Medical oncology considerations in patients with metastatic neuroendocrine carcinomas.
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Antineoplastic Agents↗
Biomedical subjects
L Kvols
Publications and source records attributed to L Kvols.
Gastroenteropancreatic neuroendocrine tumours contain a common set of synaptic vesicle proteins and amino acid neurotransmitters.
Human neuroendocrine tumours of the gastroenteropancreatic system contain major integral membrane proteins of small synaptic vesicles of neurons, together with characteristic membrane polypeptides of large dense-core vesicles of neurons and neuroendocrine cells. The membrane polypeptides characteristic for small synaptic and large dense-core vesicles are detected in pheochromocytomas (n = 6), functional (n = 6) and non-functional (n = 6) foregut, and midgut carcinoids (n = 17). All gastroenteropancreatic tumours contain large amounts of amino acid neurotransmitters, i.e. glycine and glutamate. gamma-Aminobutyric acid, however, is only found in some foregut carcinoids. Thus, neuroendocrine gastroenteropancreatic tumours possess a vesicle type with a content and membrane composition similar to small synaptic vesicles of neurons.
Animals↗
In vitro detection of somatostatin receptors in human tumors.
Somatostatin receptors (SS-R) have been identified in membrane homogenates or tissue sections from several hundred human tumors. SS-R have been found in most neuroendocrine tumors, i.e. GH- and TSH-producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTC) and small cell lung carcinomas. SS-R have also been found in the majority of malignant lymphomas, in several brain tumors (all meningiomas, most astrocytomas) and in breast tumors. The majority of tumors expressing SS-R are rather differentiated, e.g. astrocytomas in contrast to glioblastomas, but exceptions exist such as high grade malignant lymphomas. An inverse relationship exists between SS-R and receptors for epidermal growth factor in lung tumors, glial tumors and most breast tumors, whereas meningiomas express both receptors simultaneously. A minority of tumors such as ovarian tumors, MTC and insulinomas, express a subtype of SS-R, characterized by low affinity for the octapeptide SS analog octreotide. The function of SS-R in human tumors differs according to tumor type, SS-R in pituitary and GEP tumors mediate hormone secretion inhibition, and have possibly some antiproliferative effects. In meningiomas, however, activation of SS-R inhibits forskolin-stimulated adenylate cyclase activity, and weakly stimulates proliferation. Although SS-R seem to mediate antiproliferative effects in animal models and cell lines of lymphomas, breast and lung tumors, such an effect has not yet been convincingly documented in human primary tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
Biomarkers, Tumor↗
Elevated neuropeptide levels decrease during liver transplant.
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Analysis of Variance↗
Somatostatin receptors in human renal cell carcinomas.
The presence of somatostatin receptors was evaluated in samples of 39 surgically removed human renal cell carcinomas with receptor autoradiography on tumor sections by using iodinated [Tyr3]octreotide as the radioligand. All types, grades and stages of tumors were represented. Twenty-eight of 39 renal cell carcinomas (72%) were shown to be somatostatin receptor positive. The receptors were saturable, of high affinity (KD = 0.8 nM), and were specific for somatostatin and bioactive somatostatin analogues. No evident correlations were found between the status of somatostatin receptors in the tumor and the age or sex of the patients, the histopathological type or grade of the tumor, or the tumor-node-metastasis stage of the disease. However, numerous cases considered to be of poor prognosis were somatostatin receptor positive. No functional correlates for these receptors have been established, although the presence of somatostatin receptors in human kidneys and somatostatin effects on renal tubular functions in normal human volunteers have been reported. In a patient scanned in vivo for islet cell carcinoma with an 123I-labeled somatostatin analogue, bilateral renal cell carcinomas were also visualized; multiple bilateral renal cell carcinomas were identified on the 1- and 4-h images taken after injection of 123I-labeled somatostatin analogue. In conclusion, the high incidence of somatostatin receptors in renal cell carcinomas may have diagnostic value when performing in vivo imaging of somatostatin receptors and it may have potential therapeutic implications.
