High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: clinical and biological effects

Pure geometric isomers of conjugated linoleic acid were prepared from castor oil as the primary starting material. Methyl octadeca-9Z,11E-dienoate (2) and methyl octadeca-9Z,11Z-dienoate (4) were obtained by zinc reduction of methyl santalbate (1, methyl octadec-11E-en-9-ynoate) and methyl octadec-11Z-en-9-ynoate (3), respectively, as the key intermediates. Methyl octadeca-9E,11E-dienoate (8) and methyl octadeca-9E,11Z-dienoate (9) were prepared by demesylation of the mesyloxy derivative of methyl ricinelaidate (6, methyl 12-hydroxy-octadec-9E-enoate). A study of the nuclear magnetic resonance spectral properties was carried-out, and the shifts of the olefinic carbon atoms of 18:2(9Z,11E) (2) and 18:2(9E,11Z) (9) were readily identified by a combination of incredible natural abundance double quantum transfer experiment, heteronuclear multiple bond correlation, and 1H-13C correlation spectroscopy correlation techniques. Doubts remain in the absolute identification of the individual olefinic carbon atoms of the 18:2(9Z,11Z) (4) and 18:2(9E,11E) (8), except the fact that the shifts of the "inner" (C-10 and C-11) and "outer" (C-9 and C-12) positioned olefinic carbon atoms of the conjugated diene system are distinguishable.     

Endoscopic palliative treatment of tumors of the gastrointestinal tract

Patients with nonresectable gastrointestinal tumors have a life expectancy of a few months only. Effective palliative treatment has to ensure a good quality of life with minimal morbidity and mortality. Esophageal carcinoma: Endoscopic intubation or stent implantation guarantee a prompt improvement of dysphagia with minimal morbidity and mortality in esophageal carcinoma. Only in cervical or noncircumferential stenosis laser therapy is preferable. Obstructive jaundice: Metal stents offer the best quality of life after palliative treatment of malignant obstructive jaundice. However, in patients with bad general conditions and a short life expectancy a pigtail catheter is less expensive. Colorectal cancer: Laser therapy and cryosurgery offer uncomplicated nonsurgical therapy in rectal carcinoma. Stents in the colorectum have a high complication rate. Endoscopic palliative treatment of gastrointestinal tumors can be performed with minimal morbidity and mortality. However, it is essential that a surgeon is involved in the decisionmaking between endoscopic or operative treatment.     

Quality of life in patients with endocrine tumors of the gastrointestinal tract: patient and staff perceptions

Myo-inositol (mI) as a precursor in the phosphatidylinositol second messenger system has been reported to be reduced in depression. By means of proton-magnetic resonance spectroscopy (1H-MRS) the mI levels in the frontal brain were investigated in vivo in the present study. Twenty-two patients (mean age: 42.8 +/- 10.7 years) with depressive episodes according to ICD 10 (HAMD score > 17) were compared to 22 healthy subjects (28.0 +/- 5.3 years). Two voxels (30 x 20 x 20 mm3) in the frontal lobes were examined in a Siemens Magnetom SP 4000 at 1.5 T (STEAM sequence: TR = 3500 ms, TE = 55 ms). With the total creatine (Cr) as an internal standard, mI/Cr ratios were calculated to follow the mI levels. In the left frontal lobe, mI/Cr was 0.43 +/- 0.06 in depressive patients and 0.46 +/- 0.07 in healthy subjects; concerning the right frontal lobe, mI/Cr was 0.46 +/- 0.08 and 0.48 +/- 0.06, respectively. There were neither significant differences between the two groups nor between the hemispheres. Since there was a significant positive correlation (R = 0.6) between the age and the mI/Cr in the right frontal lobe of depressed patients, age matched pairs analysis was performed (n = 2 x 10, in each group: nine females, one male, < 40 years). In the right frontal lobe, the patients' mI/Cr of 0.40 +/- 0.05 was now significantly lower than the controls' mI/Cr of 0.45 +/- 0.06. However, most of the patients were on antidepressive medication. Interestingly, it was exactly this group of patients which showed significantly lower mI levels. We regard our investigation as a pilot study which suggests an influence of age and antidepressants on mI levels and should be taken into consideration in further investigations in depressive patients.     

