Search PubMed⌕ Search

Biomedical subjects

K Kuma

Publications and source records attributed to K Kuma.

At least 55 records · Page 3Linked to original sources
PubMed1999

Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation.

Multiple endocrine neoplasia (MEN) type 2B is a clinically distinct entity among the autosomal dominant MEN 2 syndromes. Most patients with MEN 2B carry a germline mutation (M918T) of the RET proto-oncogene, while a few carry A883F. We examined a patient with MEN 2B, but without M918T or A883F, and her relatives. Here, we report the presence in this patient of 2 germline mutations, V804M and Y806C in the same allele. While the novel Y806C was inherited from her father, its carriers (her father and brother) was not affected by MEN 2. In contrast, V804M was a de novo mutation, that has been reported in patients with familial medullary thyroid carcinoma. Combinations of mutations of the RET proto-oncogene may cause oncogenic activities different from those of single mutations.

Base Sequence↗
PubMed1999

Thyrotropin regulates c-Jun N-terminal kinase (JNK) activity through two distinct signal pathways in human thyroid cells.

c-Jun N-terminal kinases (JNK) participate in cellular responses to mitogenic stimuli and environmental stresses. We investigated whether and how TSH, which promotes the proliferation and differentiation of thyroid cells, regulates JNK activity in primary cultured human thyroid cells. TSH stimulated JNK activity in cytosolic fractions of thyroid cells measured by in vitro kinase assay. A low concentration of TSH (10(-11) M) stimulated JNK activity but at a higher dose (10(-8)-10(-7) M), TSH suppressed JNK activity without any change of JNK protein level. Activation of JNK by TSH was also observed in CHO cells stably transfected with TSH receptor complementary DNA (cDNA), suggesting a ligand-receptor specific interaction. TSH stimulated JNK activity through a pertussis toxin-sensitive pathway. We next elucidated the signal transduction pathways in TSH-induced JNK activation by examining the involvement of four distinct intracellular signal molecules; protein kinase C (PKC), cAMP, Ca2+, and PI3-kinase. The stimulation of JNK by TSH was blocked by two PKC inhibitors and suppressed by 8-bromo-cAMP or forskolin. These findings demonstrate that TSH regulates JNK activity biphasically in human thyroid cells through an interaction between Gi-PKC and cAMP-PKA pathways.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Preoperative diagnosis of medullary thyroid carcinoma by RT-PCR using RNA extracted from leftover cells within a needle used for fine needle aspiration biopsy.

Fine needle aspiration Biopsy (FNAB) is commonly used to diagnose thyroid tumors. In some clinical situations, however, accurate diagnosis requires a more objective method than cytological examination alone. Medullary thyroid carcinomas (MTC) derive from C cells in the thyroid and express some specific messenger RNAs (mRNA), such as those transcribed from the RET proto-oncogene, the calcitonin gene, and the gene for carcinoembryonic antigen (CEA), which usually do not exist in normal thyroid follicular cells or thyroid tumors of follicular epithelial descent. Recently, we established a new method for the molecular diagnosis of thyroid tumors without additional invasion to the patient by extracting RNA for RT-PCR from the leftover cells inside the needles used for fine needle aspiration biopsy (Aspiration Biopsy-Reverse Transcription-Polymerase Chain Reaction, ABRP). By applying the ABRP method to the detection of RET, calcitonin, and CEA mRNAs, an accurate molecular-based diagnosis for MTC maybe established as an adjunct to cytological diagnosis. In this study, 35 aspirates were obtained at the time of surgery from thyroid tumors, including 11 MTCs. The expression of these mRNAs in the leftover cells inside the needles used for the aspiration was then examined. Transcripts from all three genes were detected in the samples from all 11 MTCs, but none of these mRNAs were detected in the other tumors or normal thyroid tissues. Furthermore, MTC was preoperatively diagnosed in three patients by ABRP detection of these mRNAs, and these diagnoses were confirmed by subsequent cytological and histopathological analyses. Thus RT-PCR detection of RET, calcitonin, and CEA mRNAs in FNABs may be an efficient molecular adjunct for diagnosing MTC.

Adult↗
PubMed1999

Two novel cysteine substitutions (C1263R and C1995S) of thyroglobulin cause a defect in intracellular transport of thyroglobulin in patients with congenital goiter and the variant type of adenomatous goiter.