Adult↗
In vitro detection of somatostatin receptors in human tumors.
Somatostatin receptors (SSR) have been identified in membrane homogenates or tissue sections from several hundred human tumors. SSR have been found in most neuroendocrine tumors, ie, growth hormone (GH)- and thyrotropin (TSH)-producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinomas (MTC), and small-cell lung carcinomas. SSR have also been found in the majority of malignant lymphomas, in several brain tumors (all meningiomas, most astrocytomas), and in breast tumors. The majority of tumors expressing SSR are rather differentiated, eg, astrocytomas in contrast to glioblastomas, but exceptions such as high-grade malignant lymphomas do exist. An inverse relationship exists between SSR and receptors for epidermal growth factor in lung tumors, glial tumors, and most breast tumors, whereas meningiomas express both receptors simultaneously. A minority of tumors such as ovarian tumors, MTC, and insulinomas express a subtype of SSR characterized by low affinity for the octapeptide SS analogue, octreotide. The function of SSR in human tumors differs according to tumor type; SSR in pituitary and GEP tumors mediate hormone secretion inhibition and possibly have some antiproliferative effects. However, in meningiomas, activation of SSR inhibits forskolin-stimulated adenylate cyclase activity and weakly stimulates proliferation. Although SSR seem to mediate antiproliferative effects in animal models and cell lines of lymphomas and breast and lung tumors, such an effect has not yet been convincingly documented in human primary tumors.(ABSTRACT TRUNCATED AT 250 WORDS)
Autoradiography↗
In vitro and in vivo detection of somatostatin receptors in pheochromocytomas and paragangliomas.
Fifty-one adrenal pheochromocytomas and 14 paragangliomas were evaluated for somatostatin (SRIH) receptor content with in vitro autoradiography on tissue sections from surgically removed tumors, using iodinated 125I[Tyr]3 octreotide as radioligand. Thirty-seven of 51 pheochromocytomas were SRIH receptor positive (73%), as well as 13 of 14 paragangliomas (93%). These SRIH receptors were of high affinity, pharmacologically specific for SRIH and localized on the tumor tissue. Using in vivo imaging techniques with radiolabeled SRIH analogs, paragangliomas could be visualized in five patients, as well as pheochromocytomas in two of three patients. All tumors tested subsequently in vitro (n = 7) were shown to contain SRIH receptors. A majority of pheochromocytomas were also shown to have a high tumoral SRIH content as measured by immunohistochemical techniques. Detection of SRIH messenger RNA in pheochromocytomas by in situ hybridization indicated that the SRIH was produced in the tumors. A weak inverse correlation was observed between SRIH receptor status and tumoral SRIH content, suggesting that SRIH receptors may be down-regulated by high levels of endogenous SRIH in some tumors. There was no correlation between the SRIH receptor status and sex, age, tumor size, benign vs. malignant tumor, or urinary metanephrine excretion. These tumors were also analyzed for allelic losses on various chromosomes and showed significant loss of heterozygosity (LOH) on chromosomes 1p, 3p, 17p, and 22q. All eight tumors with LOH on chromosome 1p were SRIH receptor positive (100%), whereas only 6 of 11 tumors without LOH on 1p (55%) were SRIH receptor positive, suggesting a correlation between LOH on 1p and SRIH receptor positive status. SRIH receptors thus represent a consistent pathobiochemical marker for most of these adrenal and extra-adrenal tumors. In addition, these receptors may be of potential interest for the in vivo localization of these tumors.
Adrenal Gland Neoplasms↗
In vitro and in vivo detection of somatostatin receptors in human malignant tissues.
High affinity somatostatin receptors (SS-R) have been identified in membrane homogenates or tissue sections from several hundred human tumors. SS-R were found in most tumors originating from SS target tissues, i.e. GH and TSH producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors and brain tumors. SS-R were also expressed in several tumors originating from various other tissues, i.e. breast and small cell lung carcinomas, some colorectal cancers, and medullary thyroid carcinomas. In general, most of the SS-R positive tumors are well differentiated and/or have neuroendocrine features. Among endocrine GEP tumors, more than 80% of carcinoids and 70-100% of islet cell carcinomas have a high density of SS-R. All their metastases are SS-R positive. Undifferentiated, atypical carcinoids are usually SS-R negative. SS-R are functional and mediate hormone secretion inhibition. SS-R positive tumors and metastases can easily be localised non-invasively in vivo by scanning techniques after 123I-SS analog injection.
