[A case of crizotinib-associated renal cysts].

Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

Retraction Note: METTL3 promotes the progression of nasopharyngeal carcinoma through mediating M6A modification of EZH2.

The article "METTL3 promotes the progression of nasopharyngeal carcinoma through mediating M6A modification of EZH2, by Q.-Z. Meng, C.-H. Cong, X.-J. Li, F. Zhu, X. Zhao, F.-W. Chen, published in Eur Rev Med Pharmacol Sci 2020; 24 (8): 4328-4336-DOI: 10.26355/eurrev_202004_21014-PMID: 32373970" has been retracted by the authors. After publication, several issues were raised on PubPeer about the reliability of the published results. The same authors stated that the study was not performed in accordance with the standard procedures required. In particular, Figure 1 also presents some concerns as it does not reflect the experimental data reported in the study. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/21014.

MiR-29c-3p reduces bone loss in rats with diabetic osteoporosis via targeted regulation of Dvl2 expression.

OBJECTIVE: The aim of this study was to investigate the influence of micro ribonucleic acid (miR)-29c-3p on rats with diabetic osteoporosis (DOP) and its underlying mechanism. MATERIALS AND METHODS: A total of 30 specific pathogen-free (SPF)-grade male Wistar rats aged 6-week-old were randomly selected and divided into three groups according to different intervention means, including: NC group (control rats only injected with normal saline), DOP group (rats with DOP induced by injection of streptozotocin), and ME group (DOP rats injected with miR-29c-3p agonist for 4 consecutive weeks). The changes in blood glucose and body weight were recorded in the rats of each group every week. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the content of bone turnover markers (BTMs) in serum, such as alkaline phosphatase (ALP), osteocalcin (OC), and procollagen type I N-terminal propeptide (PINP). The variations in serum calcium (Ca) and phosphorus (P) levels in the abdominal aorta were determined using an atomic absorption spectrometer in the three groups. Meanwhile, bone mineral density (BMD) of femur and lumbar vertebra (L1-L4) were examined. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the changes in messenger RNA (mRNA) expressions of miR-29c-3p and Disheveled 2 (Dvl2) in the bone tissues of intervened rats. In addition, the staining and expression changes of Dvl2 protein in bone tissues were determined via immunohistochemistry. RESULTS: The rats in NC group had normal behavioral activities, normally increased body weight, sensitive responses, as well as normal and stable blood glucose. In DOP group, the rats manifested clinical symptoms of diabetes mellitus (DM) (i.e., polydipsia, polyphagia, polyuria, and weight loss), lackluster hairs, decreased behavioral activities, slow responses, and blood glucose at a concentration higher than 16.7 mmol/L. However, the blood glucose rose first, and then, declined and it was maintained at a level higher than normal concentration in ME group. Meanwhile, the rate of weight loss significantly decreased. The results of qRT-PCR indicated that the relative expression level of miR-29c-3p in bone tissues of DOP group was remarkably lower than that in NC group (p<0.01). However, it was significantly higher in ME group than that in DOP group (p<0.05). DOP group exhibited significantly upregulated serum BTMs (ALP, CTX-1, OC, TRACP-5b, and PIPN) when compared with NC group (p<0.05) and ME group (p<0.05). Furthermore, femoral BMD decreased in DOP group (p<0.05) while increased in ME group, showing statistically significant difference between the two groups (p<0.05). Immunohistochemistry results indicated that the bone tissues of DOP rats were deeply stained, and protein expression of Dvl2 protein was significantly higher in comparison with NC group. The bone tissues were lightly stained in ME group, and the protein expression of Dvl2 was lower than that in DOP group. Besides, qRT-PCR results demonstrated that the mRNA expression changes of Dvl2 were consistent with its protein expression trends. CONCLUSIONS: MiR-29c-3p reduces bone loss in rats with DOP via targeted regulation of Dvl2 expression.

METTL3 promotes the progression of nasopharyngeal carcinoma through mediating M6A modification of EZH2.