We analyzed the thyroglobulin (Tg) gene of 2 unrelated patients with congenital goiter and the Tg gene of 2 siblings with the variant type of adenomatous goiter. The clinical characteristics of the patients with congenital goiter and the variant type of adenomatous goiter were very similar, except for serum Tg levels, which were less than 15 pmol/L in the patients with congenital goiter, but 117-181 pmol/L in the patients with the variant type of adenomatous goiter (normal, 15-50 pmol/L). The tissue content of Tg in the thyroid glands of all 4 patients was reduced at 0.9-3.8% of total protein (normal, 19-40%). The missense mutation C1263R was detected in the 2 unrelated patients with congenital goiter; the pedigree study showed an autosomal recessive pattern of inheritance. In the 2 siblings with the variant type of adenomatous goiter, the missense mutation C1995S was homozygously detected. In the Tg complementary DNA of 110 normal subjects, the allelic frequencies of the C1263R and C1995S mutations were each less than 0.5%. Also in the normal subjects were detected 35 nucleotide polymorphisms, the insertion of 3 nucleotides, and 1 alternative splicing, each of which was not associated with any specific thyroid disease. From these data, the molecular mechanism of the C1263R and C1995S mutations was elucidated. We first analyzed the carbohydrate residues of C1263R Tg and C1995S Tg. Sensitivity to treatment by endoglycosidase H suggests that C1263R Tg and C1995S Tg were retained in the endoplasmic reticulum (ER). Also, the presence of endoglycosidase H-resistant Tg as well as endoglycosidase H-sensitive Tg in the patients with the variant type of adenomatous goiter suggests that a fraction of C1995S Tg was transported to the Golgi and associated with the mildly increased serum Tg levels. Native PAGE and Western blot analysis with anti-Tg antibody showed that C1263R Tg and C1995S Tg form high mol wt aggregates in the ER. Our results suggest that missense mutations that replace cysteine with either arginine or serine cause an abnormal three-dimensional structure of Tg. Such misfolded Tg polypeptides are retained in the ER as high mol wt aggregates.

Adenoma↗
PubMed1999

Screening of specific changes in mRNAs in thyroid tumors by sequence specific differential display: decreased expression of c-fos mRNA in papillary carcinoma.

To examine the specific changes in gene expression in thyroid carcinomas, we performed sequence specific-differential display (SS-DD) analysis by using a specific degenerate primer for the superfamily of the small G protein. After subcloning and sequencing analysis, one of the genes that showed decreased expression in thyroid papillary carcinomas was revealed to be the proto-oncogene c-fos. Expression of c-fos mRNA in benign and malignant tissues was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blotting. The expression of c-fos was detected in all twelve normal thyroid tissues, whereas it decreased in thirteen of fifteen papillary carcinomas. These results indicate that the increased expression of c-fos mRNA is not necessarily to be an oncogenic feature of thyroid tumors. Further, its constant expression in normal thyroid tissues may play a role in the maintenance of thyroid function.

Adenoma↗
PubMed1998

Accurate and objective preoperative diagnosis of thyroid papillary carcinomas by reverse transcription-PCR detection of oncofetal fibronectin messenger RNA in fine-needle aspiration biopsies.

Recently, the restricted expression of oncofetal fibronectin mRNA was reported in thyroid papillary and anaplastic carcinomas. In this study, by extracting RNA from the leftover cells inside the needles used for fine-needle aspiration biopsy, we establish a new method for gene diagnosis of these carcinomas without further invasiveness to the patient (aspiration biopsy-reverse transcription-PCR, ABRP). RNA was extracted from 177 fine-needle aspiration biopsies of thyroid nodules that were suspicious for malignancy, and then the gene diagnoses made by reverse transciption-PCR detection of oncofetal fibronectin mRNA were compared with cytological diagnoses. Thirty-five (94.6%) of 37 samples that were diagnosed as papillary or anaplastic carcinomas by cytological examination showed a positive result by gene diagnosis, whereas only 4 (3.7%) of 109 samples that were cytologically diagnosed negative for both carcinomas showed a positive result. Among all of the cases, 50 patients underwent surgery, and a histological diagnosis was consequently made. The sensitivity and specificity of this method were 96.9 and 100%, respectively. A combined examination using both genetic and cytological approaches may contribute to a more precise preoperative diagnosis of papillary and anaplastic carcinomas.

