Glial cell-derived neurotrophic factor upregulates the expression and activation of matrix metalloproteinase-9 in human pancreatic cancer

BACKGROUND: We have previously reported that the glial cell-derived neurotrophic factor (GDNF) promotes pancreatic cancer cell invasion in vitro. The purpose of this study was to determine whether GDNF regulates the expression and activation of matrix metalloproteinase-9 (MMP-9) in human pancreatic cancer cells. METHODS: We used human pancreatic cancer cell line MIA PaCa-2. The effect of GDNF on mRNA and protein expression was measured by Northern blot, Western blot and enzyme-linked immunosorbent assay. MMP proteolytic activity was detected by gelatin zymography. To determine which intracellular pathways were involved, we used the following inhibitors: tyrosine kinase inhibitor Genistein, MEK-1 inhibitor PD98059 and PI3-K inhibitor Wortmannin. RESULTS: GDNF increased MMP-9 mRNA and protein expression in MIA PaCa-2 cells in a dose-dependent manner. Treatment with GDNF enhanced gelatinolytic activity of the pro and active form of MMP-9. Inhibitor experiments showed that the expression and activity of pro MMP-9 was totally inhibited by Genistein and partially by Wortmannin, whereas PD98059 had no effect. All three compounds inhibited the activity of the active form of MMP-9. CONCLUSIONS: GDNF upregulates the expression and enzymatic activity of MMP-9 through different signaling pathways in MIA PaCa-2. These findings suggest that GDNF modulates MMP-9 expression and activation, and this may promote pancreatic cancer invasion.     

Interstitial CT lymphography-guided localization of breast sentinel lymph node: preliminary results

BACKGROUND: Accurate localization of the breast sentinel lymph node (SLN) can be challenging as a minimally invasive approach to the treatment of early-stage breast cancer. We tested the potential capability of interstitial computed tomographic lymphography (CT-LG) using a conventional contrast agent (iopamidol) for SLN mapping. METHODS: In 14 female dogs, 0.5 and 1 mL of undiluted iopamidol was injected subcutaneously into the 2 skin areas overlying the mammary gland. Contiguous, 2 mm-thick multidetector helical CT images were obtained through the upper breast and axilla before, and for 60 minutes after, gentle massage at the injection site. Three-dimensional (3D) CT images were obtained from the postcontrast images showing the greatest SLN enhancement. This CT-LG with 2 mL of iopamidol was also evaluated in 5 human female volunteers. RESULTS: The direct connection of SLN and lymphatic vessels draining from the injection sites in the animal models was clearly visualized, even with 0.5 mL of iopamidol. With this dose, the SLN attenuation was maximally enhanced, with a mean of 274 Hounsfield units (HU) on the first postcontrast images. The topographic 3D images provided the comprehensive anatomy of these lymphatic pathways. Of the 28 SLNs and 184 distant nodes visualized on CT images, all of the SLNs (100%) and 161 (87.5%) of the distant nodes could be resected at premortem and/or postmortem, with a good correlation in the locations and sizes with those on the CT images. The CT-LG effectively localized 5 SLNs with averaged maximum attenuation of 223 HU in the human volunteers, without any significant adverse effects. CONCLUSION: Interstitial CT-LG using small volumes of iopamidol can sufficiently visualize breast lymphatic drainage and may have potential utility for breast SLN mapping.     

Endobronchial carcinoid tumor combined with pulmonary non-tuberculous mycobacterial infection: report of two cases

We report here two cases of endobronchial carcinoid tumor complicated with pulmonary infection with non-tuberculous mycobacteria (NTM). Case 1 was an 81-year-old woman with the left lower lobe atelectasis. Bronchoscopy showed complete obstruction of the left basal bronchus by a tumor and a sleeve lower lobectomy with mediastinal lymph node dissection was performed. Pathological examination showed typical carcinoid located in the left basal bronchus and many caseous granulomas containing mycobacteria in the lung parenchyma distal to the bronchus. Bacterial examinations of sputum and gastric juice after the operation showed a growth of Mycobacterium kansasii. Case 2 was a 50-year-old woman with the atelectasis of the left upper division. Bronchoscopy showed complete obstruction of the left upper division bronchus by a tumor and a left upper lobectomy with mediastinal lymph node dissection was performed. Pathological examination showed typical carcinoid located in the left upper division bronchus and many caseous granulomas in the lung parenchyma distal to the bronchus. The Ziehl-Neelsen stain showed many mycobacteria in these granulomas and they were identified as Mycobacterium avium by PCR analysis. Although NTM are not well recognized as possible pathogens of pulmonary infection related to bronchial obstruction by endobronchial carcinoma, our experiences rouse a caution to consider NTM as potential pathogens. We also discuss the possible mechanisms responsible for the specific relationship between carcinoid tumor and TNM.     

Sentinel lymph node detection with Tc-99m tin colloids in patients with esophagogastric cancer

