PTK787/ZK222584 Combined with Interferon Alpha and 5-Fluorouracil Synergistically Inhibits VEGF Signaling Pathway in Hepatocellular Carcinoma

Background

The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus remains poor. We previously reported the beneficial effects of interferon alpha (IFN) and 5-fluorouracil (5-FU) combination therapy for these patients. We showed that the mechanism of therapy was regulation of vascular endothelial growth factor (VEGF). Here, we combined IFN/5-FU therapy with the VEGF receptor–selective inhibitor PTK787/ZK222584 (PTK/ZK) and examined the antitumor effects and the mechanism of action.

Methods

We studied two HCC cell lines, PLC/PRF/5 and HuH7, and a human umbilical vein endothelial cell line, HUVEC. We studied the effects of IFN/5-FU with or without PTK/ZK in growth inhibition assays, immunohistochemistry, Western blot analysis, and immunocytochemistry.

Results

In a HuH7 xenograft model, the combination of PTK/ZK and IFN/5-FU significantly inhibited proliferation, induced apoptosis, decreased microvessel density, reduced the number of tumor cells that expressed VEGF receptor 2 (VEGFR-2), and repressed the phosphorylation of Akt in vivo. In HCC cells and HUVECs in vitro, IFN/5-FU plus PTK/ZK repressed the expression of VEGFR-2 and repressed the phosphorylation of VEGFR, Akt, Erk, and p38MAPK.

Conclusions

VEGF signaling inhibition enhanced the antitumor effects of IFN/5-FU therapy on HCC cells and endothelial cells via Erk, Akt, and p38MAPK pathways.

     

Inhibitory effects of IL-12 on experimental tooth movement and root resorption in mice

ObjectiveInterleukin (IL)-12 is an important cytokine for innate and adaptive immunity. We previously reported that IL-12 inhibits tumour necrosis factor (TNF)-α-mediated osteoclast formation by inducing apoptosis. We also reported that TNF-α plays an important role in mechanical loading-induced osteoclast formation and bone resorption during orthodontic tooth movement. In this study, we investigated the effects of IL-12 on mechanical tooth movement in mice.DesignA Ni–Ti closed coil spring was inserted between the upper incisors and the upper left first molar in mice. IL-12 was injected locally adjacent to the first molar every other day during the experimental period, at doses varying from 0 to 1.5 μg/day. After 12 days, the animals were killed and their jaws were processed for histological evaluation using tartrate-resistant acid phosphatase (TRAP) and TdT-mediated dUTP-biotin nick end-labelling (TUNEL) staining, and measurements of the root resorption area.ResultsIn the IL-12-treated mice, tooth movement and root resorption appeared to be reduced. In TUNEL-stained sections, many apoptotic cells were recognized on the pressure side in the IL-12-treated mice.ConclusionsOur findings suggest that IL-12 inhibits not only mechanical tooth movement, but also root resorption during orthodontic tooth movement. These findings may arise through apoptosis induced by IL-12.     

Diagnostic and management difficulties in a case of multiple intracranial juvenile xanthogranuloma

Introduction

Juvenile xanthogranuloma (JXG) preferentially occurs in childhood, and its characteristics have been thought to be benign and with slow growth. JXG is classified as an inflammatory disease, which forms multiple lesions in the patients’ head, neck, and other organs and typically skin. JXG is rare, and few case reports have been published in the past, particularly with multiple intracranial lesions, which as in our case, is an extremely rare finding.

Case

Patient is a 4-year-old boy who presented with polydypsia and polyuria for 1 year. He had been followed up only under l-deamino-8-d-arginine vasopressin until he started vomiting and his level of consciousness deteriorated. Then, magnetic resonance imaging (MRI) revealed multiple intracranial lesions. He underwent biopsy via small craniotomy, and pathology was confirmed as juvenile xanthogranuloma. The patient received chemotherapy, in complete compliance with JLSG-02 protocol.

Findings

JXG is characteristic with homogenous enhancement with contrast matter and, most importantly, high intensity on diffusion-weighted image (DWI). The DWI was high when the degree of diffusion of water is restricted, as seen in inflammation and, additionally, the change of intensity after administration of steroid would reflect its anti-inflammatory nature. However, though the steroid therapy made high-intensity lesions decrease signal intensity, the size and the number of lesions did not change at all. As we expected, after we stopped steroid administration to the patient, his consciousness deteriorated and we found again the very-high-intensity lesions. We consider the intensity on DWI to reflect progression of the lesions.     

The efficacy of continuous subcostal transversus abdominis plane block for analgesia after living liver donation: a retrospective study

Purpose

Postoperative pain management for living liver donors has become a major concern as a result of the increasing number of living liver donations. Transversus abdominis plane (TAP) block has been known to provide effective analgesia for abdominal surgery. The aim of this study was to evaluate the efficacy of ultrasound-guided continuous subcostal TAP block as a part of a multimodal analgesic regimen in comparison with conventional intravenous (IV) fentanyl-based analgesia in living liver donors.

