Use of islet cells in cell therapy

The results of our previous work [Hibino et al., Biochim. Biophys. Acta 1174 (1993) 162-170] suggested that a highly repetitive DNA component facilitates bending of the helix axis to be recognized by the nuclear scaffold proteins from rat liver, P123 and P130. In the present experiment, it was shown that binding of these proteins to such a repetitive DNA component from rat liver nuclei (370-bp XmnI fragment) is based on a cooperative mode of interaction, although the binding activity of P130 is much higher than that of P123. The immunoblot analysis with anti-phosphoamino acid antibodies suggested that phosphorylation of serine and threonine residues occurs on P123 and P130, but also of tyrosine residue(s) on P130. The phosphatase assay showed that phosphoryl groups on these proteins may be involved in altering the DNA binding activities of the proteins. Thus, the results in the present study imply that phosphorylation of a nuclear scaffold protein in addition to the degree of bending of the DNA helix axis plays an important role in anchoring chromatin to the nuclear scaffold and in construction of a higher-order chromatin structure.     

Somatostatin receptor subtypes, octreotide scintigraphy, and clinical response to octreotide treatment in patients with neuroendocrine tumors

Several types of neuroendocrine tumor express high numbers of somatostatin receptors (sstr). We have compared the expression of sstr subtypes with the outcome of octreotide scintigraphy in patients with carcinoids and medullary thyroid carcinoma (MTC) in comparison with Hürthle cell tumors. The effect of sstr activation (octreotide treatment) on tumor markers was also studied in patients with disseminated carcinoid tumors. Six patients with carcinoid tumors (four midgut and two foregut), and three patients with thyroid tumors (one MTC, one Hürthle cell carcinoma, and one Hürthle cell adenoma) were studied. Octreotide scintigraphy visualized tumor sites in all nine patients. Macroscopic tumor was verified at these sites at subsequent surgical exploration. Using Northern blotting and subtype-specific riboprobes, sstr could be detected in all tumors examined. All five sstr subtypes were detected in most of the carcinoid tumors. All six carcinoids expressed sstr2. This was in contrast to the findings for the thyroid tumors analyzed, which also expressed several sstr subtypes but in some cases lacked expression of sstr2. This was also the case for normal thyroid tissue. Clinically, octreotide treatment of the patients with midgut carcinoid tumors resulted in palliation of hormonal symptoms accompanied by a significant reduction of urinary 5-HIAA levels (28-71%). These results indicate that carcinoid tumors frequently express all five sstr subtypes. The thyroid tumors also expressed multiple sstr but could lack expression of sstr2. Nevertheless, these tumors were visualized by octreotide scintigraphy, indicating that sstr2 expression is not a prerequisite for tumor imaging.     

Effect of oral medroxyprogesterone acetate on menopausal symptoms in patients with endometrial carcinoma

A double-blind cross-over study was performed on 21 patients treated for endometrial carcinomas who had severe menopausal symptoms. The patients were randomized into two groups and received medroxyprogesterone acetate (MPA) 100 mg twice daily per os for 12 weeks and a placebo for 12 weeks. A significantly better effect on hot flushes and sweating was obtained with MPA than with the placebo. On average the maximum effect was achieved by MPA after 4-6 weeks. Six patients had a weight gain of more than 3 kg during the MPA administration, compared with none during the placebo administration. No significant difference was found in the blood pressure increase above 160/90 mmHg between MPA and placebo groups. Patients with endometrial carcinoma may risk exacerbation of their disease by undergoing therapy with exogenous estrogen. In contrast, MPA has been found of value in the treatment of disseminated endometrial carcinomas. In this study oral MPA was effective in the treatment of vasomotor menopausal symptoms and may be an alternative in women for whom estrogens might be hazardous.     

