[show abstract][hide abstract] ABSTRACT: Solitary gallbladder metastasis of malignant melanoma is rare and generally originates from skin melanoma. We report a case of gallbladder metastasis from a malignant melanoma of the nasal mucosa that was surgically treated.
A 77-year-old Japanese woman diagnosed with malignant melanoma of the left sinonasal cavity three years ago underwent follow-up PET-CT and FDG uptake was detected only at the gallbladder. The nasal melanoma had been stable for the last 1.5 years after chemoradiation and her general condition was good. Cholecystectomy was performed with partial liver resection. Lymphadenectomy of the hepatoduodenal ligament was also performed. The tumor was soft and whitish, and was microscopically diagnosed as a poorly differentiated malignant melanoma that was not similar to the nasal cavity melanoma. No further metastasis is observed for more than 13 months after surgery.
In the literature, cutaneous melanoma is described as the origin of most metastatic gallbladder melanomas; however, no skin lesion was evident in this case. We believe that the poorly differentiated compartment of the nasal melanoma had metastasized to the gallbladder.
For patients with melanomas and gallbladder tumors, the possibility that metastasis could occur should be considered when selecting optimal treatment. Even when original melanoma is present, surgical treatment for gallbladder metastasis may be useful depending on the patient's conditions.
International journal of surgery case reports. 08/2013; 4(11):965-968.
[show abstract][hide abstract] ABSTRACT: Skeletal muscle metastases from carcinomas, especially to intercostal muscles, are rare. Most metastatic chest wall tumors from hepatocellular carcinoma (HCC) result from disseminations through needle tracts of intrahepatic HCC treatments.
We report the case of a 65-year-old man with chronic viral hepatitis B whose intrahepatic lesions were stabilized by repeated radiofrequency ablations and transcatheter arterial chemoembolization. Follow-up computed tomography demonstrated a well-enhanced mass in the right chest wall. Because α-fetoprotein and des-γ-carboxy prothrombin levels were elevated and no other tumors were detected, we diagnosed the mass as an extrahepatic metastasis from the HCC and resected it along with the surrounding ribs. There was no involvement of the bone, pleura, and lung.
The tumor was microscopically diagnosed as an intercostal muscle tumor metastasized from HCC, which has not been documented previously. The resection rate of extrahepatic tumors of HCC is low in literature. No other apparent extrahepatic recurrence has been observed for more than 20 months after the surgery.
We report the case of HCC patient who underwent surgical resection of an intercostal muscle tumor that had metastasized from HCC. Pathological examination of the tumor revealed the tumor cells in the blood vessels, and we speculate it hematogeneous metastasis.
International journal of surgery case reports. 04/2012; 3(7):322-6.
[show abstract][hide abstract] ABSTRACT: We report a patient with unresectable remnant gastric cancer with common bile duct stricture, whose quality of life(QOL) was improved by switching to cholecystojejunostomy from percutaneous transhepatic gallbladder drainage(PTGBD). He was a 69-year-old man who underwent distal gastrectomy(Billroth I reconstruction)3 years previously, and he vomited many times due to cancer at the anastomosis. It could not be resected because of its involvement with the hepatoduodenal ligament, and therefore, gastrojejunostomy was performed. Four days later, abdominal pain occurred and gallbladder swelling was observed, resulting from common bile duct obstruction. PTGBD relieved the pain, and four courses of S-1/cisplatin (CDDP)treatment were performed. The bile duct stenosis was still so severe that the chemotherapy regimen was changed to weekly paclitaxel(PTX). The bile amount of PTGBD decreased after its four courses and the tube, which was a great burden for the patient, was removed. Because abdominal pain recurred in 2 weeks, the tube needed to be reinserted. An endoscopic stent was not inserted successfully. We performed cholecystojejunostomy and he was finally free from the PTGBD tube. The spread of cancer to the cystic duct was controlled by continuing the PTX for more than 20 courses. Thus, this case highlights PTX's contribution toward improving the patient's QOL.
