MUC4 expression increases progressively in pancreatic intraepithelial neoplasia

Pancreatic adenocarcinoma is believed to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs) that undergo a series of architectural, cytologic, and genetic changes, a progression model similar to the adenoma-carcinoma sequence in the colon. The apomucin MUC4 has been implicated in invasive pancreatic adenocarcinoma. MUC4 expression is not detectable at the RNA level in normal pancreas but is detectable at high levels in invasive pancreatic adenocarcinoma. We documented the pattern of expression of MUC4 in PanINs by studying a series of 71 PanIN lesions immunohistochemically using a new monoclonal antibody to MUC4. Five (17%) of 30 PanIN-1 lesions, 10 (36%) of 28 PanIN-2 lesions, 11 (85%) of 13 PanIN-3 lesions, and 25 (89%) of 28 invasive adenocarcinomas labeled with the MUC4 antibody used in the study. In addition, afew nonneoplastic lesions labeled with the MUC4 antibody, including reactive ducts in chronic pancreatitis, atrophic ducts filled with inspissated secretions, and ducts showing squamous metaplasia. Our data help establish the patterns of MUC4 expression in neoplastic precursors in the pancreas and add further support to the progression model for pancreatic adenocarcinoma.     

Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.     

Basaloid squamous cell carcinoma - larynx

Basaloid squamous cell carcinoma is a rare variant of squamous cell carcinoma, Larynx has been an uncommon site of this tumour which is said to have aggressive biological behaviour with high incidence of cervical and distant metastasis along with second primary. Two cases of laryngeal basaloid squamous cell carcinoma are reported with relevant review of literature. The submucosal spread of tumour is highlighted alongwith role of preoperative radio therapy.     

Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial

Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m², achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold of 3 μM for the “therapeutic window” of 120 min after dosing, but the presence of residual prodrug after the first administration of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible at 18 ± 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place, but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly by at least 50% at between 10 and 60 min with a half-life of 36 ± 14 min. Analysis of the plasma extracts by LC/MS indicated that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites. Received: 21 July 1996 / Accepted: 20 January 1997     

Tracheoesophageal fistula: New option in management

Tracheoesophageal fistula is a life threatening condition. Patients not managed surgically ultimately die of their disease. Surgical management is the treatment of choice. We present a case of a patient that developed a tracheoesophageal fistula after tracheostomy. Surgical repair was done which failed due to infection. The patient was managed with the help of an esophageal stent and Trichloroacetic Acid cautery. This approach can be used in selected patients, depending upon the size and site of TEE Larger fistulae and those situated lower down e.g. supra carinal cannot be managed by this technique.     

Acute,sub-acute and general pharmacological evaluation of 5-(3,4-methylenedioxyphenyl)-4-ethyl-2E,4E-pentadienoic acid piperidide (SK-20): A novel drug bioavailability enhancer

An efflux pump inhibitor, SK-20 (5-(3,4-methylenedioxyphenyle)-4 ethyl-2E,4E-pentadienoic acid piperidide), was assessed for its toxicity at three different pharmacological profiles: acute, sub-acute and general pharmacology with pharmacokinetics. In acute study, the SK-20 was found safe up to a dose of 2000 mg/kg (b.wt.); and at sub-acute, dosages of 50 and 100 mg/kg (b.wt.) were found to be safe. However, dosages of 200 mg or above per kg (b.wt.) showed some morphological alterations in cellular architecture of both liver and kidneys in both sexes, viz., mild vascular congestion along with sporadic hemorrhages and infiltration into renal and hepatic parenchyma by mononucleate cell. General pharmacological studies did not result into any alterations in analgesic, convulsions, rectal temperatures and in the rhythm or the rate of the intestinal motility or the secretion of the bile. While the respiratory and the cardiac rate remained normal, the only parameter to show was the blood pressure, which at all the doses tested, showed a tendency toward reduction. Characteristically, the SK-20 at all doses influenced pentobarbital-induced hypnosis positively and negatively to spontaneous motor activity in a dose dependent manner. Pharmacokinetics of SK-20 revealed it to have retention time at 10.2 min and half life 2.47 h.