Methods

Thirty-two donors were retrospectively classified into either the continuous subcostal TAP block group (TAP group) or the IV fentanyl-based analgesia group (control group). TAP group donors received bilateral continuous subcostal TAP infusion of 0.125 % levobupivacaine at 6 ml/h. Control group donors did not receive any neural blockade.

Results

Cumulative fentanyl consumption was significantly lower in the TAP group for 48 h (P < 0.01) as compared to the control group. Further, the donors in the TAP group had significantly lower incidence of nausea and vomiting during 24–48 h postoperatively (P < 0.01) and fewer delays in the initiation of oral intake than those in the control group (P = 0.02).

Conclusions

In conclusion, continuous subcostal TAP block provided an effective opioid-sparing analgesia for living liver donors.

     

Distribution and significance of the oesophageal and gastric cardiac mucosae: a study of 131 operation specimens

AIMS: To clarify the distribution and significance of the oesophageal and gastric cardiac mucosae at the oesophago-gastric junction (EGJ). METHODS AND RESULTS: Oesophagectomy specimens from 131 consecutive patients with middle and upper thoracic oesophageal cancer were examined. The surgically resected specimens including the EGJ were cut into 5 mm thick serial sections and examined histopathologically for the length of the oesophageal and gastric cardiac mucosae and the incidence of columnar epithelial islands (CEIs). We also determined the presence of short-segment Barrett's oesophagus (SSBE) and goblet cell metaplasia in SSBE. Oesophageal cardiac mucosa was found in 125 cases (95%) and gastric cardiac mucosa was found in all cases. The mean length of the oesophageal and gastric cardiac mucosa was 4 mm (range 1-26 mm) and 13 mm (range 2-64 mm), respectively. CEIs were found in 75 cases (57%). SSBE was found in 70 cases (53%), among which goblet cell metaplasia was found in 28 cases (21%). No long-segment Barrett's oesophagus was found. The mean length of oesophageal cardiac mucosa (6 mm) and gastric cardiac mucosa (17 mm) in SSBE was significantly greater than that (3 mm and 8 mm, respectively) in non-SSBE cases (P < 0.0001 and P < 0.0001). The incidence (69%) of CEIs in SSBE was significantly higher than that (44%) in non-SSBE cases (P = 0.005). CONCLUSIONS: Oesophageal and gastric cardiac mucosae were found frequently. Oesophageal cardiac glands and CEIs might play an important role in the development of SSBE.     

ASO Visual Abstract: A Prospective Multicenter Interventional Study of Surgical Resection for Liver Metastasis from Gastric Cancer: R0 Resection Rate and Operative Morbidity and Mortality

Annals of Surgical Oncology -     

ASO Visual Abstract: Preoperative FDG Positive Lymph Nodes Predict the Postoperative Prognosis in Resectable Biliary Tract Cancers

Annals of Surgical Oncology -     

PLXND1/SEMA3E Promotes Epithelial–Mesenchymal Transition Partly via the PI3K/AKT-Signaling Pathway and Induces Heterogenity in Colorectal Cancer

Annals of Surgical Oncology - Colorectal cancer (CRC) is a major cause of cancer-related deaths. Metastasis is enhanced through epithelial-mesenchymal transition (EMT), a process primarily induced...     

Etidronate inhibits human osteoblast apoptosis by inhibition of pro-apoptotic factor(s) produced by activated T cells

Humoral factors produced by activated T cells are thought to be important in the development of bone loss in patients with rheumatoid arthritis (RA). We investigated the inhibitory effect of etidronate disodium (EHDP) on apoptosis of human osteoblasts induced by supernatants from in vitro activated T cell cultures. Human osteoblastic cell line MG63 cells and human primary osteoblast-like cells were used in the present study as human osteoblasts. T cells were incubated with interleukin-2 and further activated with 1 2-o-tetradecanoyl-phorbol 13-acetate and ionomycin, either in the presence or absence of EHDP. After we carried out the cultivation, we examined the cytotoxicity of cultured T cell supernatants toward MG63 cells and human primary osteoblast-like cells. Supernatants from activated but not resting T cell cultures efficiently induced apoptosis of MG63 cells and primary osteoblast-like cells. Supernatants from activated T cell cultures, incubated with EHDP, exhibited significantly less cytotoxicity than did supernatants incubated in the absence of EHDP. In contrast, the cytotoxicity of activated T cell culture supernatants was not affected by direct treatment of human osteoblasts with EHDP. The concentration of soluble Fas ligand in activated T cell culture supernatants was actually increased by EHDP. However, EHDP did not influence soluble Fas and tumor necrosis factor-alpha concentrations in the supernatant. Furthermore, treatment of human osteoblasts with EHDP did not alter their expression of Bcl-2/Bcl-xL or their sensitivity to anti-Fas immunoglobulin M-induced apoptosis. Our results suggest that EHDP inhibits the production of soluble factor that induces apoptosis of human osteoblasts and thus exhibits a protective action toward human osteoblast apoptosis induced by activated T cell culture supernatants. Although the exact EHDP-regulated molecule that induces apoptosis of human osteoblasts is unknown at present, our study may explain part of the therapeutic action of bisphosphonates in RA complicated by bone loss.