Gan to kagaku ryoho. Cancer & chemotherapy 01/2012; 39(1):123-6.
[show abstract][hide abstract] ABSTRACT: We experienced 3 cases of anti-cancer drug-resistant recurrent breast cancer with liver metastasis showing significant improvement by S-1. Almost all patients maintained the full dose through the whole course of treatment, and the drug showed good tolerability. Furthermore, long-term therapeutic efficacy(more than 2 years)and QOL have been maintained for all patients. We concluded that S-1 is not only effective as a therapeutic agent, but is safe and maintains QOL.
Gan to kagaku ryoho. Cancer & chemotherapy 09/2011; 38(9):1495-8.
[show abstract][hide abstract] ABSTRACT: We report a resected case of ascending colon cancer with left supraclavicular and paraaortic lymph nodes and liver metastases which completely responded in terms of metastases but not the primary tumor to FOLFOX4 therapy. A 62-year-old woman with epigastric discomfort was initially diagnosed as malignant lymphoma by FDG-PET with abnormal accumulation at left supraclavicular and paraaortic lesions. Pathological examination of the supraclavicular lymph nodes showed undifferentiated adenocarcinoma, and ascending colon cancer was detected by colonoscopy which was a mixture of various types of differentiation. FOLFOX4 therapy was effective for metastatic lesions but colon tumor did not regress and was accompanied by abdominal pain. Macroscopically, a curative right hemicolectomy was performed, and microscopic examination revealed that the tumor had become a mass of undifferentiated cancer cells. Thus, the present case demonstrates the dedifferentiation of colon cancer during chemotherapy.
Gan to kagaku ryoho. Cancer & chemotherapy 02/2010; 37(2):323-6.
[show abstract][hide abstract] ABSTRACT: We report 3 cases of gastric carcinoids with hypergastrinemia. Case 1: A 60-year-old man had a 2 cm carcinoid of the stomach and underwent partial resection. Involvement of the muscularis propria and lymph nodes metastasis were observed microscopically. Follow-up gastroscopy revealed another carcinoid lesion and total gastrectomy was performed. Case 2: A 67-year-old woman with multiple carcinoids of the entire stomach underwent antrectomy. No growth of residual tumors has been detected so far. Case 3: A 61-year-old man had a tumor near the esophagogastric junction and underwent total gastrectomy. Carcinoid component was diffusely intermingled with adenocarcinoma in the tumor and invaded into the subserosa. In all 3 cases, the serum gastrin level was high and atrophic gastritis was microscopically observed. Carcinoid tumor in Case 3 was different from those in Cases 1 and 2 and interestingly, gastric carcinoid with hypergastrinemia showed various types of appearance.
[show abstract][hide abstract] ABSTRACT: Adenovirus (Ad) vectors are widely used for gene transfer. Efficient gene transfer into malignant cells is an important requirement for anticancer gene therapy, but transgene expression after transfer with adenoviral vectors varies among different cancer cell lines. Recently, Ad vectors containing chimeric type 5 and 35 fiber proteins have been developed. We evaluated the expression of coxsackie and adenovirus receptor (CAR), as well as integrins alphaV, beta3 and beta5, in seven human pancreatic cancer cell lines and assessed the relationship between expression of these molecules and Ad transfection efficiency. We compared the transfection efficiency of a conventional type 5 Ad vector (Ad5GFP) with that of an Ad vector containing chimeric type 5 and 35 fiber proteins (Ad5/35GFP), which expressed green fluorescent protein (GFP) driven by the cytomegalovirus promoter. There was strong CAR expression by AsPC-1, CFPAC-1 and PANC-1 cells, whereas the other cell lines showed weak expression. There was strong integrin beta3 expression by MIAPaCa-2, PANC-1 and Suit-2 cells, but expression by AsPC-1, BxPC-3, CFPAC-1 and HPAC cells was weak. Transfection efficiency of the vectors for human pancreatic cancer cell lines was not directly related to the CAR or integrin expression. However, transfection by Ad5/35GFP was significantly greater than by Ad5GFP at MOIs of 10 and 25 in all five human pancreatic cell lines. In conclusion, the Ad5/35GFP vector mediates more efficient gene transfer to human pancreatic cancer cells. These results may have implications for improving the efficiency of Ad-mediated gene transfer and developing adenoviral vectors.
