoral angiography using a 4 French sheath

PURPOSE: Our objective was to evaluate the feasibility of early resumption of ambulation 3 hours after transfemoral angiography using a 4 French sheath. SUBJECTS AND METHODS: This prospective study was carried out in a selected group of men and women without impaired blood clotting (prothrombin time > 15 sec) or thrombocytopenia (platelet < 55,000/mm3). The subjects consisted of 66 men and 34 women with a mean age of 62.3 years (range 27-90 years). Incidences of rebleeding or hematoma at the site of femoral catheter insertion were investigated before and after ambulation. Rebleeding was defined as bleeding that required recompression. Hematoma was defined as a palpable, firm collection of subcutaneous blood. RESULTS: Of 100 patients who resumed full ambulation after three hours of bed rest, none (0%) had acute groin hematoma and only three (3%) showed rebleeding that had to be manually compressed. The remaining 97 patients (97%) had no problem after ambulation. CONCLUSION: Supervised resumption of ambulation 3 hours after angiography with a 4 French sheath is safe and feasible in most ambulatory patients undergoing transfemoral angiography.     

Activation of Akt by mechanical stretching in human epidermal keratinocytes

Mechanical stretching represents an important part of the signaling in skin. We have previously demonstrated that mechanical stretching induced proliferative phenotypes in human keratinocytes, as shown in increased 5-bromo-2'-deoxyuridine (BrdU) incorporation, ERK1/2 activation, and keratin K6 induction. Here we have further investigated the antiapoptotic signals in human keratinocytes provoked by mechanical stretching in vitro. Keratinocytes were plated on flexible silicone supports to transmit mechanical stretching to keratinocytes, involving continuous stretching by +20%. Stretching of these cells for 15-30 min caused the phosphorylation and activation of Akt. Inhibition of mitogen and extracellular signal-regulated kinase (MEK1/2) with U0126 and phosphoinositide 3-OH kinase (PI 3-K) with Wortmannin attenuated Akt activation. The epidermal growth factor (EGF) receptor kinase inhibitor, AG1478, and calcium channel inhibitor, gadolinium (Gd3+), also inhibited Akt activation. In summary, our results demonstrate the activation of the Akt signaling pathway by mechanical stretching, generating not only proliferative but also antiapoptotic signals in human keratinocytes.     

Suboptimal therapy controls clinically apparent disease but not subclinical progression of Vogt-Koyanagi-Harada disease

Purpose To evaluate clinical and angiographic differences in patients with Vogt-Koyanagi-Harada (VKH) disease during the early 4-month treatment phase with high- or medium-dose systemic corticosteroid therapy. Methods VKH patients treated at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland (n = 4), or the Department of Ophthalmology, Tokyo Medical and Dental University, Tokyo, Japan (n = 5), underwent a pre-treatment indocyanine green angiography (ICGA) and a follow-up ICGA four months after treatment began. Lausanne patients received high-dose, systemic corticosteroid therapy, with or without immunosuppressive therapy. Tokyo patients received medium-dose systemic corticosteroid therapy that included 3 days of intravenous pulse methylprednisolone. ICGA signs including choroidal stromal vessel hyperfluorescence and leakage, hypofluorescent dark dots (HDD), fuzzy vascular pattern of large stromal vessels and disc hyperfluorescence were retrospectively compared. Results The pre-treatment ICGA demonstrated that each of the nine patients had choroidal inflammatory foci, as indicated by HDD. At 4-month follow-up, clinical and fluorescein findings had improved almost equally in both groups. HDD had resolved in the Lausanne group but persisted in the Tokyo group. Sunset glow fundus occurred in three of the Tokyo patients and none of the Lausanne patients. Conclusions Submaximal doses of inflammation suppressive therapy are sufficient to suppress clinically apparent disease but not the underlying lesion process. This explains the propensity for sunset glow fundus in seemingly controlled disease.     

