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O H Clark

Publications and source records attributed to O H Clark.

At least 91 records · Page 5Linked to original sources
PubMed1996

Thyroid-stimulating hormone promotes the secretion of vascular endothelial growth factor in thyroid cancer cell lines.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a vascular endothelial cell-specific mitogen secreted by some cancer cells and is a major regulator of angiogenesis. Because thyroid-stimulating hormone (TSH) promotes growth and progression of thyroid cancers, we postulated that TSH may increase the production and secretion of VEGF by thyroid cancer cells. METHODS: We examined primary cultures of normal human thyroid (NT 1.0), medullary thyroid cancer (MTC 1.1), and cell lines derived from the papillary (TPC-1), follicular (FTC-133), and Hürthle cell (XTC-1) thyroid cancer. We quantified the concentration of VEGF in conditioned medium by means of enzyme-linked immunosorbent assay. RESULTS: Cell lines derived from thyroid secrete VEGF. Basal VEGF secretion was similar in normal and thyroid cancer cells, except XTC-1, which has high basal secretion (p < 0.01). All thyroid cancer cells secrete significantly more VEGF than normal thyroid cells after TSH (10 mIU/ml) stimulation (p < 0.05). TSH stimulated secretion of VEGF in FTC-133 (8.2 ng/dl versus 18.8 ng/dl), TPC-1 (5.5 ng/dl versus 26.9 ng/dl), and MTC 1.1 (5.9 ng/dl versus 13.4 ng/dl) cell lines (p < 0.01), but not in NT 1.0 (8.4 ng/dl versus 9.9 ng/dl) and XTC-1 (25.4 ng/dl versus 31.2 ng/dl) cells. CONCLUSIONS: These results suggest that VEGF secretion is constitutively activated in some thyroid cancers and that VEGF secretion is stimulated by TSH; thus TSH may promote growth in some thyroid cancers by stimulating VEGF secretion and angiogenesis.

Endothelial Growth Factors↗
PubMed1996

Surgical considerations and approach to thyroid cancer.

Patients with thyroid cancer can be safely treated by an experienced endocrine surgeon. More extensive initial surgery such as total or near-total thyroidectomy seems to decrease tumor recurrence and prolong life. When such operations can be done with minimal complications, we believe it is the treatment of choice because even low-risk patients have a 4% or 5% risk of eventually dying of thyroid cancer. If this risk of death from thyroid cancer can be decreased to 1% or 2% and the rate of serious complications is 1% or 2%, the authors believe total thyroidectomy is indicated. Most patients can be discharged within 1 day of total thyroidectomy.

Adenocarcinoma↗
PubMed1996

The regulation of proliferation and invasion in differentiated thyroid cancer by growth factors.

Invasion and metastasis are the primary cause of death in patients with follicular thyroid cancer (FTC). The thyroid is a micro-economic system in which proliferation and differentiation was supposed to be under the major control of only a single hormone (thyroid stimulating hormone-TSH). It has shown, however, that a complex network of various growth factors regulates growth and invasion of thyroid cancer cells. A growing literature has established the close association between malignant tumor progression and growth regulatory aberrations in cancer cells. Most of these studies have focused on the phenomenon, that advanced and more aggressive tumors or metastases lost the sensitivity to growth inhibitors, such as transforming growth factor beta. These findings highlight two aberrations of growth regulation which may favour progression of malignant disease and acquisition of metastatic competence: (1) Resistance to growth factor inhibitors and (2) growth autonomy of metastatic follicular thyroid cancer cells.

Adenoma↗
PubMed1996

RET mutation screening in MEN2 patients and discovery of a novel mutation in a sporadic medullary thyroid carcinoma.

RET germline mutations were found to predispose to the development of three variants of multiple endocrine neoplasia type 2, MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). We have screened for RET mutations at exons 10, 11, 13, and 16 in leukocyte DNA extracted from 37 individuals, and have identified RET germline mutations in 12 affected individuals from 9 unrelated families. No RET germline mutation was found in 19 individuals with apparent sporadic diseases. We have also screened for RET mutations at exons 10, 11, and 16 in tumor DNA extracted from 13 freshly frozen medullary thyroid carcinomas (MTC). RET mutation was detected in every tumor, either inherited or sporadic, indicating that RET plays an important role in the development of both inherited and sporadic MTC. We initially screened for RET mutations by direct DNA sequencing of the genomic PCR products amplified from patients' leukocyte or tumor DNA. Recently, we utilized the "Cold SSCP" method, nonradioactive single-stranded conformation polymorphism analysis, to screen for RET mutations and have identified a novel mutation, a 6-bp deletion preceding the cysteine-634, in a sporadic MTC.