Adenoma↗
Somatostatin receptors in malignant tissues.
High affinity somatostatin receptors (SS-R) have been identified in membrane homogenates or tissue sections from several hundred human tumors. SS-R were found in most tumors originating from SS target tissues, i.e. GH- and TSH-producing pituitary tumors, endocrine gastroenteropancreatic (GEP) tumors (including metastases) and brain tumors, including gliomas and neuroblastomas. SS-R were also expressed in several tumors originating from various other tissues, i.e. breast and small cell lung carcinomas, some colorectal cancers, and medullary thyroid carcinomas. In general, most of the SS-R+ tumors are well-differentiated and/or have neuroendocrine features. They often have low or absent epidermal growth factor receptor (EGF-R) expression. In some tumors (i.e. breast tumors) SS-R are not homogeneously distributed, making SS-R autoradiography a particularly useful tool for assessing SS-R status. SS-R are functional in pituitary and GEP tumors where they mediate hormone secretion inhibition. In these and in the other SS-R+ tumors, SS-R may also mediate antiproliferative effects of SS, as evidenced in animals where growth of SS-R+ tumor xenografts is inhibited by SS analogs. For diagnosis, SS-R+ tumors and metastases can be localized in vivo by scanning techniques after 123I-labelled SS analog injection.
Autoradiography↗
Synchronous and metachronous bilateral testicular tumors. Mayo Clinic experience.
The authors report a retrospective review of their experience with bilateral testicular cancers over two 10-year periods, one each from the prechemotherapy era (1935-1944) and the postchemotherapy era (1977-1986). Three of 295 patients (1.02%) evaluated at Mayo Clinic (Rochester, MN) for testicular germ cell malignancy between 1935 and 1944 had evidence of bilateral testicular malignancy. Two of these were synchronous and one metachronous occurring 3 years after the first diagnosis. In all three, the histology was pure seminoma. None of these three had a history of undescended testes. Both patients with synchronous tumours died within 2 years (6 months and 2 years, respectively) in spite of appropriate treatment at that time, and the one with metachronous tumor survived long-term (47 years). During the modern chemotherapy era, 16 of 500 (3.2%) patients evaluated at the Mayo Clinic Rochester between 1977 and 1986 for testicular germ cell malignancy had evidence of bilateral testicular cancers (four of these were synchronous and 12 metachronous [eight seminomas, four non-seminomas]) occurring between 1 to 15 years after the first diagnosis. Only two of 16 had a history of undescended testes surgically corrected while the patients were in their teens. All patients did well after appropriate treatment. This study reemphasizes the small but definite risk for development of a second testicular malignancy and suggests a recent increase in incidence of bilateral testicular tumors as possibly related to improved treatment modalities with a higher cure rate of the original tumor.
Adolescent↗
Distribution of somatostatin receptors in normal and tumor tissue.
Specific receptors for somatostatin (SS), mediating the various actions of this peptide, have been described in SS target tissues in animal and man. Using homogenate binding assays, as well as receptor autoradiography, the presence of SS receptors has been demonstrated in various regions of the brain (cortex, limbic system, basal ganglia), the anterior pituitary, the endocrine and exocrine pancreas, the gastrointestinal tract, and the adrenals. There are species-, as well as age-, related variations. Furthermore, there is evidence for different SS receptor subtypes. Interestingly, a large variety of human tumors also contain SS receptors with similar characteristics as those found in normal tissue; in numerous tumors, the SS receptor density is even higher than in healthy tissue counterparts. Most GH- and TSH-producing pituitary adenomas, but also a subgroup of endocrine inactive pituitary adenomas, have SS receptors; most carcinoids and islet cell carcinomas, as well as their metastases, also contain SS receptors. Several differentiated (usually EGF receptor negative) glia tumors possess SS receptors, whereas undifferentiated (EGF receptor positive) glia tumors lack such receptors. Furthermore, a subgroup of breast tumors, usually steroid receptor positive and neuroendocrine-differentiated, contain SS receptors. Finally, small cell lung carcinomas, but not non-small cell carcinomas, often possess SS receptors. These receptors are likely to be functional since in 11 acromegalics and 18 gastroenteropancreatic tumor patients, a positive correlation was observed between their SS receptor status and their hormone secretion sensitivity to Sandostatin.