Clinicopathological features of malignant intraductal papillary mucinous tumors of the pancreas: the differential diagnosis from benign entities

BACKGROUND: The accurate differential diagnosis of malignant intraductal papillary mucinous tumors (IPMTs) of the pancreas from benign IPMTs remains unclear. HYPOTHESIS: Predictive factors for differentiating malignant IPMTs from benign IPMTs can be documented. DESIGN: Retrospective study (1999-2003). SETTING: Wakayama Medical University Hospital, Wakayama, Japan. PATIENTS: Twenty-seven consecutive patients with IPMTs (11 with adenoma, 3 with dysplasia, 5 with adenocarcinoma, and 8 with invasive adenocarcinoma) who underwent surgery were retrospectively analyzed in terms of clinicopathological features. MAIN OUTCOME MEASURE: Clinical data, preoperative imaging findings, cytology, and tumor marker level, including carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), in serum and pure pancreatic juice. RESULTS: In preoperative imaging findings, the mean tumor size for the malignant IPMT group (81 +/- 18 mm) was significantly larger than that for the benign IPMT group (31 +/- 4 mm) (P =.002). The mean mural nodule size for the malignant IPMT group (9.8 +/- 4.4 mm) was significantly larger than that for the benign IPMT group (3.3 +/- 5.7 mm) (P =.002). The CEA levels in pure pancreatic juice in the malignant IPMT group (3051 +/- 7556 ng/mL) were significantly higher than in the benign IPMT group (41 +/- 80 ng/mL) (P =.003), although no significant differences in cytologic analyses and CA19-9 levels in pure pancreatic juice were found between the 2 groups. CONCLUSION: Our findings suggest that tumor size larger than 30 mm, mural nodule size larger than 5 mm, and CEA levels higher than 110 ng/mL in pure pancreatic juice were predictive factors for diagnosis of malignant IPMTs.     

Does family history of schizophrenia influence age at onset of schizophrenia?

The relation between age at onset of schizophrenia diagnosed using DSM-III criteria and the presence or absence of this illness among first-degree relatives was investigated in 2417 patients. The mean age at onset among those with a family history of schizophrenia was slightly and nonsignificantly earlier than that of schizophrenic patients without a positive family history. The former developed their illness before the age of 25 years more frequently than did the latter.     

Clinicopathological study of diffuse neurofibrillary tangles with calcification. With special reference to TDP-43 proteinopathy and alpha-synucleinopathy

Diffuse neurofibrillary tangles with calcification (DNTC) is a relatively rare presenile dementia that clinically shows overlapping symptoms of Alzheimer's disease and frontotemporal lobar degeneration (FTLD). DNTC is pathologically characterized by localized temporal or frontotemporal atrophy with massive neurofibrillary tangles, neuropil threads and Fahr's-type calcification without senile plaques. We tried to clarify the molecular basis of DNTC by immunohistochemically examining the appearance and distribution of accumulated alpha-synuclein (aSyn) and TAR DNA-binding protein of 43kDa (TDP-43) in the brains of 10 Japanese autopsy cases. We also investigated the clinically characteristic symptoms from the clinical charts and previous reports, and the correlations with neuropathological findings. The characteristic symptoms were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI-Q). As a result, we confirmed the high frequency of neuronal cytoplasmic accumulation of aSyn (80%) and phosphorylated TDP-43 (90%) in DNTC cases. There was a significant correlation between some selected items of NPI-Q scores and the severity of the limbic TDP-43 pathology. The pathology of DNTC included TDP-43 and aSyn pathology with high frequency. These abnormal accumulations of TDP-43 might be involved in the pathological process of DNTC, having a close relationship to the FTLD-like psychiatric symptoms during the clinical course.     

Uptake of Colchicine,a Microtubular System Disrupting Agent,by Isolated Rat Hepatocytes

The possible mechanism of hepatic uptake of colchicine (CLC), a microtubule system disrupting agent, was examined using isolated rat hepatocytes. The existence of a carrier-mediated active transport system for CLC was demonstrated. This transport system is saturable, is affected by metabolic inhibitors (dinitrophenol, KCN) and a SH-group blocker (p-hydroxymercuribenzoic acid but not N-ethylmaleimide), and is sensitive to temperature. Ouabain, an inhibitor of Na⁺, K⁺-ATPase, does not affect the transport system of CLC.