Pharmacology of histamine H2 receptor antagonists in the human gastric cancer cell line HGT-1. Structure-activity relationship of isocytosine-furan and imidazole derivatives related to cimetidine

Imidazole and isocytosine-furan derivatives inhibited H2 receptor activity in HGT-1 cells, in accordance with the following relative potencies (IC50 = 2.3 microM cimetidine as reference): SKF 93479 = cimetidine = 100 greater than metiamide = 62 greater than SKF 92408 = 2 greater than SKF 91581 = 0.07). The Schild plot for cimetidine was linear (slope = 0.97) with a pA2 value of 6.72 +/- 0.12 (Ki = 0.18 microM cimetidine), suggesting competitive inhibition. Preincubation of HGT-1 cells for 10 min with H2 antagonists at 2 microM concentration resulted in 90-100% inactivation (SKF 93479 and oxmetidine) and 65% inactivation (ranitidine) which persisted for 30 min, even after a washout period. Accordingly, the kinetics of 2 microM [3H] SKF 93479 binding to HGT-1 cells revealed a half-time for association of 10 min and a dissociation half-time of 120 min. There was a good correlation between the kinetics and relative potencies of cimetidine and SKF 93479 in inhibiting H2 receptor activity in purified plasma membranes (40 nM) as well as in intact HGT-1 cells preincubated for 2 hr with SKF 93479 before histamine addition (45 nM). Chronic treatment of HGT-1 cells for 6 days with 2 microM SKF 93479 specifically blocked H2 receptor activity since cyclic AMP generation induced by other hormones and agents such as VIP, glucagon, GIP and sodium fluoride was unaltered. In contrast, short term and chronic treatment by cimetidine was readily reversible. The isocytosine-furan derivative SKF 93479 differs from the imidazole analogue cimetidine by its apparent irreversible action, due to the slow onset of association from HGT-1 cells. The isocytosine ring in SKF 93479 and oxmetidine seems to play a preponderant role in their apparent long-lasting, irreversible actions.     

Postoperative radiation therapy in the management of lung cancer

Postoperative radiation therapy for lung cancer is still controversial. In a 9-year period, 69 patients with non-oat-cell carcinoma of the lung (16% stage I, 26% stage II, and 58% stage III) received such therapy. The radiation dose was less than 5,000 cGy in 42 patients, 5,000-5,900 cGy in 16, and 6,000 cGy or more in 11; follow-up ranged from 24 to 64 months. Actuarial survival at 2 and 4 years was 50% and 16%, respectively, for squamous cell carcinoma, and 40% and 26% for adenocarcinoma. The 5-year survival for stages I, II, and III cancer was 29%, 17%, and 19%, respectively. Histologic findings and type of surgery did not affect survival, but the radiation dose apparently did. The 3-year survival for patients who received less than 6,000 cGy was 35%, compared with 73% for patients who received higher doses. In eight patients, treatment failed within the irradiated volume: all had received doses of less than 6,000 cGy, and the volume in three was judged to be inadequate.     

Attempts to define the minimal serum level of vitamin A required for normal visual function in a patient with severe fat malabsorption

A case with severe malabsorption of fat soluble vitamins is described. The malabsorption developed after an intestinal bypass operation due to morbid obesity. Night blindness occurred as the first symptom of vitamin A deficiency. The cone visual sensory threshold was elevated about one log unit and the rod threshold abot two and a half log units. No changes of the a- and b-waves of the electroretinogram (ERG) was observed. However, during the initial phase of very low serum reninol level (0.21 mumol/l) the summed amplitudes of the oscillatory potentials (OPs) were lower. After parenteral therapy with vitamin A the night blindness disappeared and the dark-adapted rod and cone threshold sensitivity recovered to normal. However, the time-course of rod adaptation first reached normal levels after 5 months. The amplitudes of the OPs of the ERG response returned to normal when the serum retinol level had increased close to normal. Serum retinol levels of 0.7 mumol/l or higher were always associated with normal or close to normal dark-adapted rod sensitivity. However, a normal serum retinol level (> 0.95 mumol/l) and a normal dark-adapted rod threshold sensitivity were not always associated with a normal time-course of the rod adaptation. It is concluded, that the maintenance dosage of vitamin A must be individualized and that patients who have undergone jejuno-ilea bypass surgery must be carefully monitored for vitamin A deficiency by both serum levels and dark adaptation measurements.     

Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a Report by the Radiation Therapy Oncology Group

Since February 1981, 300 patients with superficial measurable tumors were randomized on an RTOG protocol (81-04) involving fractionated radiation therapy (4.00 Gy twice weekly for a total of 32.00 Gy), either alone or followed immediately by hyperthermia (42.5 degrees C, 60 min). This is a report of 218 eligible patients with single lesions: 107 treated with radiotherapy alone (RT), 111 with radiotherapy plus hyperthermia (RT + HT). Only 56% of the 24 tumors less than 3 cm and 36% of the 53 lesions larger than 3 cm received what was felt to be "adequate" therapy (greater than or equal to 29 Gy and 8 heating sessions). Overall complete response (CR) was observed in 28% of the patients treated with RT, and 32% of the patients receiving RT and heat. Response has been found in previous analyses of this and other RTOG studies to be significantly related to both maximum tumor diameter (less than 3 or greater than or equal to 3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In the head and neck tumors less than 3 cm in diameter there was no difference in CR with irradiation alone or combined with hyperthermia (46% vs 43%). However, in the breast, and trunk and extremities a better CR rate was noted with irradiation and heat (55% and 67%) than with irradiation alone (33% and 0). In lesions less than 3 cm treated with irradiation and heat the probability of remaining in response was 80% compared with 15% with irradiation alone. In lesions larger than 3 cm no difference in CR was observed in either treatment group. It has been hypothesized that the response rate is higher in patients with smaller lesions (less than 3 cm) and in breast/chest wall, trunk/extremity lesions because these tumors and anatomical sites are easier to heat adequately. Problems encountered in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to accurately represent the temperature distribution in a tumor. Furthermore, differences in equipment and treatment practices among institutions add to the variability in heat administration data collected. In addition, tumor response may be difficult to judge because of short survival of some patients and occasionally rapid tumor regression that may cause necrosis which may be misinterpreted as persistent tumor.(ABSTRACT TRUNCATED AT 400 WORDS)     

CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines.

BACKGROUND AND PURPOSE: The appropriate application of 3-D CRT and IMRT for HNSCC requires a standardization of the procedures for the delineation of the target volumes. Over the past few years, two proposals--the so-called Brussels guidelines from Grégoire et al., and the so-called Rotterdam guidelines from Nowak et al.--emerged from the literature for the delineation of the neck node levels. Detailed examination of these proposals however revealed some important discrepancies. MATERIALS AND METHODS: Within this framework, the Brussels and Rotterdam groups decided to review their guidelines and derive a common set of recommendations for delineation of neck node levels. This proposal was then discussed with representatives of major cooperative groups in Europe (DAHANCA, EORTC, GORTEC) and in North America (NCIC, RTOG), which, after some additional refinements, have endorsed them. The objective of the present article is to present the consensus guidelines for the delineation of the node levels in the node-negative neck. RESULTS AND CONCLUSIONS: First a short discussion of the discrepancies between the previous Brussels and the Rotterdam guidelines is presented. The general philosophy of the consensus guidelines and the methodology used to resolve the various discrepancies are then described. The consensus proposal is then presented and representative CTVs that are consistent with these guidelines are illustrated on CT sections. Last, the limitations of the consensus guidelines are discussed and some concerns about the direct applications of these guidelines to the node-positive neck and the post-operative neck are described.     

Circulating levels of the miRNAs,miR-194, and miR-29b,as clinically useful biomarkers for colorectal cancer

Tumor Biology - The microRNAs (miRNAs), miR-194 and miR-29b, have been shown to downregulate in colorectal cancer (CRC) and may identify and classify CRC patients as compared with those in control...     

Adamantinoma of the pelvic bone, a difficult diagnosis with fatal outcome

Adamantinoma is a primary low grade malignant bone tumor that is predominantly located in the mid-portion of the tibia. The tumor is of interest for two reasons: first, there still exists considerable dispute as to the origin of the lesion and recent reports reveal that the condition is more malignant than had previously been supposed. Although cases of adamantinoma located to the axial skeleton have been reported, this is the first case of adamantinoma located to pelvic bone in Iran. Here we present the clinical, radiological & histopathological features of a 19 year-old male with painful lesion located to the right pelvic bone which was morphologically and immunohistochemically diagnosed as adamantinoma. In general, metastasis is seen in 15%–20% of patients. The spread can occur to regional nodes, lung and infrequently to skeleton, liver and brain. Several weeks after surgery, our patient’s condition gradually worsened. A CT-scan of abdomen revealed widespread liver metastasis and the patient died due to acute liver failure. This case demonstrates that the mortality rate from adamantinoma is not always low.