Prediction of efficacy of octreotide therapy in patients with acromegaly

Octreotide (OCT) administration provides a biochemical cure in most acromegalic patients. This drug, however, causes several side effects and is very expensive. Acute testing has been reported to predict chronic responsiveness to OCT administration. The aim of this retrospective study was to evaluate which test, if any, among acute testing, short-term (1 month) administration, and 111In-pentetreotide (111In-DTPA-Phe-D-OCT) scintigraphy, is best in predicting response to long-term OCT treatment. Sixty-eight patients with active acromegaly were studied. An acute test (100 micrograms sc OCT) was performed as usual: a GH decrease greater than or equal to 50% of baseline was considered a positive response. GH and insulin-like growth factor I (IGF-I) were then assayed after 1 month (300 micrograms daily) and 3 months (150-600 micrograms daily) of OCT administration. GH was considered normalized when decreased less than or equal to 5 micrograms/L. Twenty-six of 68 patients were subjected to 111In-pentetreotide scintigraphy. Linear correlation analysis of the results was performed. Sensitivity, specificity, and positive and negative predictive values of the three tests were also calculated. Thirty-eight of 68 patients (56%) responded to the acute test. Among these 38 patients, 20 experienced normalization of GH and IGF-I levels during long-term therapy, as did 8 patients who did not respond to the acute test. No significant correlation was found between GH percent decrease during acute testing and long-term therapy (r = 0.11). Seven patients who responded to the acute test and 2 who did not respond had adenoma shrinkage during therapy. Conversely, GH and IGF-I decrease after short-term treatment significantly correlated with long-term treatment (r = 0.76 and 0.64, P < 0.01). Of the 26 patients subjected to 111In-pentetreotide scintigraphy, 13 had significant tracer uptake: normalization of GH and IGF-I was obtained in 8 patients. A significant correlation was found between tracer uptake and GH/IGF-I inhibition after 3 months of therapy (r = 0.6; P < 0.05). In the whole population, the positive predictive value of acute testing, short-term OCT administration, and 111In-penetreotide scintigraphy was 53%, 70%, and 73%, respectively, when the GH normalization (< 5 micrograms/L) after 3 months of therapy was considered. Moreover, 111-In-pentetreotide scintigraphy had the highest specificity (100% in patients with baseline GH values below 50 micrograms/L) compared with that of acute testing and short-term OCT administration. The acute test cannot be considered as a valuable index to identify patients' responsiveness to long-term OCT therapy, but it can be useful to test tolerability. By contrast, 1 month of OCT administration or the in vivo imaging of somatostatin receptors by 111-In-pentetreotide might better indicate the patients who might effectively benefit from this treatment.     

Prospective study of provocative angiograms to localize functional islet cell tumors of the pancreas

BACKGROUND: Controversy exists concerning the use of preoperative imaging studies in patients with islet cell tumors. Since 1993 we have evaluated the use of provocative angiography in patients with insulinoma or Zollinger-Ellison syndrome (ZES). METHODS: Twelve patients with a working diagnosis of insulinoma (n = 4) or ZES (n = 8) were studied. Of the eight patients with ZES, four were known to have multiple endocrine neoplasia type 1. All patients underwent conventional imaging studies followed by provocative angiography. Angiograms were graded based on the ability to detect tumor and regionalize it within the pancreas. RESULTS: Of the three patients with a working diagnosis of ZES but equivocal results of biochemical studies, none had arteriographic imaging of an islet cell tumor or a positive provocative study result (true negative result). Of the nine patients with documented islet cell tumor, seven (78%) underwent arteriographic imaging of the tumor and eight (89%) had correct regional localization by provocative angiography. Sensitivity and specificity for imaging were 78% and 100%, respectively, and for regional localization 89% and 100%, respectively. CONCLUSIONS: Provocative angiography is the localization study of choice for both gastrinoma and insulinoma. Having few false-negative results, it can be used to corroborate the diagnosis and, having few false-positive results, it detects tumor and biochemically confirms localization in nearly every patient.     

Psychological stress symptoms before and after autologous bone marrow transplantation in patients with solid tumors

This study sought to examine patterns of changes of psychological stress symptoms in autologous bone marrow transplantation (ABMT) recipients. Forty-nine patients affected by solid tumors were assessed using the Symptom Questionnaire on admission to hospital (before high-dose chemotherapy and ABMT) and before discharge. Symptoms of anxiety and anger tended to decrease and relaxation of improve over time. Nevertheless, on admission to hospital 30-50% of the patients reported severe to moderate symptoms of anxiety and depression. Before discharge, the prevalence was still high (20-35%). The implications of these findings are discussed in terms of the need to monitor the evolution of emotional functioning of cancer patients undergoing ABMT.     

