Characterization of lipophilicity and antiproliferative activity of E-2-arylmethylene-1-tetralones and their heteroanalogues.

A molecular library based on E-2-arylmethylene-1-tetralone has been designed and synthesized. A reversed phase high performance liquid chromatographic (RP-HPLC) method has been developed and applied to separate them and to characterize their lipophilicity. The chromatographic method applied here was suitable to separate the structural (ortho and para) isomers of compounds and was sensitive enough to differentiate their lipophilicities. The measured (k') and computer calculated (CLOGP) lipophilicity values has been compared. Good linear correlation has been found in the case of these structurally related molecules. In vitro biological assay has been performed with Methylene blue dying to investigate the antiproliferative potency of the compounds synthesized in this work. The measured (k') and calculated (CLOGP) lipophilicities of the compounds were compared with the antiproliferative activities and an optimum value of lipophilicity has been found for these compounds.

Antiproliferative efficacy of the somatostatin analogue TT-232 in human melanoma cells and tumours.

BACKGROUND: TT-232, a somatostatin analogue, induces apoptosis in various tumours. The aim of our study was to characterise its effect on human melanoma cells and tumours. MATERIALS AND METHODS: Proliferation of seven melanoma cell lines was tested in vitro with the methylene blue test. D10 and 205 cells were also implanted into CB17-scid mice which received 30-150-750 micrograms/kg/day of TT-232 or saline. Animals with 205 cells received twice-daily subcutaneous injections whereas animals with D10 cells were treated with osmotic mini-pumps. In addition, TT-232 metabolites were generated with tissue homogenates and tested in vitro. RESULTS: TT-232 strongly inhibited proliferation of all cell lines in vitro and tumour growth in vivo. Two out of 8 animals (30-150 micrograms/kg) in the 205 model and one out of 8(150 micrograms/kg) in the D10 model became completely tumour-free at the 11th and 9th day of treatment, respectively. TT-232 was degraded only by liver homogenate whilst its metabolite had no antiproliferative effect in vitro. CONCLUSIONS: TT-232 is a promising drug candidate for melanoma.

Influence of various administration routes on the antitumor efficacy ofTT-232, a novel somatostatin analog.

TT-232 a novel tumor-selective somatostatin analog with a five residue ring structure (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) was developed by us and published in an earlier work. This synthetic heptapeptide had no effect on growth hormone release, but had a remarkable tyrosine-kinase inhibitory effect and inducted apoptosis. The aim of this study was to compare the therapeutic efficacy of TT-232 used in various long-term administration routes and treatment schedules. The effectiveness of TT-232 was studied on different rodent tumors transplanted to inbred mice from SPF breeding. Intermittent treatment by injections and continuous infusion of TT-232 using a s.c., i.p. or i.v. implanted Alzet type osmotic minipump were compared for therapeutic efficacy. The treatments were started either on the day subsequent to tumor transplantation or after the development of a tumor. On the basis of survival and tumor growth inhibition the infusion of TT-232 for 14 days using an implantable osmotic pump proved to be a much more effective route of treatment in both s.c. and i.v. administration than the intermittent injections applied twice a day for 2 weeks. In the case of S-180 sarcoma the continuous administration of TT-232 for 14 days using s.c. implanted osmotic pump resulted in 60% the i.v. infusion produced 40% long-term (over 80 days) and tumor free survivors. By the continuous administration of TT-232, an 80-100% tumor growth inhibitory effect and a considerable retardation of tumor development could be achieved. Continuous infusion from implanted pumps ensured a constant drug level and resulted in a well-defined, consistent pattern of drug exposure over the full duration of drug administration. In our study the route of infusion has been shown to increase drug efficacy relative to conventional delivery methods.

In vivo antitumor activity of TT-232 a novel somatostatin analog.

The somatostatin analog TT-232 containing a 5 residue ring, was previously shown to inhibit the proliferation of a large number of cancer cell lines in vitro and reduce the size of tumors in animal models in vivo. Its action is accompanied by inhibition of tyrosine kinases and is characterized by the induction of programmed cell death. On the other hand, it was proved to be free of the endocrine effects of the natural compound. The aim of this study was to find the optimal dose and administration route for in vivo tumor therapy in an animal model. We have investigated the dose--and administration route-dependent antitumor activity of TT-232 on S-180 sarcoma tumor transplanted to inbred BDF1 mice from SPF breeding. Long-term administration (i.p., s.c. and i.v. injections) was started either on the day subsequent to tumor transplantation or after the development of tumor. The antineoplastic potential of TT-232 was evaluated on the basis of survival and tumor growth inhibition. In long-term administration (injections twice a day for 2 weeks) a significant, but dose- and administration route-dependent therapeutic efficacy of TT-232 was observed. The optimum dose of TT-232 15 micrograms/kg which resulted in a 30-40% cure rate and 50-70% growth inhibition in S-180 sarcoma tumor. A moderate antitumor effect was achieved by TT-232 when it was administered after the evelopment of tumor. Our study suggests that TT-232 can be a promising antitumor agent.

