ABSTRACT
BACKGROUND: The role of fundoplication in the prevention of esophageal adenocarcinoma is controversial. Development of cancer is associated with proliferation and anti-apoptosis, for which little data exist regarding their response to fundoplication. METHODS: Ki-67 and Bcl-2 expression was assessed in the esophagogastric junction (EGJ) and the distal and proximal esophagus of 20 patients with gastroesophageal reflux disease (GERD) treated by fundoplication and in 7 controls. Endoscopy was performed preoperatively and 6 (20 patients) and 48 months (16 patients) postoperatively. RESULTS: There were positive correlations between Ki-67 and Bcl-2 levels in the EGJ (p > 0.001) and in the distal (p = 0.001) and proximal esophagus (p = 0.013). Compared to the preoperative level, Ki-67 expression was elevated in the distal (p = 0.012) and proximal (p = 0.007) esophagus at 48 months. In addition, compared to control values, Ki-67 expression was lower at the 6-month follow-up in the EGJ (p = 0.037) and the proximal esophagus (p = 0.003), and higher at the 48-month follow-up in the distal esophagus (p = 0.002). Compared to control values, Bcl-2 was lower at 6 months in the EGJ (p = 0.038). CONCLUSIONS: Proliferative activity after fundoplication increased in the long term in the distal esophagus despite a normal fundic wrap and healing of GERD.
Subject(s)
Esophagus/pathology , Fundoplication , Gastroesophageal Reflux/pathology , Gastroesophageal Reflux/surgery , Adenocarcinoma/prevention & control , Adult , Aged , Apoptosis , Barrett Esophagus/metabolism , Barrett Esophagus/pathology , Barrett Esophagus/surgery , Biomarkers/metabolism , Cell Proliferation , Esophageal Neoplasms/prevention & control , Esophagus/metabolism , Female , Follow-Up Studies , Gastroesophageal Reflux/metabolism , Humans , Ki-67 Antigen/metabolism , Male , Middle Aged , Mucous Membrane/metabolism , Mucous Membrane/pathology , Prospective Studies , Proto-Oncogene Proteins c-bcl-2/metabolism , Time FactorsABSTRACT
Bleomycin (BLM) has been used successfully for treatment of head and neck cancer. Combining radionuclide therapy with chemotherapy is a fascinating possibility. We have studied the biokinetics of BLM labeled with indium-111 (In-111). A complex formed at low pH had an activity of 100 MBq/mg BLM. This substance was intravenously injected into 10 head and neck cancer patients in escalating doses of 75, 175, and 375 MBq. Scintigraphic data from these patients were compared with tissue samples obtained at surgery. The activity distribution and penetration into tumor tissue was not affected by increasing the injected activity. In-111-BLMC uptake was directly proportional to Ki-67/MIB-1 activity and number of mitoses in tumor tissue. Based on the biokinetics, dosimetric calculations for In-111 and In-114m have been performed. S values for realistic geometry (a phantom designed from Patient CT) have been calculated. In-114m could deliver a 4-fold absorbed radiation dose into the tumor compared with In-111. We think that In-111-BLMC could be used for radiochemotherapy in head and neck cancer or adjuvant Auger-electron therapy using In-114m combined with BLM. Further studies on cellular dosimetry should be undertaken.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Bleomycin/analogs & derivatives , Carcinoma, Squamous Cell/metabolism , Head and Neck Neoplasms/metabolism , Indium Radioisotopes/pharmacokinetics , Organometallic Compounds/pharmacokinetics , Adult , Aged , Antineoplastic Agents/therapeutic use , Bleomycin/pharmacokinetics , Bleomycin/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Cell Division/drug effects , Cell Division/radiation effects , Combined Modality Therapy , Female , Half-Life , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Humans , Indium Radioisotopes/therapeutic use , Kidney/metabolism , Male , Middle Aged , Monte Carlo Method , Organometallic Compounds/therapeutic useABSTRACT
Bleomycin (BLM) is used for the treatment of head and neck cancer. In order to improve the effectiveness of this chemotherapeutic drug, BLM was combined with indium-111. A complex of these agents (111In-BLMC), formed at low pH, was injected intravenously into ten head and neck cancer patients in escalating activities of 75, 175 and 375 MBq. The internally delivered dose to the tumours varied from 0.20 to 2.73 mGy at 75 MBq, from 0.33 to 2.51 mGy at 175 MBq, and from 0.87 to 31.3 mGy at the 375 MBq activity level. Uptake of radioactivity was 0.45+/-0.24x10(-3)% ID/g in primary tumours and 0. 52+/-0.20x10(-3)% ID/g in metastases (at 48 h). Tumour volumes varied from 0.51 to 49.0 cm3. The radioactivity half-lives in the tumours were 30+/-7 h. The activity distribution and penetration into tumour tissue were not affected by increasing the injected activity. There was a positive correlation between BLMC uptake and Ki-67/Mib activity as well as number of mitoses in tumour tissue. These data indicate that 111In-BLMC has potential as a radiochemotherapeutic agent in head and neck cancer and that adjuvant Auger-electron therapy is possible using 114mIn-labelled BLMC.