Negative control elements of the cell cycle in human tumors

OBJECTIVE: To report our experience with metallic self-expanding stents in the palliative care of patients with ureteric obstruction caused by advanced pelvic malignancy. PATIENTS AND METHODS: Seven patients (five men and two women, mean age 72.8 years, range 58-88) with ureteric obstruction caused by advanced pelvic malignancy were evaluated. Self-expanding metallic Memotherm stents (Angiomed, Karlsruhe, Germany) were deployed using an antegrade approach in all patients. Patients were followed for a mean (range) of 9 (4-13) months to assess renal function and survival. RESULTS: All seven patients had good palliation; their quality of life was improved and symptom such as loin pain were ameliorated. Renal function was preserved; the mean serum creatinine level before and after stenting was 636 and 263 mumol/L, respectively). The mean duration of stent patency was 9 months. Of the five patients who subsequently died, only two had recurrent renal failure, presumably caused by stent occlusion. CONCLUSIONS: The use of metallic stents in the palliative care of ureteric obstruction caused by advanced pelvic malignancy is a safe and effective treatment.     

Mechanism of gastric acid hypersecretion in patients with islet cell tumor without hypergastrinemia: studies in rats

BACKGROUND & AIMS: A nongastrin acid-stimulating peptide (NGASP) has been found in ulcerogenic pancreatic tumor syndrome without hypergastrinemia. The mechanism of gastric acid hypersecretion by NGASP was investigated in rats. METHODS: In vivo, gastric acid secretion and in vitro histamine release from enterochromaffin-like (ECL) cells in responses to tumor extract (TE) and synthetic human gastrin-17 I or pentagastrin (PG) were studied. Whether the 2 secretagogues potentiate each other was determined. RESULTS: TE dose-dependently stimulated histamine release, which was not blocked by a cholecystokinin (CCK)-B receptor antagonist. When TE was incubated with trypsin, the activity was abolished but was not affected by antibody. However, when rats were pretreated with antigastrin serum or CCK-B receptor antagonist, the acid secretion by TE was virtually abolished. The dose response of acid secretion to TE in the rats receiving PG in a threshold dose was significantly greater than that achieved by TE alone. Similarly, the dose response to PG combined with a threshold dose of TE was significantly greater than that produced by PG alone. CONCLUSIONS: NGASP stimulates histamine release from ECL cells, but the release is not mediated via CCK-B/gastrin receptor. NGASP and gastrin may potentiate each other to produce acid hypersecretion in ulcerogenic pancreatic tumor syndrome.     

Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors

Specimens from 25 consecutive patients undergoing lung resection for peripheral carcinoid tumor were examined for evidence of neuroendocrine cell hyperplasia and associated obliterative bronchiolitis. Where available, the CT scans (n = 11) were reviewed for evidence of multiple tumors, and pulmonary function data (n = 16) were reviewed for evidence of airflow obstruction. Nineteen of the 25 patients (76%) had neuroendocrine cell hyperplasia in addition to the dominant carcinoid tumor. Eight patients (32%) had lesions of obliterative bronchiolitis associated with foci of neuroendocrine cell hyperplasia, and two of these patients had asymptomatic airflow obstruction that could not be related to smoking or other lung disease. We conclude that multicentric neuroendocrine cell proliferation is common in patients with peripheral carcinoid tumor of the lung. Associated bronchiolar fibrosis occurs in a high proportion of such patients, but it is usually asymptomatic.     

Merkel cell tumor. Report of case and treatment with octreotide

Merkel cell carcinoma is a rare neuroendocrine tumor of the skin. Prognosis is very poor particularly when systemic disease is present. Surgery, chemo and/or radiotherapy treatment are not able to guarantee long survival and quality of life is also very poor. We know that neuroendocrine tumor can be in possession of receptors for somatostatin; during the past years, these receptors have been demonstrated in vivo by octreoscan. We report a case of a patient suffering from metastatic Merkel cell carcinoma; because he was elderly, neither chemotherapy nor radiotherapy were possible as a consequence of the explosion of the disease after surgery. The presence of receptors for somatostatin analogues (octreoscan) allowed treatment with octreotide causing the immediate disappearance of metastasis. After ten months of treatment the patient presents a complete remission of disease. Octreotide, the most important somatostatin analogue, represents a primary role in the neuroendocrine tumor management; the drug also lacks of toxicity.     

Effect of somatostatin and octreotide acetate on OP-CCK-stimulated exocrine secretion in the denervated canine pancreas

A 54 year old patient of average intelligence with a severe and enduring loss of old autobiographical memories after herpes simplex type 1 infection is described. She was tested with a comprehensive neuropsychological battery two years after the infection. Special emphasis was laid on examining different aspects of retrograde memory. The neurological examination involved MRI and SPECT. Brain damage was found mainly in the right temporofrontal region, but minor left sided damage to this region seems possible. The patient was in the normal or slightly subnormal range for all tested anterograde memory functions, but manifested severe retrograde memory deficits with respect to episodic old memories and more moderate deficits in tests of general knowledge (semantic old memories). It is concluded that the ecphory of old autobiographical memories relies heavily on an activation of the right lateral temporofrontal junction area, but that probably only some complementary left hemispheric damage to these regions will lead to major and persistent retrograde amnesia. Alternatively, the disconnection between major prefrontal and posterior cortical regions may provide a basis for retrograde amnesia.     