CT or US-guided fine needle aspiration biopsy in gastric neoplasms.

Gastric carcinoma of the linitis plastica type is occasionally difficult to diagnose endoscopically because of the large inflammatory response and the sparsity of tumor cells. Five patients who presented with signs and symptoms of gastric carcinoma underwent upper gastrointestinal endoscopy to confirm the diagnosis of carcinoma. In each case the gross appearance of the stomach was felt to represent gastric carcinoma but the biopsy and/or brushing specimens were unable to make the diagnosis. Ultrasound or CT in each of these five patients demonstrated thickening of the gastric wall and, in one instance, evidence of extensive metastatic disease. Fine needle aspiration biopsy was performed and a diagnosis of adenocarcinoma was made cytologically. Four were primary gastric adenocarcinoma of the linitis plastica type and one was metastatic adenocarcinoma from the breast. It is suggested that guided aspiration biopsy be performed when the diagnosis of gastric carcinoma cannot be confirmed endoscopically.

The varied appearances of hepatic cavernous hemangiomas with sonography, computed tomography, magnetic resonance imaging and scintigraphy.

The incidental detection of an hepatic cavernous hemangioma may create a problem in differential diagnosis. The authors here review the characteristics of hemangiomas as recorded by various types of imaging.

The accuracy of CT in the staging of carcinoma of the prostate.

Previous studies have reported the accuracy of CT in distinguishing stages of prostatic carcinoma, but they lack uniform surgical proof of histopathologic stage. We evaluated CT scans in 32 patients who underwent radical prostatectomy to assess its role in the preoperative staging of prostatic carcinoma. Two experienced radiologists blindly interpreted CT scans of the pelvis; they looked for evidence of tumor beyond the prostatic capsule and involvement of the seminal vesicles (stage C) or involvement of pelvic lymph nodes (stage D). Sixty-four interpretations in 32 patients yielded a specificity of 75% for predicting stages A or B disease (local disease), a sensitivity of 50% for the prediction of stages C or D, and an overall accuracy of staging of 67%. Interpretation errors were due to an inability to detect lymph node metastases, errors in evaluating the seminal vesicles, and errors in interpreting densities surrounding the prostate gland. Our data suggest that CT should not be used to influence decisions concerning surgical vs nonsurgical treatment in patients with clinically staged local disease and is only useful when unsuspected metastatic nodal disease is detected.

Duodenal neoplasms: role of CT.

In a retrospective study of 14 cases of duodenal neoplasms evaluated by computed tomography (CT), there were four primary adenocarcinomas of the duodenum, one lymphoma, five metastatic carcinomas, two duodenal lipomas, one villous adenoma, and one leiomyoma. The CT findings were diagnostic in patients with duodenal lipomas. In 11 cases, a primary origin of the mass was clearly identifiable in the duodenum. Thickening of the bowel wall, tumor necrosis, ulceration, and intraluminal defects were common. The relationship of the masses to adjacent structures was clearly shown on CT scans. Extraluminal extent of the lesion was noted on CT scans in seven patients; however, at surgery only four of six were found to have extramural disease. The presence of adenopathy, liver metastases, and vascular and mesenteric invasion were also demonstrated on CT scans. Twelve patients underwent upper gastrointestinal tract series. A duodenal abnormality was seen in all 12 patients, but the extramural extent and distant metastatic involvement could not be seen on these examinations. CT scans allowed the accurate staging of eight of ten malignant lesions and thus helped in the management of duodenal tumors.

CT diagnosis of dorsal pancreas agenesis.

We report a case of agenesis of dorsal pancreas diagnosed by CT. This anomaly can easily be confused with pancreas divisum on endoscopic retrograde cholangiopancreatography alone.

Further observations in the ultrasound evaluation of renal allograft rejection.

In order to determine whether sonographic parenchymal changes and volume changes are reliable predictors of acute transplant rejection, 36 recipients of renal allografts were studied. The significance of graft volume changes was evaluated, since most previous studies have not utilized routine immediate postoperative baseline scans for comparison to follow-up scans. All patients had baseline scans within 24 hours of the transplant. All 24 acute rejection patients had biopsy proof of rejection within three days of the follow-up scans. Seven clinically normal and five clinically designated acute tubular necrosis (ATN) patients were studied for comparison. A retrospective blind review utilizing three sonologists and previously described criteria combined with calculated volume changes demonstrated an overall sensitivity of 85 per cent and specificity of 94 per cent for the detection of acute rejection. The kidneys with acute rejection had an average volume increase of 73 per cent vs. 27 per cent for ATN patients and 24 per cent for normal patients, a statistically significant difference.