International Journal of Oncology 01/2009; 33(6):1141-7. · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: To develop a novel therapeutic strategy for human pancreatic cancer using a midkine promoter-based conditionally replicating adenovirus.
We examined midkine mRNA expression and midkine protein expression by seven human pancreatic cancer cell lines (AsPC-1, BxPC-3, CFPAC-1, HPAC, MIAPaCa-2, PANC-1, and Suit-2), as well as by non-cancerous pancreatic tissue and pancreatic cancers. Midkine promoter activity was measured in cancer cell lines by the dual luciferase reporter assay. Adenoviral transduction efficiency was assessed by fluorescent staining of cancer cell lines using adenovirus type 5 containing the green fluorescent protein gene (Ad5GFP). Replication of adenovirus type 5 containing the 0.6 kb midkne promoter (Ad5MK) was assessed by the detection of E1 protein in cancer cell lines. The cytotoxicity of Ad5MK for cancer cells was evaluated from the extent of growth inhibition after viral infection. Infection and replication were also assessed in nude mice with subcutaneous Suit-2 tumors by intratumoral injection of Ad5MK, Ad5GFP, or vehicle. E1a mRNA expression in the treated tumors and expression of the replication-specific adenoviral hexon protein were evaluated. Finally, the anti-tumor activity of Ad5MK against intraperitoneal xenografts of Suit-2 pancreatic cancer cells was examined after intraperitoneal injection of the virus.
Both midkine mRNA expression and midkine protein expression were strong in AsPC-1 and CFPAC-1 cell liens, moderate in BxPC-3, HPAC, and Suit-2 cell lines, and weak in PANC-1 and MIAPaCa-2 cell lines. Expression of midkine mRNA was significantly stronger in pancreatic cancers than in non-cancerous pancreatic tissues. The relative luciferase activity mediated by the 0.6 kb midkne fragment in AsPC-1, PANC-1, and Suit-2 cell lines was approximately 6 to 20 times greater than that in midkne-negative MIAPaCa-2 cell lines. Pancreatic cancer cell lines exhibited a heterogeneous adenoviral transduction profile. E1A expression was higher in cell lines with strong midkine expression than in cell lines with weak midkine expression. Ad5MK showed much greater cytotoxicity for midkine-expressing Suit-2 and PANC-1 cell lines than for midkine-negative MIAPaCa-2 cell lines. In the Suit-2 subcutaneous xenograft model, expression of E1A was detected in Ad5MK-treated tumors, but not in untreated and Ad5GFP-treated tumors. In the Suit-2 intraperitoneal xenograft model, the Ad5MK group survived for significantly longer than the Ad5GFP, PBS, and untreated groups.
Ad5MK has an anti-tumor effect against human pancreatic cancer cell lines that express midkine mRNA. Midkine promoter-based conditionally replicative adenovirus might be a promising new gene therapy for pancreatic cancer.
Journal of Experimental & Clinical Cancer Research 02/2008; 27:30. · 3.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in a wide variety of tumor cells, while it has no toxicity for the majority of normal cells.Therefore, TRAIL may be a suitable agent for anticancer therapy. We previously reported that a number of pancreatic cancer cell lines show resistance to TRAIL-induced apoptosis via overexpression of XIAP and FLIP. The present study was conducted to further examine TRAIL-based therapeutic strategies by aiming to restore functional apoptotic pathways in resistant pancreatic cancer cells.