Diagnosis and treatment of insulin-secreting pancreatic islet cell tumors in ferrets: 57 cases (1986-1994)

OBJECTIVE: To evaluate clinical, laboratory, radiographic, ultrasonographic, surgical, and histologic findings in ferrets with insulinoma and to determine their long-term outcome. DESIGN: Retrospective study. ANIMALS: 57 ferrets with a histopathologic diagnosis of pancreatic islet cell tumor. PROCEDURE: Medical records of ferrets with pancreatic islet cell tumors were reviewed. RESULTS: Lethargy, weakness, and collapse were the most common clinical signs. All ferrets had hypoglycemia, and hyperinsulinemia was documented in 39 of 47 (83%) ferrets. Ultrasonographic examination of the abdomen revealed pancreatic nodules in 5 of 23 ferrets. Surgical treatment was performed in 50 ferrets, 3 were treated by medical management alone, and 4 did not have treatment. At the time of surgery, 1 pancreatic nodule was found in 13 (26%) ferrets and multiple nodules were found in 37 (74%) ferrets. Pancreatic carcinoma alone was found in 34 ferrets. Whereas a combination of carcinoma and either hyperplasia or adenoma was found in 23 ferrets; 4 ferrets had metastasis to regional lymph nodes or liver. In 26 (53%) ferrets, hypoglycemia persisted after surgery, necessitating medical treatment with prednisone, diazoxide, or both. Sixteen (33%) ferrets had redevelopment of hypoglycemia at 1 to 23.5 months (median, 10.6 months) after surgery. Only 7 of the 50 (14%) ferrets remained euglycemic after surgery. CLINICAL IMPLICATIONS: In ferrets, surgical removal of insulin-secreting pancreatic islet cell tumors is recommended as definitive treatment; however, multiple pancreatic nodules are common, making complete excision of all tumor tissue difficult. Persistent hypoglycemia after surgical treatment indicates that lifelong medical management with prednisone or diazoxide or both may be necessary in many ferrets. Finally, because the insulin-secreting tumors are malignant, long-term cure and survival are not likely.     

Use of a long-acting gonadotropin-releasing hormone agonist for treatment of steroid cell tumors of the ovary

OBJECTIVE: To report a complete serologic response in a 50-year-old women who received long-acting gonadotropin-releasing hormone agonist (GnRH-A) therapy for steroid cell tumor of the ovary, not otherwise specified. DESIGN: Case report. SETTING: University hospital-based reproductive biology unit. PATIENT(S): A 50-year-old female patient exhibited persistent elevation of T (>2.0 ng/mL) after surgery for steroid cell tumor of the ovary, not otherwise specified, stage IIA for 3 months. This elevation suggested the presence of some residual active tumor. INTERVENTION(S): All tumor evaluations, including those for tumor markers, a thorough physical examination, imaging studies, and evaluations of nuclear medicine studies were negative except for elevated serum T levels. The patient was treated with GnRH-a between the fourth month and sixth month postoperatively. MAIN OUTCOME MEASURE(S): Serum levels of T and tumor survey. RESULT(S): The serum T levels returned to normal limits after administration of the first dose of GnRH-a. Follow-up of tumor survey was negative. The patient was alive and free of disease 26 months after treatment with GnRH-a. CONCLUSION(S): GnRH-a may be an alternative choice as adjuvant therapy for managing a persistent or recurrent hormone-producing steroid cell tumor of the ovary.     

Misunderstood symptoms in patients with infectious endocarditis

Infectious endocarditis was diagnosed in four patients, men aged 18, 44, 35 and 22; the bacteria involved were Streptococcus viridans, Eikenella corrodens, Staphylococcus aureus and Streptococcus mutans, respectively. In all patients mycotic aneurysms were observed which had led to seemingly unrelated neurological or abdominal complaints. In one patient an aneurysm of the A. cerebri media resolved in two years, another patient died following fatal bleeding of a ruptured aneurysm in the A. hepatica propria. Mycotic aneurysms may be found in all parts of the body. This complication is often diagnosed too late because it is not considered.