Adolescent↗
PubMed1996

A novel multicolor hybridization scheme applied to localization of a transcribed sequence (D10S170/H4) and deletion mapping in the thyroid cancer cell line TPC-1.

The sequence-tagged site (STS) D10S170, also referred to as H4, is a gene of unknown function. Its 5' end was found fused to the catalytic domain of the RET protooncogene to generate RET/PTC 1, the most common form of PTC oncogenes in human papillary thyroid carcinoma. This gene has previously been assigned to a very large genomic region, 10q11.22-->q22.1. Here, we describe the application of a novel hybridization scheme to the physical and genetic mapping of D10S170. First, we selected a homologous large-insert DNA clone from a human P1 library by filter hybridization and confirmed its authenticity by Southern blot analysis. Triple-color fluorescence in situ hybridization (FISH) experiments mapped this clone to l0q21.2-->q21.3. "Binning" experiments were performed using a quadruple-color FISH approach aimed toward placing the gene in a genetic interval defined by differentially labeled P1 DNA probes containing known polymorphic markers. We found that multicolor FISH greatly expedites chromosomal mapping. Finally, we applied our FISH approach to determine the extent of deletion involving this locus (D10S170) in a papillary thyroid cancer cell line, TPC-1.

Carcinoma, Papillary↗
PubMed1996

Immunocytochemical detection of p53 in human thyroid carcinomas is associated with mutation and immortalization of cell lines.

Mutations in the tumor suppressor gene p53 are the most-common mutations found in human cancers. In thyroid cancers, p53 mutations generally are found only in poorly differentiated and undifferentiated tumors and in cell lines. To determine the prevalence of p53 mutations in thyroid neoplasms and thyroid cell lines, we screened 58 thyroid tissues and 3 thyroid cell lines, p53 primers bracketing exons 4, 5/6, 7, and 8 were used to amplify genomic DNA using the PCR. Mutations were screened by denaturing gradient gel electrophoresis and confirmed by sequencing. The two papillary thyroid cancer cell lines and the follicular thyroid carcinoma cell line (positive control) had transitions (CGT->CAT) in exon 8, codon 273, resulting in the replacement of arginine with histidine. No normal thyroid tissues or primary tumors from which the cell lines were derived demonstrated exon 8 mutations, using this technique. p53 immunocytochemistry demonstrated a progression of p53 immunopositivity between synchronous and metachronous neoplasms, paralleling the neoplastic progression from a benign adenoma to primary carcinoma, regional, and distant metastasis and ultimately, the cell lines, where intense immunopositivity is noted. In addition, fluorescence in situ hybridization, using probes specific for the p53 locus, revealed the presence of 3 homologues of p53 in the follicular cell line and 2 homologues in the papillary and Hürthle cell lines. These results suggest that a point mutation present in a small number of original tumor cells and amplification of the mutant allele may be responsible for immortalizing well-differentiated thyroid cancer cells into cell lines.

Adenocarcinoma, Follicular↗
PubMed1996

Somatostatin analog octreotide inhibits the growth of differentiated thyroid cancer cells in vitro, but not in vivo.