In various pancreatic cancer cell lines, TRAIL-induced apoptosis was evaluated in the presence or absence of an XIAP-inhibitor (Smac peptide). Second, TRAIL-induced apoptosis was evaluated in TRAIL-resistant AsPC-1 cells with or without FLIP antisense. Third, the combined effect of Smac peptide and FLIP antisense was tested, and the activation of apoptosis-related caspases and poly (ADP-ribose) polymerase was evaluated. Finally, TRAIL-induced apoptosis was evaluated in the presence or absence of FLIP antisense and an XIAP inhibitor (embelin).
Smac peptide enhanced TRAIL-induced apoptosis in a dose-dependent manner for several pancreatic cancer cell lines, but showed no effect on TRAIL-resistant AsPC-1 cells. Smac peptide alone had no influence on cell viability. TRAIL-induced apoptosis was restored in TRAIL-resistant AsPC-1 cells by exposure to FLIP antisense, which suppressed the expression of FLIP. The effect of TRAIL was augmented by the combination of FLIP antisense and Smac peptide. Similarly, TRAIL-induced apoptosis was restored by the combination of FLIP antisense and embelin. Activation of apoptotic caspases and cleavage of poly (ADP-ribose) polymerase was observed after sensitization of TRAIL-resistant pancreatic cancer cells.
Pancreatic cancer cells gain resistance to TRAIL-induced apoptosis via expression of the antiapoptotic proteins XIAP and FLIP. Smac peptide and FLIP antisense could restore the apoptotic effect of TRAIL. An XIAP inhibitor, embelin, enhanced the effect of TRAIL in the presence of FLIP antisense. These findings may provide useful information for the development of TRAIL-based therapeutic strategies by restoring functional apoptotic pathways in resistant pancreatic cancer cells. In addition, a low molecular weight XIAP inhibitor like embelin could be a lead compound for the development of effective XIAP inhibitors.
Journal of Surgical Research 11/2007; 142(2):281-6. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: The survival curve of patients who undergo surgical resection of pancreatic cancer displays a steep decline within 1 year and a relatively slow decline thereafter. The patients with a short survival time may have identifiable clinicopathologic factors that lead to rapid relapse.
We analyzed clinicopathologic factors in 133 patients who underwent margin-negative pancreatoduodenectomy with extended radical lymphadenectomy for invasive ductal carcinoma of the pancreas to detect factors that could be responsible for the short survival.
Tumor size, invasion of the anterior pancreatic capsule, retroperitoneal invasion, portal venous invasion, major arterial invasion, and metastasis to the para-aortic lymph nodes were variables associated with survival time in univariate analysis. Metastasis to the para-aortic lymph nodes was the single independent factor with a significant association with mortality in multivariate analysis. Some 84% of the patients who had positive para-aortic lymph nodes died within 1 year, versus 46% of the patients with negative nodes.
Although tumors that involve the para-aortic lymph nodes may technically be resectable, the expected postoperative survival time for most patients is less than 1 year. If para-aortic nodal metastasis is detected, alternative treatment strategies should be considered.
World Journal of Surgery 02/2007; 31(1):147-54. · 2.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the developmental stage, pancreas derives from the endodermal cells where the transcription factor, pancreatic duodenal homeobox gene-1 (pdx-1) is expressed. In adulthood, pdx-1 expression is localized to pancreatic beta cells, which is necessary for maintenance of beta cell function. Recently, ectopic expression of pdx-1 in the liver successfully induced insulin production and ameliorated hyperglycemia. Our study was designed to investigate the effects of forced expression of pdx-1 in ileal epithelia by adenovirus-mediated gene transfer.