Intraoperative radiotherapy in gastrointestinal tumors

Intraoperative radiotherapy has proved its worth for curative and palliative treatment of gastrointestinal tumors. IORT indications comprise cancer of the stomach, of the pancreas and colorectal carcinomas. Most authors are cautious to apply it to carcinoma of the esophagus, of the small intestine and of the hepatobiliary system. IORT is applied as adjuvant treatment alone or in combination with postoperative external-beam photon irradiation +/- chemotherapy. There is evidence of an improved local control rate. Pain can be relieved in symptomatic patients by an IORT dose of > or = 20 Gy. Until now, however, there is no evidence of a prolonged relapse-free and overall survival.     

Characterization of gastrointestinal tumors

Transabdominal ultrasonography is used increasingly for the evaluation of gastrointestinal disorders in small animals, including neoplasms such as lymphosarcoma, carcinoma, and smooth muscle tumors (leiomyoma, leiomyosarcoma). An updated summary of the clinical studies currently investigating the use of ultrasonography to detect and to characterize gastrointestinal neoplasia is presented in this article.     

Telomerase activity in gastrointestinal stromal tumors

BACKGROUND: Telomerase activity has been observed in 80-90% of carcinomas derived from various organs. However, to the authors' knowledge this report is the first assessment of telomerase activity in gastrointestinal stromal tumors (GISTs). METHODS: Telomerase activity was analyzed by the telomerase repeat amplification protocol assay in 29 tumors from 26 patients (23 primary tumors from 22 patients, 1 pair of primary and metastatic tumors from 1 patient, and 4 metastatic tumors from 3 patients). Phenotypes, tumor cell proliferation, and overexpression of p53 protein were evaluated immunohistochemically. RESULTS: Seven of 24 primary tumors (29%) and 5 of 5 metastatic tumors (100%) showed telomerase activity. Telomerase activity positive (+) GISTs were significantly larger (P < 0.05) and showed a significantly higher rate of proliferation than telomerase activity negative (-) tumors (P < 0.0001). All telomerase activity (+) GISTs were classified histologically as high risk tumors. Conversely, 15 of the 17 telomerase (-) GISTs were classified histologically as low risk tumors (P < 0.0001). With regard to p53 immunoreactivity, two and seven telomerase activity (+) tumors showed diffuse and sporadic positivity, respectively, whereas only five telomerase activity (-) tumors showed only focal or sporadic positivity. Telomerase activity was correlated significantly with poor prognosis (P < 0.05) in the patients in whom the primary GISTs were evaluated (n = 23). CONCLUSIONS: Telomerase activity may be a useful marker for evaluating the malignant potential of GIST. A distinct subgroup of GISTs is a target for therapy with a telomerase inhibitor.     

Immunohistochemical localization of chromogranin A in endocrine tissues and endocrine tumors of dogs

BACKGROUND: Research on health care quality and effectiveness often relies on global health status measures, such as functional status, but little is known about the functional status of patients in the primary care setting (without limitation to specific diseases) and even less about the function of the poor or ethnic minorities. In preparation for a planned practice-based research network, we administered a functional-status survey to patients visiting an inner-city family practice center. METHODS: Over 9 weeks, 555 established patients older than 18 years, as well as adolescents accompanied by a parent or guardian, completed a survey that included the SF-36 Health Survey and questions about demographic variables and cigarette use. The survey was self-administered in the waiting area and examination room, and patients received no assistance from staff. RESULTS: Functional-status scores reported by this primary care cohort were significantly lower than those of the general population (P < .001) and comparable with those reported nationally for patients with chronic diseases (e.g., congestive heart failure, diabetes). Functional-status scores were associated with age, sex, and, most strikingly, socioeconomic status. For example, patients with a yearly income of less than $15,000 had lower mean physical function scores than those reported nationally for patients with hypertension, diabetes, depression, recent myocardial infarction, or hypertension (P < .05). Patients who currently smoked reported lower physical function (P = .004) and strikingly lower mental function (P < .001) than nonsmokers. CONCLUSIONS: Although patients completing the survey included healthy persons seeking preventive care and sick patients with acute and chronic illnesses, their overall functional status resembled that reported nationally for patients with chronic disease, perhaps reflecting the influence of poverty. Few studies have reported the association we observed between smoking and lower functional status. Further longitudinal studies in the primary care setting are necessary to fully interpret these associations and to evaluate the true impact of interventions on outcomes.     