Animals↗
Observation after orchiectomy in clinical stage I nonseminomatous germ cell tumor of testis. Mayo Clinic experience.
We report a retrospective review of our experience with close observation after orchiectomy in clinical stage I nonseminomatous germ cell tumors (NSGCT) of the testis during a 10-year period. Twenty-four patients were followed between 1977 and 1986 for a median duration of 47 months (24-112 months). Six of 24 (25%) relapsed at a median of 3.5 months (2-46 months) after orchiectomy; all of these were treated with chemotherapy and are in complete remission at a median of 55 months (27-69 months) after diagnosis of recurrence. Eighteen other (75%) who did not relapse are without evidence of disease at a median of 39 months (24-112 months) after orchiectomy. Orchiectomy alone followed by close observation in clinical stage I NSGCT is a reasonable approach in reliable patient populations at well-equipped centers where adequate follow-up is possible.
Adolescent↗
Metastatic cancer to the testes: a report of 20 cases and review of the literature.
Metastatic carcinoma to the testis is an extremely rare but interesting phenomenon. A variety of neoplasms have been reported to involve the testis metastatically. We report our experience with 20 cases of unilateral and bilateral testicular metastases during an 11-year period and review the relevant literature.
Carcinoma↗
Phase II trial of misonidazole (MISO) and cyclophosphamide (CYC) in metastatic renal cell carcinoma.
In animal models pre-treatment with misonidazole, a hypoxic cell radiosensitizer, enhances the antineoplastic effects of alkylating agent chemotherapy. Laboratory data suggest that hypoxic tumor cells may be more resistant to chemotherapy because of suboptimal drug delivery, reduced rates of cell division, or because hypoxia confers relative drug resistance. The therapeutic potential depends on the tumor type, doses of radiosensitizer and alkylating agent, the time interval between drug administration, and the ratio of sensitization of normal and malignant tissues. A Phase II trial of misonidazole and cyclophosphamide was initiated by the Eastern Cooperative Oncology Group to determine the response rate and toxicity in patients with metastatic renal cell cancer. Patients received 5 gm/m2 of misonidazole intravenously two hr before 1200 mg/m2 of cyclophosphamide every 3 wk. Patients with prior chemotherapy or radiotherapy received 1000 mg/m2 of cyclophosphamide. Misonidazole was discontinued after a total dose of 15 gm/m2. The median total misonidazole dose was 23.5 gm (range 4.5-34.5 gm). The median number of cyclophosphamide cycles was 2 (range 1-12). Of the 30 patients evaluable for response, only one patient had an objective partial response. Twenty-nine patients had stable or progressive disease. One patient remains on cyclophosphamide after 9 mo. Estimated median survival is 4.8 mo. There have been no lethal toxicities; however, 9 patients (25%) experienced life-threatening leukopenia and an additional 42% experienced severe hematologic toxicity. Eight patients had WBC less than 1000 on days 7-14 of cycle 1. Thrombocytopenia and grade 3 anemia occurred in 1 and 2 patients, respectively. Moderate or severe nausea and vomiting occurred in 47% and 19% of patients, respectively. Only 3 patients experienced severe neurotoxicity. Four additional patients had moderate neurotoxicity. In summary, misonidazole in this dosing schedule does not enhance the antitumor activity of cyclophosphamide in renal cell carcinoma.
Carcinoma, Renal Cell↗