The recombinant, replication-deficient adenovirus carrying the pdx-1 gene was constructed using the COS-TPC method. ICR mice were treated with intraperitoneal injection of 220 mg/kg streptozotocin (STZ). After determining the hyperglycemia, a loop of ileum was constructed and the adenovirus solutions (Ad-pdx-1 and Ad-lacZ 1 x 10(8) PFU/body) were injected into the lumen of the ileal loop. In this model, immunohistochemical or fluorescent analyses of PDX-1 and insulin in the adenovirus-infected ileal epithelia were carried out. Reverse transcription polymerase chain reaction of pdx-1 and other pancreatic markers were investigated. Blood glucose concentrations were measured by drawing blood from ocular veins. Immunoreactive insulin extracted from the adenovirus-infected ileum was measured.
Ad-pdx-1 induced ectopic PDX-1 expression in the ileum. The PDX-1 positive cells in the ileal epithelia were positive for insulin; mRNA of insulin-1, insulin-2 and pdx-1 were expressed in mice infected with Ad-pdx-1. Hyperglycemia was improved in STZ-treated mice infected with Ad-pdx-1. Immunoreactive insulin in the ileum extract was increased significantly in mice with Ad-pdx-1.
Gene transfer of PDX-1 in intestinal epithelia could be a promising strategy for diabetes mellitus by inducing ectopic insulin producing cells.
Surgery 09/2006; 140(2):273-80. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Invasive ductal carcinoma of the pancreas (pancreatic cancer) is mainly treated by operative resection, radio-chemotherapy, or chemotherapy. The survival rate of the patients with each treatment is not good when compared with that in other cancers. Meanwhile, it is still true that surgical resection remains the only method offering pancreatic cancer patients long-term survival or cure. The indications for surgical resection should be considered based on whether margin-free resection can be achieved in individual patients. In addition, the volume of pancreatic cancer patients treated at the institution and the surgeon's personal experience may greatly affect the decision. A recent randomized clinical trial from Japan revealed that surgical resection has a survival advantage over chemo-radiation therapy for locally advanced pancreatic cancer, which is defined as stage IVa in the fourth Japanese edition of the Classification of Pancreatic Carcinoma. Moreover, guidelines for clinical practice for pancreatic cancer by the Japan Pancreas Society have been issued very recently. In addition, the surgical indications should be reevaluated in combination with the adjuvant or neoadjuvant chemotherapy in future.
[show abstract][hide abstract] ABSTRACT: Pancreatic cancer is highly resistant to radiation and chemotherapy, and its resistance reflects the enhancement of apoptosis inhibitory genes, including Bcl-2 family. Antennapedia (pAnt) is capable of almost 100% internalization into cells through the lipid bilayer without any cytotoxic effect. The aim of this study was to examine the effects of the Bcl-XL antisense oligonucleotide for radiosensitivity of in vitro and in vivo pancreatic cancer using oligonucleotide conjugated with antennapedia.
In in vitro experiments, expression of Bcl-XL protein was examined in 5 pancreatic cancer cell lines. In AsPC-1 cells, internalization of the oligonucleotide was confirmed, and the effects of antennapedia-antisense (pAnt-AS) or antennapedia-scramble (pAnt-Scr) on Bcl-XL protein expression were examined. Cells were treated with pAnt-AS, pAnt-Scr or phosphorothioate antisense (S-AS) for 3 days, then the effects of irradiation on the cell survival, caspase-3 activity, and apoptotic index were evaluated. In AsPC-1 xenograft mice, pAnt-AS, pAnt-Scr, or S-AS was injected, and 5 or 10 Gy irradiation was added. Bcl-Xl protein expression was measured before irradiation. Apoptosis was evaluated at 48 hours after irradiation. On the 14th day after 10-Gy irradiation, tumor wet weight was measured, and tumor growth was estimated over 5 weeks.