Immunoreactivity and expression of amylin in gastroenteropancreatic endocrine tumors

Amylin was isolated from human insulinomas, but there has been only preliminary data regarding whether this peptide can also be detected in other types of gastroenteropancreatic endocrine tumors. In the present study, immunohistochemical staining of 87 gastroenteropancreatic endocrine tumors demonstrated amylin immunoreactivity in 21.8% of the neoplasmas. Thirteen of 15 insulinomas, three of 21 gastrinomas, two of 29 nonfunctioning tumors, and one of 18 carcinoids were amylin-immunoreactive. Seventeen of the 19 amylin-immunoreactive tumors were primarily located in the pancreas, but two tumors were found in the intestine. Measurements of amylin messenger RNA expression in a few tumors revealed amylin synthesis in these tumors. Amylin immunoreactivity did not correlate with invasion and metastasis. However, the rate of curative resections was significantly higher in amylin-immunoreactive tumors. These results demonstrate for the first time that amylin immunoreactivity is not restricted to insulinomas and can also occur rarely in endocrine tumors of the intestine.     

Aspiration cytology in the diagnosis of gastrointestinal tumors

Early experiences with the new endoscopic aspiration cytology method in the diagnosis of gastrointestinal malignancies are discussed. It was performed in five patients in case of gastric and cardiac cancers and in fifteen ones of colon tumours. Results are compared with those of biopsies and brush cytologies. The new method is quick, reliable and suggested to be widely used in the gastrointestinal endoscopy.     

Surgical therapy for endocrine tumors of abdominal origin

Surgery continues to be the primary treatment of endocrine neoplasia. Only occasionally are other therapies appropriate and, in those cases, usually only for palliation. In this review, we address the surgical management of endocrine tumors of the pancreas, the adrenal glands, and the gastrointestinal tract (specifically carcinoid tumors). Endocrine tumors, although rare, often present in quite dramatic fashion but are generally associated with excellent survival rates when treated with appropriate surgical resection.     

Mutation of the MENIN gene in sporadic pancreatic endocrine tumors

Pancreatic endocrine tumors occur both sporadically and as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome. MEN1 is an autosomal dominant disease characterized by parathyroid hyperplasia, pancreatic endocrine tumors, and pituitary adenomas. The MEN1 gene called MENIN maps to chromosome 11q13 and is thought to function as a tumor suppressor gene. We previously demonstrated loss of heterozygosity (LOH) at 11q13 in approximately 40% of sporadic pancreatic endocrine tumors and hypothesize that MENIN is involved in the development of these tumors. Thirty-one sporadic pancreatic endocrine tumors were analyzed for mutation of MENIN by nonradioactive single-stranded conformation polymorphism. Twelve mutations were detected in 31 sporadic pancreatic endocrine tumors (34%). Twelve of these 31 tumors previously demonstrated loss of heterozygosity at 11q13. Of the tumors with LOH, seven contained mutations of the MENIN gene (58%). The majority of the MENIN mutations occurred within exon 2. Two independent mutations in MENIN were detected in a gastrinoma that also revealed LOH, leading to the possibility of another tumor suppressor gene locus at 11q13. Mutations were present in both benign and malignant pancreatic endocrine tumors, suggesting that a MENIN gene mutation is a frequent and early event in the tumorigenesis. The high incidence of truncating mutations in tumors with LOH at 11q13 support the hypothesis that MENIN is a tumor suppressor gene.     