Somatostatin and its analogs are antiproliferative in a wide range of normal and neoplastic tissues. In this study we investigated the effect of octreotide (SMS 201-995) on the invasion and growth of three follicular thyroid cancer (FTC) cell lines from one patient in vitro and in vivo. FTC133 was established from the primary tumor, FTC236 from a cervical lymph node metastasis, and FTC238 from a lung metastasis. Invasion was the ability of tumor cells to penetrate 8-microns pore polycarbonate membranes coated with Matrigel. Invasion and proliferation were analyzed using the MTT assay. For in vivo experiments, athymic nude mice were sc inoculated with 500,000 calls of FTC133. The animals were treated twice daily with octreotide sc (100-300 micrograms/kg). RIA studies yielded dose-dependent high plasma levels of octreotide (3.43-6.5 ng/mL). Octreotide had a biphasic effect, enhancing growth at low concentrations (1-10 nmol/mL) and inhibiting it at high concentrations (100 nmol to 1 mumol/mL). Octreotide had also a dose-dependent biphasic effect on the invasion of FTC, inhibiting the invasion of all follicular thyroid cancer lines at high concentrations. However, it affected invasion less than growth. Octreotide (10 nmol/mL) stimulated the invasion of FTC133 by 13%, whereas stimulation was lower in both FTC metastases (FTC236, 6%; FTC238, 7%; P < 0.01). At higher concentrations (100 nmol to 1 mumol/mL), octreotide inhibited invasion of FTC133 by 17% (FTC236, 15%; FTC238, 17%; P < 0.01). During a 3-week treatment period, octreotide had no antiproliferative effect on the growth of FTC133 cells in nude mice. In conclusion, octreotide at low concentrations stimulates and at high concentrations inhibits the growth and invasion of follicular thyroid cancer cells in culture. However, it has no effect on the growth of FTC cells in animal experiments. Thus, the value of octreotide as an antitumoral agent in follicular thyroid cancer must be critically questioned.

Animals↗
PubMed1996

Predictors of thyroid tumor aggressiveness.

Thyroid cancers are classified as papillary, follicular (including Hürthle cell), medullary, and anaplastic. Papillary cancers account for about 82% of all thyroid cancers, follicular about 8%, medullary about 6%, Hürthle cell 3%, and anaplastic 1%. The prognosis of patients with papillary thyroid cancer is usually favorable, whereas most patients with anaplastic cancer die within 6 months. The behavior of papillary thyroid cancer can be predicted by patient age, sex, tumor size, local invasion, angioinvasion, lymph node metastases, distant metastases, as well as tumor differentiation and ability to take up radioactive iodine. Thus, older male patients with larger or invasive tumors, with angioinvasion, lymph node or distant metastases, and with tumors that do not take up radioactive iodine or cannot be completely surgically resected have a worse prognosis. Anaploid tumors, tumors with a low adenylate cyclase response to thyroid-stimulating hormone tumors, tumors that are ras-and gsp-positive, and tumors that are p21-positive and p53-positive also appear to behave in a more aggressive manner. In contrast, lymphocytic thyroiditis associated with papillary thyroid cancer predicts fewer recurrences and an improved survival. The treatment of patients with papillary thyroid cancer is controversial primarily because most patients do well with relatively minimal therapy, and there are no prospective studies concerning the merits of various treatments. Much of the controversy relates to the safety of thyroidectomy versus other procedures and, to a lesser extent, when to do a central or modified radical neck dissection. The rate of recurrence is lower, and the death rate may also be lower when patients are treated initially by total thyroidectomy. The rationale for total thyroidectomy is that it enables one to use radioactive iodine to detect and treat local and distant metastases, and it makes serum thyroglobulin determination more sensitive for detecting persistent disease. Total thyroidectomy should be associated with a permanent complication rate of less than 2%. Thyroid-stimulating hormone suppression therapy is recommended by most experts for patients with differentiated thyroid cancer and supported by most clinical and laboratory studies. Central and lateral node selection is recommended for patients with palpable lymphadenopathy.

Adult↗
PubMed1995

Familial nonmedullary thyroid cancer. An emerging entity that warrants aggressive treatment.

OBJECTIVE: To determine whether familial nonmedullary thyroid carcinoma behaves like sporadic carcinoma of follicular cell origin. DESIGN: Retrospective review. SETTING: University medical center. PATIENTS: Fourteen patients were treated for familial nonmedullary thyroid carcinoma between 1980 and 1994. Thirteen families were identified, with 30 affected individuals. INTERVENTIONS: Patients were treated with total or completion total thyroidectomy. Thirteen additional operations were performed to control recurrent disease. MAIN OUTCOME MEASURES: Stage, recurrence, and survival. Patients were followed up for a mean of 6.5 years. RESULTS: In our 14 patients, 13 tumors were multifocal, and six of these were bilateral. The incidences of lymph node metastasis and local invasion were both 57% (n = 8). Seven patients (50%) had recurrences during follow-up. CONCLUSIONS: Familial nonmedullary thyroid carcinoma has a high incidence of multifocality and invasion and a high rate of local recurrence. Aggressive initial treatment and careful follow-up seem to be indicated.