CT detection of skeletal muscle metastases.

The CT appearance of skeletal muscle metastases, proven by biopsy, is presented in a series of 11 patients. Primary sites of neoplasm included chest, head and neck, breast, esophagus, uterus, ovary, prostate, and lymph nodes. Computed tomographic guided biopsies were performed in seven patients and four patients underwent open biopsy. The CT findings consisted primarily of muscle enlargement with the masses containing low density and loss of normal fat and vascular planes. Invasion of adjacent bony structures

Computed tomographic studies of the painful abdomen.

Abdominal CT scans were reviewed in a series of 53 patients who had abdominal pain without objective physical, radiographic, or laboratory abnormalities. Forty patients presented with abdominal pain alone, while the remaining patients had abdominal pain associated with nausea, vomiting, or mild weight loss. Abdominal CT scans in all patients were interpreted as normal. In all but one patient, the final diagnosis was an insignificant benign condition. One patient had a pancreatic carcinoma discovered at surgery one month after the CT scan was obtained. The patients were followed up for 6 to 12 months to confirm absence of significant disease. Our analysis suggests a very low yield from abdominal CT in patients with abdominal pain and no other objective findings.

Abdominal fine needle aspiration biopsies with CT and ultrasound guidance: techniques, results and clinical implications.

Experience with fine needle aspiration biopsy (FNAB) of solid intraabdominal masses with computed tomography and ultrasound guidance in 117 patients at a large community hospital is described. An overall accuracy of 86%, sensitivity of 86%, and specificity of 93% was obtained. FNAB was found to be safe and accurate and obviated the need for surgery in nearly 50% of patients. Further experience is required to assess the value of FNAB in solid renal masses and in abdominal lymphoma.

Inflammatory pseudotumor from sclerosing cholangitis.

We report the computed tomographic (CT) findings in a case of primary sclerosing cholangitis. A "mass" demonstrated on CT and ultrasound examination in the region of the common bile duct and extending into the head of the pancreas was shown to be diffuse fibrosis and thickening of the common bile duct at surgery.

Computed tomography and ultrasound findings in Klippel-Trenaunay syndrome.

Computed tomography (CT) and ultrasound were used to evaluate two patients with Klippel-Trenaunay (K-T) syndrome. Bowel and bladder hemangiomas were demonstrated in these cases. Computed tomography demonstrated multiple low attenuation areas in the liver and spleen in one case. Computed tomography is capable of noninvasively demonstrating bowel and bladder wall hemangiomas in K-T syndrome. Both CT and ultrasound may reveal silent lesions in the upper abdominal viscera, such as liver and spleen.

A comparison of radionuclide hepatobiliary imaging and real-time ultrasound for the detection of acute cholecystitis.

The relative value of hepatobiliary scintigraphy vs. real-time ultrasound for the identification of acute cholecystitis was evaluated. No significant difference in sensitivity (97% vs. 97%) existed between the two modalities. Scintigraphy demonstrated better specificity (93% vs. 64%) and predictive value (77% vs. 40%). Although real-time ultrasound provided improved sensitivity over static gray-scale imaging for identification of gallbladder disease, hepatobiliary scintigraphy remains the procedure of choice for acute cholecystitis detection.

Pulmonary hemangiopericytoma.

The computed tomographic (CT) evaluation of a case of primary pulmonary hemangiopericytoma in a 27-year-old woman is reported. The tumor was shown by CT to arise from lung parenchyma but could not be definitely separated from the contiguous hilar structures. There was no evidence of mediastinal involvement. These features corresponded well to the surgical and pathological findings. Computed tomography may suggest the possibility of pulmonary hemangiopericytoma in the proper setting and help to define the extent and location of the lesion for the surgeon.

CT of renal and perirenal non-Hodgkin lymphoma.

The CT findings from a retrospective review of 16 patients (32 kidneys) with non-Hodgkin lymphoma involving the kidney are presented. In all cases, computed tomography (CT) accurately depicted the presence, location, and size of the renal lesions and provided information about the adjacent retroperitoneum. CT was helpful in evaluating the course of the disease and its response to therapy. The CT manifestations of renal lymphoma included: solitary nodules (four kidneys), multiple nodules (nine), focal infiltration (five), diffuse infiltration (two), engulfment of the kidney by contiguous retroperitoneal disease (three), and renal enlargement (13 kidneys). Bilateral renal involvement was noted in seven patients. All 16 patients had retroperitoneal adenopathy. The CT findings of intraparenchymal renal nodules, renal infiltration, or renal engulfment by retroperitoneal disease in association with retroperitoneal adenopathy should suggest the possible diagnosis of renal lymphoma.