Effectiveness of slow-release lanreotide, a long-acting somatostatin analogue, in the treatment of acromegaly

We report the use of MRI in the diagnosis, follow-up and therapeutic management of three cases of intralabyrinthine Schwannoma. The diagnosis was based on the history and initial and follow-up MRI findings. The main feature suggesting the diagnosis was a nodular intralabyrinthine mass of low signal intensity on T2-weighted images, and high or isointense signal on T1-weighted images (relative to cerebrospinal fluid), which showed contrast enhancement. Follow-up imaging showed growth of the tumour in one patient. One patient underwent surgery for severe tinnitus. To detect these lesions, MRI should be focussed on the inner ear, using thin-section T2-weighted and T1-weighted images before and after contrast medium. MRI allowed informed surgical planning.     

Epstein-Barr virus and CD21 expression in gastrointestinal tumors

OBJECTIVES: Animal inhalation studies and theoretical models suggest that the pattern of formation of benzene metabolites changes as exposure to benzene increases. To determine if this occurs in humans, benzene metabolites in urine samples collected as part of a cross sectional study of occupationally exposed workers in Shanghai, China were measured. METHODS: With organic vapour monitoring badges, 38 subjects were monitored during their full workshift for inhalation exposure to benzene. The benzene urinary metabolites phenol, catechol, hydroquinone, and muconic acid were measured with an isotope dilution gas chromatography mass spectroscopy assay and strongly correlated with concentrations of benzene air. For the subgroup of workers (n = 27) with urinary phenol > 50 ng/g creatinine (above which phenol is considered to be a specific indicator of exposure to benzene), concentrations of each of the four metabolites were calculated as a ratio of the sum of the concentrations of all four metabolites (total metabolites) and were compared in workers exposed to > 25 ppm v < or = 25 ppm. RESULTS: The median, 8 hour time weighted average exposure to benzene was 25 ppm. Relative to the lower exposed workers, the ratio of phenol and catechol to total metabolites increased by 6.0% (p = 0.04) and 22.2% (p = 0.007), respectively, in the more highly exposed workers. By contrast, the ratio of hydroquinone and muconic acid to total metabolites decreased by 18.8% (p = 0.04) and 26.7% (p = 0.006), respectively. Similar patterns were found when metabolite ratios were analysed as a function of internal benzene dose (defined as total urinary benzene metabolites), although catechol showed a more complex, quadratic relation with increasing dose. CONCLUSIONS: These results, which are consistent with previous animal studies, show that the relative production of benzene metabolites is a function of exposure level. If the toxic benzene metabolites are assumed to be derived from hydroquinone, ring opened products, or both, these results suggests that the risk for adverse health outcomes due to exposure to benzene may have a supralinear relation with external dose, and that linear extrapolation of the toxic effects of benzene in highly exposed workers to lower levels of exposure may underestimate risk.     

Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.     

Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide

Treatment options for hepatocellular cancer apart from surgical resection are limited because of the drug-refractory nature of this disease. Little is known about the role of somatostatin-receptors in hepatocellular cancer, and somatostatin analogs have not been investigated for treatment of this malignancy. We present the case of a 68-yr-old male, who was successfully treated with the long-acting somatostatin analog lanreotide.     