Adolescent↗
PubMed1998

Ancient gene duplication and domain shuffling in the animal cyclic nucleotide phosphodiesterase family.

The animal cyclic nucleotide phosphodiesterases (PDEs) comprise at least seven subtypes, PDE1-7, which differ from each other in domain organization and primary function, and they diverged from an ancestral gene by gene duplication and domain shuffling during animal evolution. To obtain rough estimates for the divergence times of these subtypes, cloning of PDE cDNAs from Ephydatia fluviatilis (freshwater sponge) by RT-PCR was carried out. We obtained four cDNAs, EFPDE1, EFPDE2, EFPDE3, and EFPDE4, which are possibly homologs of the vertebrate PDE1, PDE2, PDE3, and PDE4, respectively, judging from the sequence similarity, domain organization, and branching pattern in the phylogenetic tree. The phylogenetic tree of the PDE family revealed that most gene duplications and domain shufflings that gave rise to different subtypes had been completed in the early evolution of animals before the separation of sponges and eumetazoans.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Oligoclonal development of B cells bearing discrete Ig chains in chicken single germinal centers.

Chicken single germinal centers enable us to analyze the postbursal diversifications of B cells due to their easy isolation. Germinal center formation has peaked by day 7 of primary responses and begins to wane 14 days after immunization. To detail the kinetics of Ig mutation and selection, we analyzed Ig light chain sequences recovered from single germinal centers at 7 and 11 days postimmunization with an artificial Ag. Our observations show that multiple, Ag-activated B cells migrating into single germinal centers are diversified by gene conversion in the very early phase of the germinal center reaction and are subsequently subjected to point mutations and selection for oligoclonality.

Amino Acid Sequence↗
PubMed1998

Ionizing radiation activates c-Jun NH2-terminal kinase (JNK/SAPK) via a PKC-dependent pathway in human thyroid cells.

Thyroid gland is known to be higher sensitive to carcinogenic effects of external ionizing radiation (IR) than other tissues. To clarify the cell-specific response following irradiation, activations of c-Jun NH2-terminal kinases (JNKs), which is one of mitogen-activated protein kinases (MAPKs) family members, and extracellular signal-regulated kinase (ERK) were examined in primary cultured human thyroid cells in comparison with human diploid fibroblast cells, WI-38. Although UV exposure strikingly induced JNK activity in both cells, the dose-response increase following IR exposure was observed in thyroid cells with the maximal JNK activity (3.5 fold induction) obtained at 10 Gy exposure, but no increase in WI-38 cells. The JNK activity was reached a maximum of 2.2 fold induction at 30 min after 5 Gy exposure and then sustained for at least 12 hr. On the other hand, ERK activity was not stimulated in thyroid cells following irradiation. The effects of 12-O-tetradecanoylphorbol beta-acetate (TPA) mimicked those of radiation on JNK cascade and 1-(5-isoquinolinesulphonyl)-2,5-dimethylpiperazine 2HCl (H7) and pretreatment with TPA blocked JNK activation following irradiation. Our results demonstrate that IR stimulates JNK activity in cultured human thyroid cells but not in fibroblasts indicating distinct activation and regulation mechanisms of JNK cascade. The JNK activation following IR exposure is mediated at least partially through a PKC-dependent pathway.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1998

Sponge Pax cDNA related to Pax-2/5/8 and ancient gene duplications in the Pax family.