BACKGROUND: The aim of this study was to determine by radioisotope use whether the sentinel lymph node concept is applicable to esophagogastric cancers. In addition, we examined radioactivities of hot nodes and compared them with the sensitivity of a gamma probe. METHODS: The subjects were 44 patients, 23 with esophageal cancer and 21 with gastric cancer. The day before surgery, patients underwent endoscopic submucosal injection of 184 MBq of Tc-99m tin colloids into sites surrounding the tumor. Radioisotope activities of lymph nodes dissected at surgery were measured with a well-typed gamma detector and each lymph node was categorized as a hot or cold node. Histopathology of the lymph nodes was examined by hematoxylin and eosin staining. Radioisotope activities and histopathological results were compared to determine whether radioisotope flow reflects lymphatic flow to regional lymph nodes. The sensitivity of a gamma probe was measured in a laboratory study and the relation between the radioisotope activities of hot nodes and the detection sensitivity of the gamma probe was examined. RESULTS: Histopathological examination revealed lymph node metastasis in 18 of the 44 patients. In 15 of these 18 patients, metastatic foci were recognized in at least one hot node. Subsequent analysis was performed on the 36 patients in whom tumor invasion was confined to the muscle layer and in whom endoscopic clippings had not been applied. Lymph node metastases were observed in 12 of these 36 patients. In these 12 patients, at least one hot node was positive for metastasis. The laboratory study revealed that the gamma probe was able to detect radioisotope activities of >/=0.02 micro Ci. Thirty-two of 63 (51%) esophageal cancer hot nodes and 16 of 86 (19%) gastric cancer hot nodes showed radioisotope activities below the detection sensitivity of the gamma probe. CONCLUSION: The sentinel lymph node concept is applicable to patients with esophageal and gastric cancers; however, further studies are necessary to identify hot nodes accurately using gamma probes.     

A case of advanced gastric cancer which became operable after chemotherapy with combination of TS-1/CDDP and in which complete disappearance of liver metastasis was histopathologically confirmed

We encountered a patient in whom TS-1/cisplatin (CDDP) combination chemotherapy was effective. The cancer became operable, and complete disappearance of liver metastasis was histopathologically confirmed. The patient was a 65-year-old man who presented with complaints of epigastric discomfort and anorexia. Based on upper GI endoscopy and abdominal CT, type 1 gastric cancer associated with liver and abdominal lymph node metastases was diagnosed. The cancer was judged to be inoperable, and chemotherapy with a combination of TS-1 and CDDP was initiated. One course of treatment consisted of administration of 120 mg/day of TS-1 for 21 days followed by 14 days of withdrawal, and administration of 100 mg/body/day of CDDP on day 8 (80 mg/body/day in the second course). After two courses of treatment, the primary lesion and the liver and lymph node metastatic lesions decreased in size (reduction ratios were 42.3%, 90.5% and 85.2%, respectively). The tumor marker values became normal. Subsequently, the cancer was judged to have become operable. After consultation with the patient, total gastrectomy, splenectomy, partial hepatectomy, and D3 dissection were performed, and curability B was achieved. The only adverse event of Grade 2 or more severity observed during drug administration was anorexia. Liver metastasis was judged from pathological findings to have disappeared. The postoperative course was uneventful and the patient was discharged from the hospital. To date, there have been no signs of recurrence. TS-1/CDDP therapy is believed to provide effective treatment against liver metastasis and lymph node metastasis of gastric cancer.     

Successful treatment of postoperative multiple hepatic recurrence with hepatic arterial infusion of cisplatin and degrable starch microspheres

A 38-year-old man had multiple recurrence of hepatocellular carcinoma (HCC) with portal vein thrombosis after hepatectomy and postoperative transcatheter arterial chemotherapy with 5-fluorouracil (5-FU). He was treated by trans hepatic arterial embolization (TAE) with 100 mg of cisplatin (CDDP) and degrable starch microspheres (DSM). After 3 courses were administered, the recurrent lesions almost disappeared on CT, and the postoperative rise in PIVKA-II level and AFP level normalized. There were no side effects except slight fever and general fatigue. We recognized a partial response, and the patient is still alive 14 months after hepatectomy. This case suggests that TAE with CDDP and DSM might be useful for prolonging the survival of advanced HCC patients.     

A case of advanced thymic cancer successfully treated with neoadjuvant intra-arterial infusion chemotherapy

We report the case of a 68-year-old man with advanced thymic cancer who was diagnosed as having squamous cell carcinoma by percutaneous needle biopsy. The CT scan showed pre-cardiac and pulmonary invasion, therefore the tumor was classified as Masaoka's stage III. Induction systemic chemotherapy consisting of CDDP (70 mg/m2, day 1), ADM (40 mg/m2, day 1) and ETP (70 mg/m2, day 1-3) was performed for the purpose of reducing the tumor size; however, the tumor's size did not shrink. Therefore, second line chemotherapy combined with selective intra-arterial infusion chemotherapy and systemic chemotherapy consisting of CDDP (70 mg/m2, day 1; intra-arterial), ADM (30 mg/m2, day 1; intra-arterial), VCR (0.5 mg/m2, day 3; systemic) and CPA (500 mg/m2, day 3; systemic) was performed. After this treatment, the tumor was reduced in size, and an extended thymectomy was subsequently performed. The histological diagnosis of the resected tumor was squamous cell carcinoma. Examination of the resected tumor revealed extensive necrosis and only a few cancer cells. These results show that intra-arterial infusion chemotherapy may be effective for local control of advanced thymic cancer.     

Two cases of recurrent breast cancer successfully treated with paclitaxel weekly therapy

The patients were a 57-year-old and a 38-year-old woman who had supraclavicular lymph node and multiple lung metastases from breast cancer. They were given 3 and 4 courses of paclitaxel (TXL) weekly therapy (80 mg/m2, day 1, 8, 15, repeated every 4 weeks). One patient had received docetaxel (TXT) and CEF therapy previously. There were no severe adverse effects except leukopenia, neutropenia and alopecia. The weekly TXL therapy brought complete remission against the supraclavicular lymph node and multiple lung metastases. The durations of the response to this weekly therapy were 15 and 5 months, respectively, and their effects have continued to the present. We believe that the weekly TXL therapy is a well-tolerated, feasible and safe administration schedule on an outpatient basis, and improves the patient's quality of life. Furthermore, we suggest the possibility of TXL being effective against both TXT and anthracycline-resistant breast cancer.