In in vitro experiments, all pancreatic cancer cell lines expressed Bcl-XL protein. pAnt-AS was internalized into AsPC-1 cells within 2 hours. pAnt-AS at 10 mumol/L reduced more than 90% of the Bcl-XL protein in AsPC-1 cells, whereas pAnt-Scr or S-AS treatment at the same concentration reduced as much as 10% of the Bcl-XL protein. Treatment with pAnt-AS followed by irradiation significantly reduced cell viability when compared with that of pAnt-Scr or S-AS. Caspase-3 activity was significantly upregulated in the pAnt-AS-treated group (P = .033). The rate of nuclear fragmentation was significantly higher in the pAnt-AS group (P = .013). In in vivo experiments, Bcl-XL protein was reduced about 40% in the pAnt-AS-treated mice. Tumor doubling time of the pAnt-AS-treated mice was elongated by 10-Gy irradiation. The tumor wet weight of mice treated with pAnt-AS and 10-Gy irradiation was significantly reduced when compared with mice treated with pAnt-Scr and 10-Gy irradiation (P = .046). The apoptosis index at 48 hours after irradiation was significantly increased in pAnt-AS-treated mice (P < .01).
The results suggest that, when coupled with antennapedia, the antisense oligonucleotide against Bcl-XL could be a good therapeutic tool for radiosensitization of pancreatic cancer.
Surgery 08/2006; 140(2):149-60. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mammalian target of rapamycin (mTOR) is considered to be a major effector of cell growth and proliferation that controls protein synthesis through a large number of downstream targets. We investigated the expression of the phosphatidylinositol 3'-kinase (PI3K)/mTOR signaling pathway in human pancreatic cancer cells and tissues, and the in vivo antitumor effects of the mTOR inhibitor CCI-779 with/without gemcitabine in xenograft models of human pancreatic cancer. We found that the Akt, mTOR and p70 S6 kinase (S6K1) from the PI3K/mTOR signaling pathway were activated in all of the pancreatic cancer cell lines examined. When surgically resected tissue specimens of pancreatic ductal adenocarcinoma were examined, phosphorylation of Akt, mTOR and S6K1 was detected in 50, 55 and 65% of the specimens, respectively. Although CCI-779 had no additive or synergistic antiproliferative effect when combined with gemcitabine in vitro, it showed significant antitumor activity in the AsPC-1 subcutaneous xenograft model as both a single agent and in combination with gemictabine. Furthermore, in the Suit-2 peritoneal dissemination xenograft model, the combination of these 2 drugs achieved significantly better survival when compared with CCI-779 or gemcitabine alone. These results demonstrate promising activity of the mTOR inhibitor CCI-779 against human pancreatic cancer, and suggest that the inhibition of mTOR signaling can be exploited as a potentially tumor-selective therapeutic strategy.
International Journal of Cancer 06/2006; 118(9):2337-43. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Focal adhesion kinase (FAK) is a non-receptor, cytoplasmic protein tyrosine kinase that is involved in the regulation of cellular signaling, migration, apoptosis, and cell cycle progression. Previous reports have shown that FAK is expressed in various kinds of cancer tissues and cancer cell lines; however, no information is available about human pancreatic carcinoma specimens. Tissue such specimens were obtained from 50 patients who underwent pancreatic resection for pancreatic invasive ductal carcinoma at our institute from 1996 to 2002. Immunohistochemical analysis of FAK was performed in the resected specimens. Focal adhesion kinase expression in seven human pancreatic cancer cell lines was analyzed by reverse transcription polymerase chain reaction (PCR) analysis and Western blot analysis. Focal adhesion kinase expression was detected in 24 of 50 cases (48%). There was a statistically significant correlation between FAK expression and tumor size (P=0.004), although FAK expression did not significantly correlate with other factors such as tumor histological grade, lymph node metastasis, distant metastasis, histological stage, and overall survival. Reverse transcription PCR analysis and Western blot analysis showed that FAK was expressed in all seven pancreatic cancer cell lines. Focal adhesion kinase expression was not directly related to clinicopathological factors except tumor size in pancreatic carcinoma. Focal adhesion kinase expression may not be a prognostic marker for pancreatic cancer patients.
World Journal of Surgery 03/2006; 30(2):219-26. · 2.23 Impact Factor