Members of the Pax gene family encode transcription factors containing a DNA-binding paired domain which is involved in developmental control and the formation of the central nervous system (CNS). The family members are classified into six classes or subfamilies, depending on the presence or absence of paired-type homeobox and octapeptide. To obtain rough estimates of times when the different classes of the Pax family diverged by gene duplication, we cloned and sequenced a Pax-related cDNA, sPax-2/5/8, from Ephydatia fluviatilis, a freshwater sponge, which encodes a paired-type homeobox and an octapeptide, in addition to a paired domain. A phylogenetic tree based on the paired domain sequences suggest that sPax-2/5/8 is a homologue of vertebrate Pax-2/5/8. It was also suggested that the majority of gene duplications that gave rise to distinct classes has been completed in the very early evolution of animals before the parazoan-eumetazoan split. Long after the ancient gene duplications, further gene duplications that gave rise to members in each subfamily occurred on the chordate lineages and completed before the fish-tetrapod split. This suggests that the major classes of the Pax genes involved in the formation of CNS characteristic of triploblasts had already existed long before the Cambrian explosion of triploblasts, and there is no direct link between the creation of new genes with novel functions and the Cambrian explosion. The pattern of gene diversification found in the Pax family is similar to those in five gene families involved in the signal transduction analyzed by us. Furthermore, the evolutionary rates of the Pax proteins have been shown to decrease with increasing organismal complexity during animal evolution.

Amino Acid Sequence↗
PubMed1998

Gene rearrangement of immunoglobulin as a marker of thyroid lymphoma.

Thyroid lymphoma occurs most commonly in the thyroid gland in association with Hashimoto's thyroiditis. Histologic findings occasionally cannot distinguish lymphoma from Hashimoto's thyroiditis, which creates a serious problem of whether treatment should be initiated. For this study, we examined 33 lymphoma tissues and 10 thyroid tissues from patients with Hashimoto's thyroiditis for the presence of gene rearrangement of immunoglobulin, which represents clonality of B-cell-derived tumors. Genomic DNA from thyroid tissues was digested with Bam H1 and Hind III restriction enzymes followed by electrophoresis. A Southern blot was performed with an IgH-JH probe or IgL-J kappa probe to detect gene rearrangement. Of the 33 lymphoma tissues, 27 (85%) showed gene rearrangement of immunoglobulin, whereas none of Hashimoto's thyroiditis tissue showed gene rearrangement. Five patients with a positive histologic diagnosis of lymphoma showed a negative gene rearrangement and were treated as having lymphoma. We encountered one case of lymphoma (plasmacytoma) in which gene rearrangement (not histologic findings) was diagnostic. Gene rearrangement of immunoglobulin can be used to detect thyroid lymphoma, particularly when the histologic diagnosis is inconclusive. The sensitivity of detecting thyroid lymphoma by the Southern blot method was about 85% in the present series.

Aged↗
PubMed1998

Restricted expression of oncofetal fibronectin mRNA in thyroid papillary and anaplastic carcinoma: an in situ hybridization study.

Restricted expression of oncofetal fibronectin mRNA in the tissues of thyroid papillary and anaplastic carcinoma has recently been shown by both Northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR). Oncofetal fibronectin mRNA can be a target of gene diagnosis and targeted gene therapy, provided it is expressed in all cancer cells in the tissues. To investigate this criterion in thyroid cancer tissues, we measured their expression of oncofetal fibronectin mRNA using in situ hybridization. An abundant expression of oncofetal fibronectin mRNA was found in all the observed cancer cells of six papillary carcinomas and an anaplastic carcinoma, but not in the tissues of normal thyroid, Graves' disease, adenomatous goitre, follicular adenoma, follicular carcinoma or medullary carcinoma. This result encourages us to establish gene diagnosis of thyroid papillary and anaplastic carcinomas by detecting oncofetal fibronectin mRNA in biopsies.

Antigens, Neoplasm↗
PubMed1998

The role of ansa-to-recurrent-laryngeal nerve anastomosis in operations for thyroid cancer.