Adult↗
PubMed1995

[Growth and invasion of differentiated thyroid gland carcinoma: importance of signal transduction].

We investigated the role of three different signal transduction systems adenylate-cyclase (AC), protein kinase C (PKC) and tyrosine kinase (TK) for growth and invasion of a human follicular (FTC133) and a human papillary thyroid cancer cell line (PTC-UC1). Cyclic AMP stimulators and inhibitors had no effect at any concentration. The PKC agonist TPA enhanced both growth and invasion of FTC133 by 15%, whereas staurosporine, a PKC antagonist, inhibited growth by 47% and invasion by 32%. The latter also reversed thyrotropin (TSH) stimulation, but not epidermal growth factor (EFG) stimulation. EGF-stimulated growth and invasion of both cell lines were abolished by EGF-receptor antagonism using a monoclonal antibody. The tyrosine kinase antagonist genistein reversed EGF, but not TSH, stimulation. Pertussis toxin inhibited growth (FTC133: 22%) and invasion (FTC133: 18%). Cholera toxin was less inhibitory. Obviously, signal transduction of differentiated thyroid cancer is complex and systems other than adenylate cyclase are crucial for basal invasion and growth of follicular thyroid cancer cells in culture.

Adenocarcinoma, Follicular↗
PubMed1995

Molecular and cytogenetic characterization of a t(1;10;21) translocation in the human papillary thyroid cancer cell line TPC-1 expressing the ret/H4 chimeric transcript.

BACKGROUND: Activation of the ret proto-oncogene by three different chromosomal rearrangements occurs in up to 25% of papillary thyroid carcinomas. We developed a rapid screening technique to detect ret rearrangements in human interphase and metaphase cells on the basis of multicolor fluorescence in situ hybridization (FISH) of locus-specific DNA probes. METHODS: DNA from individual clones representing the respective ends of a yeast artificial chromosome (YAC) contig spanning the entire ret gene locus were labeled with either digoxigenin (visualized in red) or biotin (green) and hybridized to normal human lymphocytes and the papillary thyroid cancer cell line TPC-1 expressing the ret/H4 chimeric transcript. Further detailed analysis was performed with whole chromosome painting probes and locus-specific probes (YACs, P1s, DNA repeat probes) on tumor metaphase spreads. RESULTS: Hybridization of the YACs to unrearranged ret loci in normal human lymphocyte interphase nuclei showed two yellow domains because of probe overlap. Hybridization to TPC-1 interphase nuclei showed one yellow domain, and 1 red and 1 green domain separated by a large physical distance. Further analysis of metaphase spreads revealed a complex translocation t(1;10;21)(1pter > 1q31::21q22.1 > 21qter; 10q11.2 > 10pter::1q31 > 1qter; 21pter > 21q22.1;;10q21.2 > 10q11.2::10q21.2 > 10qter) and loss of the H4 gene locus on the nontranslocated chromosome 10. CONCLUSIONS: Break point spanning probes can reliably detect ret rearrangements in interphase nuclei. Locus-specific and whole chromosome painting probes can be used to further characterize complex rearrangements by fluorescence in situ hybridization to metaphase spreads. The papillary thyroid cancer cell line TPC-1 carries the paracentric inversion 10q, inv(10)(q11.2q21) and a complex t(1; 10; 21) translocation. Deletion of the H4 gene on the chromosome 10 not involved in the t(1; 10; 21) translocation suggests lack of normal H4 expression in the TPC-1 cell line. Further studies will have to address the role of the H4 gene product in tumor genesis and progression.

Carcinoma, Papillary↗
PubMed1995

Persistent or recurrent hyperparathyroidism in patients with double adenomas.