Value of quantitative DNA analysis in endocrine tumors of the pancreas

BACKGROUND: In 55% of progressive care units, someone is assigned to watch the cardiac monitors at all times, but the effect of this practice on patients' outcomes has not been examined. OBJECTIVE: To evaluate the effect of continual observation of telemetry units by a monitor watcher on mortality, frequency of transfer to a critical care unit, and the occurrence of five life-threatening dysrhythmias. METHODS: Data for this quasi-experimental study were collected on 1185 patients for a 9-month period in 1993 when the cardiac progressive care unit had a monitor watcher and on 1198 patients for a 9-month period in 1994 when the unit had no monitor watcher. RESULTS: We found no significant differences in mortality, frequency of transfer to a critical care unit, or the occurrence of three of the five dysrhythmias examined. The presence of a monitor watcher was associated with significantly fewer episodes of sustained ventricular tachycardia but more bradyarrhythmias. For both sustained ventricular tachycardia and bradyarrhythmias, the monitor watcher variable remained in the final multivariate logistic regression models. CONCLUSIONS: The presence of a monitor watcher was not associated with lower rates of most adverse outcomes evaluated; however, fewer episodes of sustained ventricular tachycardia occurred when a monitor watcher was present. Sustained ventricular tachycardia is life-threatening, disturbing to the patient, and may result in a longer hospital stay while medical therapy is being adjusted. The results of this study support the use of a monitor watcher to prevent sustained ventricular tachycardia.     

123I-vasoactive intestinal peptide (VIP) receptor scanning: update of imaging results in patients with adenocarcinomas and endocrine tumors of the gastrointestinal tract

Restriction fragment length polymorphism (RFLP) analysis of polymerase chain reaction-amplified gene fragments was used to characterize 24 isolates of spotted fever group rickettsiae previously identified as Rickettsia sibirica from their serologic properties. These strains were obtained in Russia between 1946 and 1991 from humans and different species of Ixodid ticks. The RFLP analysis was performed using amplified DNA products obtained with a genus-specific primer pair derived from the R. prowazekii citrate synthase gene and two group-specific primer pairs from the R. rickettsii 190-kD and 120-kD surface protein antigen genes followed by Alu I, Pst I, and Rsa I restriction endonuclease digestions. Although some differences were detected in biological characteristics among the examined strains, only a single R. sibirica genotype was found with these molecular tools of identification.     

Immunohistologic analysis of gastrointestinal and pulmonary carcinoid tumors

Carcinoid tumors are potentially malignant neoplasms that arise in various body sites, including the lung and gastrointestinal tract. Those that appear cytologically atypical are more likely to behave aggressively than more typical carcinoid tumors. However, in the absence of cytological atypia or large tumor size, it is difficult to predict the biology of an individual tumor, because some lesions metastasize, whereas others do not. This study had four aims: (1) To study the expression pattern of p53, Ki-67, NCAM, and S-100 in carcinoid tumors and to relate these expression patterns to classical histopathologic features and to tumor location. (2) To identify nonhistological markers that might more accurately predict the early behavior of carcinoid tumors. (3) To determine whether sustentacular cells are present in carcinoid tumors arising in tissues derived from different embryological derivatives. (4) To determine the synaptophysin and chromogranin immunoreactivity in neuroendocrine tumors arising in various locations. The immunostaining reactions were quantitatively scored by three observers. Only 3 of the 39 tumors (all histologically atypical) were strongly positive for Ki-67; two of these were also strongly p53 immunoreactive. NCAM immunostaining differed according to the site of origin: 76.5% of foregut lesions, 58% of the midgut lesions, and 20% of hindgut lesions were positive. S-100 immunostaining ranged from 41% in foregut lesions to 50% in both the hindgut- and midgut-derived tumors. S-100-positive sustentacular cells were present in 20.5% of carcinoid tumors. All tumors stained with antibodies against synaptophysin. In contrast, 100% of midgut, 60% of hindgut, and 88% of foregut tumors were chromogranin positive. Carcinoid tumors tend to have low proliferative rates. p53 immunostaining tends to be strongly positive in tumors that are histologically atypical, but it is negative in typical carcinoid tumors arising in the gastrointestinal tract and lungs. Immunostaining reactions with antibodies to NCAM, S-100, and chromogranin differ depending on the site of origin. Synaptophysin stains 100% of carcinoid tumors regardless of their site of origin. In contrast, antibodies to chromogranin fail to stain 40% of hindgut tumors and 12% of foregut carcinoid tumors. S-100-positive sustentacular cells are present in foregut and midgut tumors but not in hindgut tumors.