OBJECTIVE: To study the recovery in phonation after reconstruction of the recurrent laryngeal nerve (RLN) in patients whose thyroid cancer was invading the nerve, and to evaluate the role of ansa cervicalis to RLN anastomosis (ARA) in operations for thyroid cancer. DESIGN: Retrospective study. SETTING: University hospital and private thyroid clinic hospital, Japan. SUBJECTS: 34 patients with thyroid cancer who underwent reconstruction of unilateral RLN and 331 consecutive patients operated on for thyroid cancer. INTERVENTIONS: Reconstruction was direct anastomosis (DA), free nerve grafting (FNG), vagus-RLN anastomosis (VRA) or ARA, including anastomosis behind the thyroid cartilage. MAIN OUTCOME MEASURES: Maximum phonation time (34 normal subjects and 26 patients with vocal cord paralysis served as controls), laryngoscopic examination, and the ratio of reconstruction in patients who needed resection of the RLN. RESULTS: The maximum phonation time started to increase rapidly 2-5 months postoperatively in most cases as the patients' voices recovered, and 12 months after reconstruction was significantly longer than in those patients with vocal cord paralysis (P < 0.0001). It was comparable to that of the normal subjects, although the reinnervated cords were fixed in the median. The number of reconstructions in the series of 331 patients increased from 18% to 82% after we started doing ARA with the meticulous technique of anastomosis inside the thyroid cartilage. CONCLUSIONS: ARA is as effective as DA or FNG in improving phonation in patients who need resection of a unilateral RLN. As ARA has several advantages over FNG it has a definite place in operations for thyroid cancer.

Adult↗
PubMed1998

Correlation of antithyroglobulin and antithyroid-peroxidase antibody profiles with clinical and ultrasound characteristics of chronic thyroiditis.

Patients with chronic thyroiditis were selected for study according to specific selection criteria, and comparisons of an enzyme-linked immunosorbent assay (ELISA) method to a hemagglutination method were performed. The ELISA assays contained antithyroglobulin (TG) antibody and antithyroid-peroxidase (PO) antibody, the latter using recombinant human TPO. Four groups were established from 437 patients with chronic thyroiditis; 316 with both antibodies (TG + PO group), 75 with TG antibody alone (TG group), 10 with PO antibody alone (PO group), and 36 with no such antibodies (N group). The hemagglutination assay resulted in much different antibody profiles: PO group based on ELISA occurred in only 2%, whereas a group with microsome antibody alone based on hemagglutination assay occurred in 39%. Subsequently, studies of disease characteristics including age, gender, familial predisposition, thyroid function, and morphology of the gland were performed among the four groups of patients based on ELISA profiles but not on hemagglutination results. The subgroups of TG + PO and TG were derived from randomly selected patients (40 out of a much larger number of patients in each). The results showed that the PO group had smaller thyroid volume (25+/-16 mL, mean +/- SD) with normal echogenicity, and 50% prevalence of hypothyroidism. The TG group had larger thyroid volume (57+/-42 mL) with frequent association of small nodular formation (53%) but less frequent hypothyroidism (23%). In summary, compared to the hemagglutination method, the ELISA was noted to have both a higher sensitivity and specificity for detection of chronic thyroiditis. Correlation of ELISA profiles with ultrasonography of the thyroid gland detected subtle differences in subgroups that may account for differences in thyroid gland morphology and prevalence of hypothyroidism: the PO group has normal echogenicity but high incidence of impaired thyroid function, whereas in the TG group small nodules were associated with a lesser incidence of hypothyroidism.

Adult↗
PubMed1998

Persistently increased gastrin and decreased pepsinogen concentrations in serum from some patients with Graves' disease of triiodothyronine-predominant type and common type.

This study aimed to investigate the cause of persistently increased serum gastrin concentration seen in some Graves' disease patients even when euthyroid during antithyroid drug treatment. The subjects studied consisted of three groups: 33 patients with a common-type of Graves' disease, 14 with triiodothyronine (T3)-predominant Graves' disease (characterized from previous studies as having potent immunologic abnormalities including greater concentrations of thyroid-stimulating antibodies together with larger goiter size), and a group of 20 normal subjects. Fasting serum gastrin concentrations in common Graves' disease patients were significantly higher than those of normal subjects (58.4 +/- 38.9 pmol/L vs. 37.8 +/- 18.9 pmol/L [mean +/- SD], p < 0.05). The serum gastrin concentrations were even greater in T3-predominant Graves' disease patients than common Graves' disease patients (162.9 +/- 224.0 pmol/L vs. 58.4 +/- 38.9 pmol/L, p < .05). Serum pepsinogen I (PGI) concentrations were significantly lower in the T3-predominant patient group than the common Graves' group (24.0 +/- 12.9 ng/mL vs. 39.7 +/- 19.6 ng/mL, p < .05). Serum ratios of PG I to PG II were significantly lower in the T3-predominant Graves' disease patients than normal subjects (3.59 +/- 2.66 vs. 5.97 +/- 1.56, p < .01). The ratios also had a significant (p < .05) inverse correlation with serum gastrin concentrations in T3-predominant Graves' disease patients. The results suggest that autoimmune gastritis is associated with Graves' disease, particularly in patients with potent thyroid-autoimmunity.

