Hedgehog signaling pathway is a potential therapeutic target for gallbladder cancer.

Gallbladder cancer (GBC) is a particularly deadly type of cancer with a 5-year survival rate of only 10%. New effective therapeutic strategies are greatly needed. Recently, we have shown that Hedgehog (Hh) signaling is reactivated in various types of cancer and is a potential therapeutic target. However, little is known about the biological significance of Hh signaling in human GBC. In this study, we determined whether Hh signaling could be a therapeutic target in GBC. The Hh transcription factor Gli1 was detected in the nucleus of GBC cells but not in the nucleus of normal gallbladder cells. The expression levels of Sonic Hh (Shh) and Smoothened (Smo) in human GBC specimens (n = 37) were higher than those in normal gallbladder tissue. The addition of exogenous Shh ligand augmented the anchor-dependent and anchor-independent proliferation and invasiveness of GBC cells in vitro. In contrast, inhibiting the effector Smo decreased the anchor-dependent and anchor-independent proliferation. Furthermore, the suppression of Smo decreased GBC cell invasiveness through the inhibition of MMP-2 and MMP-9 expression and inhibited the epithelial-mesenchymal transition. In a xenograft model, tumor volume in Smo siRNA-transfected GBC cells was significantly lower than in control tumors. These results suggest that Hh signaling is elevated in GBC and may be involved in the acquisition of malignant phenotypes, and that Hh signaling may be a potential therapeutic target for GBC.

[Chemotherapy for non-small cell lung cancer: split-dose administration of Cisplatin over four consecutive days and Vinorelbine ditartrate].

PURPOSE: At present, combination chemotherapy with Cisplatin (CDDP) and Vinorelbine ditartrate (VNR) is one of the standard regimens for non-small cell lung cancer (NSLC). To avoid renal damage by CDDP, hydration and diuretic are indicated. But elderly/postoperative patients who have reduced lung vessel capacity are a high-risk group for pulmonary edema/right heart failure by hydration. In our hospital, CDDP is administered on four consecutive days without large hydration. MATERIAL & METHODS: CDDP: 80 mg/m2 (over four consecutive days)without large hydration+VNR: 20 mg/m2 was administered 30 NSLC patients(Stage III A & IV). Serum concentration of CDDP was monitored. RESULT: Response rate was CR: 0 case; PR: 9 cases; SD: 16 cases; PD: 5 cases. Mean survival time (MST) was 292 days. The efficacy and prognosis are equivalent to a conventional CDDP+VNR regimen. On the other hand, side effects were reduced; neutrocytopenia (> Grade 3): 17%, renal dysfunction (>Grade 1): 17%. Mean serum concentrations of CDDP were accumulated day by day, 0.91 microg/mL(Day 1), 2.44 microg/mL(Day 4), but were all under the toxic threshold(8 microg/mL). CONCLUSION: Our regimen (CDDP given over four consecutive days without large hydration) may become a regimen for the high-risk patient.

Presacral myelolipoma as a possible parasymptom of cancer: A case report.

Presacral myelolipomas are rare, benign, asymptomatic tumors composed of mature adipose tissue and hematopoietic elements. Presacral myelolipomas can occur in patients with a medical history of malignancy, steroid use, and/or endocrine disorders including diabetes mellitus. A 65-year-old man with no specific medical history experienced temporal abdominal pain without bowel symptoms that lasted a few hours. By the time he visited a hospital, the pain had diminished. Computed tomography failed to detect any abnormality in the abdominal or pelvic organs that would have caused the abdominal pain but revealed a lesion 4 cm in diameter in the frontal sacrum. Magnetic resonance imaging showed that the lesion contained fat elements with a high signal intensity on T1- and T2-weighted images, which was decreased on fat-suppression T2-weighted images. Computed tomography-guided biopsy and imaging allowed a diagnosis of presacral myelolipoma. After 3 months, hematochezia was observed, and follow-up examination revealed rectal carcinoma with multiple lung metastases. He died due to spread of the cancer despite chemotherapy, 6 months after the cancer was found. Considering the possible association between presacral myelolipoma and cancer, presacral myelolipoma might be a cancer parasymptom. Checking for possible malignancy may therefore be warranted in patients with presacral myelolipoma, especially in those without diabetes mellitus.

NOTCH4 is a potential therapeutic target for triple-negative breast cancer.

BACKGROUND/AIM: The prognosis for triple-negative breast cancer (TNBC) is poor. In the present study, we evaluated whether NOTCH4 receptor is a potential new therapeutic target for TNBC. MATERIALS AND METHODS: In vitro proliferation and invasiveness were evaluated in TNBC cells with or without small-interfering RNA (siRNA) for NOTCH4, and with or without NOTCH4 plasmid transfection. In vivo, MDA-MB-231 cells with or without NOTCH4 siRNA were subcutaneously implanted into the flank regions of mice. The frequency of nuclear translocation of NOTCH4 was assessed by immunohistochemistry in 21 TNBC samples and 46 non-TNBC samples. RESULTS: NOTCH4 inhibition in TNBC cells reduced proliferation and invasiveness, and NOTCH4 overexpression in TNBC cells increased proliferation and invasiveness. NOTCH4 inhibition reduced tumour volume and tumourigenicity of mouse xenografts. TNBC cells had a higher frequency of nuclear translocation of NOTCH4 than other cells. CONCLUSION: NOTCH4 is a new potential therapeutic target for triple-negative breast cancer.

Combinatorial cytotoxicity of gemcitabine and cytokine-activated killer cells in hepatocellular carcinoma via the NKG2D-MICA/B system.

AIM: Natural-killer group 2, member D (NKG2D) is an activating receptor on natural killer cells and activated T-cells, designated cytokine-activated killer (CAK) cells here. The MHC class I chain-related A and B (MICA and MICB, respectively) are ligands of NKG2D and are expressed on various human tumor cells, including hepatocellular carcinoma (HCC) cells. Here, we investigate whether gemcitabine, a chemotherapeutic agent, affects MICA/B expression in HCC. MATERIALS AND METHODS: We used ELISA, RT-PCR and adherent target detachment assays to determine expression of MICA/B in HepG2 HCC cells and the level of cellular cytotoxicity generated by treatment with gemcitabine and/or CAK cells. RESULTS: Surface expression of MICA/B was evident after gemcitabine treatment, and MICB-specific mRNA was up-regulated. Pre-treatment with gemcitabine and subsequent exposure to CAK cells induced greater cytotoxicity than either treatment alone. Inclusion of soluble MICB significantly reduced cytotoxicity. CONCLUSION: Gemcitabine induced MICA/B expression in HepG2 cells, resulting in synergistic enhancement of the cytotoxic effects of NKG2D-high CAK cells. The combination of gemcitabine and CAK cells may have clinical therapeutic significance for HCC.