BACKGROUND: Are double parathyroid adenomas a discrete clinical entity or are all hyperplastic parathyroid glands of varying size? This investigation was done to determine whether patients with persistent or recurrent hyperparathyroidism and double adenomas (DA) differ in clinical profile or in response to treatment from patients with hyperplasia. METHODS: From 1982 to 1993, 37 unselected patients with persistent (11) or recurrent hyperparathyroidism (26) were treated. Twenty-one had DA and 16 had hyperplasia. DAs were defined as two abnormal and two normal parathyroid glands. RESULTS: Patients with persistent or recurrent hyperparathyroidism caused by DA were older and had more muscle weakness, neuropsychiatric disorders, constipation, and weight loss (p < 0.001) than patients with persistent or recurrent hyperparathyroidism caused by hyperplasia. Nephrolithiasis was more common in patients with recurrent hyperparathyroidism caused by hyperplasia than in patients with recurrent hyperparathyroidism caused by DA (p < 0.001). Serum Ca2+ levels before operation were similar in these groups with variable parathyroid hormone levels. No recurrences occurred in either group (DA [mean, 6 yr]; hyperplasia [mean, 5 yr]). Postoperative levels of serum Ca2+ and parathyroid hormone were normal in both groups. CONCLUSIONS: Patients with persistent or recurrent hyperparathyroidism caused by DA are older, have different clinical manifestations, and are cured by resection of the second adenoma. These findings support the concept that DA and hyperplasia are distinct entities.

Adenoma↗
PubMed1995

Immunoprecipitation isolates multiple TSH receptor forms from human thyroid tissue.

Attempts to purify the thyroid-stimulating hormone receptor (TSHR) have been complicated by its susceptibility to proteolysis and its low level of expression in thyrocytes and many transfected cells. Controversy exists over its size and structure. Multiple, single-polypeptide forms of the TSHR (230, 187, and 95-100 kDa) have been recently identified in immunoblots of crude plasma membranes prepared from COS-7 cells transfected with rat or human cDNA, but the relationship of these receptor species to the TSHR in human thyroid tissue has been heretofore unknown. We have developed a technique for immunoprecipitation of the TSHR which employed IgG purified from a polyclonal rabbit antiserum to TSHR residues 352-366. We have used immunoprecipitation to isolate the previously characterized 95-100 kDa TSH-holoreceptor, 187 kDa intermediate, and 230 kDa precursor forms of the TSHR from plasma membrane prepared from transfected COS-7 cells and human thyroid tissue. The presence of all three forms was not altered by the addition of reducing agent to the sample buffer, demonstrating the single polypeptide structure of the TSHR. This is, to our knowledge, the first report of the purification from transfected COS-7 cells of these TSHR species identified previously only in immunoblots of crude plasma membrane, and the first report of the identification by any means of these TSHR forms in human thyroid tissue. The isolation of TSHR from human thyroid tissue requires confirmation by direct means, but promises to make the receptor available in a soluble form for studies of its structure and function.

Cell Line↗
PubMed1995

Biphasic effects of thyrotropin on invasion and growth of papillary and follicular thyroid cancer in vitro.

The rationale for TSH suppression in the treatment of follicular thyroid cancer (FTC) and papillary thyroid cancer (PTC) is to inhibit tumor growth, prevent recurrent disease, and eventually prolong survival. We analyzed the effects of TSH on invasion and growth of 3 FTC cell lines from 1 patient (FTC133, primary; FTC236, lymph node; FTC238, lung metastasis) and 2 PTC cell lines (PTC-UC1, PTC-UC3). Cell growth and invasion through an 8-micron pore polycarbonate membrane coated with Matrigel were measured using the MTT assay. The dose-response to TSH was biphasic, stimulating invasion and growth of FTC and PTC at low concentrations (0.1-10 mU/mL), and inhibiting them at high concentrations (100 mU/mL). Interestingly, the metastatic FTC cell lines had higher basal invasion, but were less responsive to TSH than the primary tumor. TSH (1 mU/mL) stimulated invasion of FTC133 by 21%, FTC236 by 8%, and FTC238 by 8% (p < 0.01). At 100 mU/mL, TSH inhibited invasion of FTC133 by 21%, compared to 11% in FTC236 and 12% in FTC238. Also, TSH dose-dependently influenced proliferation of follicular thyroid cancer cells. At low concentrations it stimulated growth of FTC133 (20%) and inhibited it at high concentrations (23%; p < 0.01). Again, the amplitude of TSH effects was significantly smaller in the cell lines from metastatic tumors. TSH affected invasion and growth of PTC-UC1 and PTC-UC3 also biphasically. These results show that TSH may act as a mitogenic and antimitogenic growth factor for invasion and proliferation of well-differentiated thyroid cancer cells in vitro.