Adolescent↗
PubMed1998

Expression profile of receptor-type protein tyrosine kinase genes in the human thyroid.

Protein tyrosine kinases (PTKs) play a role in regulating the growth and differentiated functions of thyroid cells and are probably involved in tumorigenesis of papillary-type thyroid carcinoma. To better understand the roles of PTKs in the physiology and pathophysiology of the thyroid, we analyzed the expression profile of receptor-type PTKs in normal human thyroid tissues. Highly conserved regions in the catalytic domains of receptor-type PTKs were amplified by RT-PCR using degenerate oligonucleotide primers. Nucleotide sequencing of about 100 clones identified 21 PTKs, including 16 receptor type and 5 nonreceptor type; no novel PTK was identified. Insulin-like growth factor I receptor, platelet-derived growth factor receptor (PDGFR), TrkE, Axl, epidermal growth factor receptor, etc., appear to be the most abundant receptor-type PTKs in the thyroid; many of which (PDGFR, TrkE, Axl, etc.) have never previously been demonstrated to be expressed in the thyroid. The expression of messenger RNAs (mRNAs) for PDGFR, axl, and trkE in normal thyroid cells was confirmed by Northern blot analysis, and interestingly, the expression levels of PDGFR and trkE mRNAs were decreased in all three thyroid carcinoma cell lines examined (FRO, WRO, and NPA), whereas axl mRNA and protein were overexpressed in 2 of 3 thyroid carcinoma cell lines (FRO and WRO) compared with that in normal tissue. The axl gene was, however, neither amplified nor rearranged. The biological activity of the ligand for Axl, the product of growth arrest-specific gene 6 (Gas6), was then evaluated, demonstrating modest mitogenic activity in thyroid carcinoma cells overexpressing Axl. Furthermore, gas6 mRNA was expressed in FRO cells. Thus, we here identify a variety of PTKs expressed in the thyroid gland, many of which may participate in the regulation of thyroid cell function. Variable expression levels of some PTKs in normal and cancerous cells suggest that there may be an imbalance and disarray of phosphorylation events in thyroid carcinoma cells. Furthermore, Gas6 is identified as a novel growth factor for thyroid carcinoma cells overexpressing Axl receptor tyrosine kinase.

Amino Acid Sequence↗
PubMed1998

Childhood thyroid cancer: comparison of Japan and Belarus.

The high incidence of childhood thyroid cancer in Belarus is suspected to be due to radiation exposure after the Chernobyl reactor accident. To clarify the clinical and histological characteristics of childhood thyroid cancer in Belarus, we therefore compared these patients to a radiation non-exposed control series in Japan. In Belarus, 26 thyroid cancers in subjects aged 15 or younger were diagnosed among 25,000 screened between 1991 and 1995 by Chernobyl-Sasakawa Health and Medical Cooperation Project. The clinical and morphologic features of these 26 cases were compared to 37 childhood thyroid cancers in Japan diagnosed between 1962 and 1995. The age distribution at operation in Belarus showed a peak at 10 years old, with a subsequent fall in numbers. In contrast, the age distribution at operation in Japan showed a smooth increase between the ages of 8 and 14. The mean tumor diameter was smaller in Belarus than that in Japan (1.4 +/- 0.7 vs. 4.1 +/- 1.7 cm, P < 0.001). The sex ratio, regional lymph node metastasis, extension to surrounding tissues or lung metastasis did not differ significantly. Histologically, all cases in Belarus were papillary and in Japan 33 cases were papillary and 4 cases were follicular carcinomas. Among papillary carcinomas, the frequency of a solid growth pattern, a criteria for classifying a tumor as poorly differentiated, was higher in Belarus than that in Japan (61.5 vs. 18.2%, P < 0.001). The difference between the features of childhood thyroid cancer in Japan and Belarus may be due to the difference in the process of carcinogenesis, but more direct evidence and further analysis by molecular epidemiology are needed in Belarussian cases.

Adenocarcinoma, Follicular↗