Adenocarcinoma, Follicular↗
PubMed1995

Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case-control study.

BACKGROUND: There has been an National Institutes of Health consensus meeting concerning the management of patients with "asymptomatic" primary hyperparathyroidism, yet there is no clear definition of this condition. The authors, therefore, documented the clinical manifestations and frequencies of these manifestations in unselected patients with primary hyperparathyroidism and determined whether these clinical manifestations resolved after parathyroidectomy. METHOD: The authors studied 152 unselected consecutive patients with primary hyperparathyroidism and 132 control patients with nontoxic thyroid disorders who were treated by parathyroidectomy or thyroidectomy, respectively, between January 1986 and June 1991. All patients received a questionnaire during their initial office visits and the same questionnaire again after their operations. Patients were also questioned about their perception of the success of the operation. Eighty percent of the parathyroid patients and 70.5% of the thyroid patients completed the questionnaires, and the mean follow-up time was 20 months. RESULTS: Only 7 (4.6%) patients with primary hyperparathyroidism had no symptoms, and 26 (17.1%) had no associated conditions despite 74.3% of these patients having serum calcium levels less than 12 mg/dL. Symptoms including fatigue, exhaustion, weakness, polydipsia, polyuria, nocturia, joint pain, bone pain, constipation, depression, anorexia, nausea, heartburn, and associated conditions, including nephrolithiasis, and hematuria occurred more often in patients with primary hyperparathyroidism than in the thyroid control patients (p < 0.05). After parathyroidectomy, only eight (5.3%) patients failed to have any improvement in symptoms or associated conditions. Fifty-seven percent of the parathyroid patients versus 30% of the thyroid patients felt better overall after the operation, strength subjectively improved in 29% of parathyroid patients versus 13% in thyroid patients; thirty-seven percent of the parathyroid patients versus 13% of the thyroid patients claimed they were less depressed. CONCLUSION: When examined thoroughly, few patients with primary hyperparathyroidism were asymptomatic or without associated conditions, and most patients experienced subjective improvement after successful parathyroidectomy.

Adolescent↗
PubMed1995

Tamoxifen inhibits growth, migration, and invasion of human follicular and papillary thyroid cancer cells in vitro and in vivo.

Prognosis of differentiated thyroid cancer is best in young women. It has been proposed that sex steroids protect premenopausal women from aggressive thyroid malignancies. Some thyroid tissues have estrogen receptors, and estrogen stimulates human thyroid cells. Tamoxifen is thought to exert its antiproliferative effects mainly by blocking estrogen stimulation. However, recently, mechanisms independent of estrogen interactions were found to be important for the favorable effect. We investigated the effect of tamoxifen on the growth, migration, and invasion in three follicular thyroid cancer cell lines (FTC133, primary; FTC236, lymph node; and FTC238, lung metastasis) from one patient and two papillary lines (PTC-UC1 and PTC-UC3). Growth was measured by dimethylthiazol-diphenyltetrazolium bromide assays, and migration was determined by the ability of cells to penetrate 8-microns pore membranes, which were covered by Matrigel for invasion assays. For in vivo experiments, we used xenografts of FTC133 in nude mice. Tamoxifen (1.5 mumol/L) inhibited the growth of all thyroid cancer cell lines (FTC133, 59%; FTC236, 42%; FTC238, 46%; P < 0.01). This effect was less pronounced in PTC-UC1 (25%) and PTC-UC3 (19%; P < 0.006) cell lines. Tamoxifen also inhibited migration and invasion of FTC more than PTC. Invasion of FTC133 was inhibited by 36% (P < 0.01), FTC236 by 30%, and FTC238 by 32%. Immunohistochemistry showed no estrogen receptors in any cell line. Also, estradiol had no significant effect on the growth, migration, or invasion of FTC or PTC. Tamoxifen treatment inhibited the growth of FTC133 xenografts in nude mice by 52% compared to that in placebo-treated controls (P < 0.002). In conclusion, tamoxifen inhibited the growth, migration, and invasion of differentiated thyroid cancer cells in vitro and in vivo. This was not reversed by estrogen. Tamoxifen acts independently of estrogen interactions and may be useful as an adjuvant treatment for some differentiated human thyroid malignancies.

Animals↗