OBJECTIVE: The aim of this study was to investigate whether METTL3 promoted the progression of nasopharyngeal carcinoma (NPC) by silencing CDKN1C through EZH2. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to examine the expression level of METTL3 in 48 pairs of NPC tissues and adjacent normal tissues. METTL3 expression in patients with different tumor lymph node metastasis (TNM) stages was detected by qRT-PCR as well. The Kaplan-Meier method was used to analyze the interplay between METTL3 expression and the prognosis of patients with NPC. At the same time, METTL3 expression in normal epithelial cell line (BEAS-2B) and NPC cell lines (SUNE-1 and C666-1) was examined using qRT-PCR. After METTL3 was knocked down in SUNE-1 cells, cell viability and migration abilities were analyzed by cell counting kit-8 (CCK-8) test and wound healing assay, respectively. The mRNA and protein expressions of EZH2 were detected by qRT-PCR and Western blot, respectively. RNA immunoprecipitation (RIP) assay was applied to detect the binding of METTL3 to EZH2 mRNA and the m6A modification on EZH2 mRNA. After knockdown of EZH2 in SUNE-1 cells, qRT-PCR was used to detect the mRNA expression of CDKN1C. Meanwhile, chromatin immunoprecipitation (ChIP) assay was conducted to analyze the binding of EZH2 to the CDKN1C promoter region. After down-regulation of METTL3 in SUNE-1 cells, the protein expressions of EZH2 and CDKN1C were detected using Western blot. After simultaneous knockdown of METTL3 and CDKN1C in SUNE-1 cells, CCK8 assay and wound healing assay were applied to examine cell viability and migration abilities. RESULTS: METTL3 expression in NPC tissues was remarkably higher than that of adjacent normal tissues. Meanwhile, METTL3 expression in T3 and T4 tumors was significantly higher than that of T1 and T2 tumors. In patients with lymph node metastasis, the expression of METTL3 was remarkably higher than those without metastasis. Survival analysis demonstrated that patients with higher expression of METTL3 exhibited significantly longer overall survival time than those with lower METTL3 expression. QRT-PCR revealed that METTL3 was highly expressed in NPC cell lines, including SUNE-1 and C666-1. After knock-down of METTL3 in SUNE-1 cells, cell viability and migration abilities were both markedly weakened. Meanwhile, the protein expression of EZH2 was remarkably reduced. However, no significant changes were observed in EZH2 mRNA level. RIP assay revealed that METTL3 could bind to EZH2 mRNA, and a m6A modification was verified on EZH2 mRNA. After knockdown of EZH2, the mRNA level of CDKN1C in SUNE-1 cells was significantly up-regulated. CHIP assay indicated that EZH2 could bind to CDKN1C. Western blot showed that, after interfering with METTL3 in SUNE-1 cells, the protein expression of EZH2 decreased significantly, while CDKN1C was up-regulated. In addition, simultaneous downregulation of METTL3 and CDKN1C in SUNE-1 cells reversed the influence of METTL3 on cell viability and migration abilities. CONCLUSIONS: METTL3 was highly expressed in NPC tissues, which might inhibit EZH2 expression by mediating M6A modification of EZH2 mRNA. Furthermore, CDKN1C could increase the malignancy of NPC cells and promote the progression of NPC.

Clinical implications of gastrointestinal symptoms in systemic amyloidosis.

BACKGROUND: Gastrointestinal (GI) symptoms in systemic amyloidosis patients are poorly characterized. This purpose of this study is to define the epidemiology and clinical implications of such symptoms. METHODS: This was a retrospective cohort study of 583 amyloid patients seen at a tertiary referral center. Of 96 symptomatic patients, 82 received endoscopic biopsies, subsequently grouped into those with histologic evidence of GI amyloid (biopsy proven) vs without (biopsy absent). KEY RESULTS: 16.8% of patients had GI symptoms, and had more abnormal NT-proBNP, cardiac ejection fraction, serum albumin, and alkaline phosphatase (P < .01). Of those who received endoscopy, the sites of highest diagnostic yield were stomach, duodenum and colon. The most common symptom was abdominal pain, nausea, or vomiting (50.0%). Of the symptomatic patients, only 37 (45%) had biopsy proven GI amyloid. Biopsy proven patients more often had cardiac involvement (P < .005), and more often received hematologic therapy or transplant (P = .01). Biopsy absent patients had more frequent neurologic involvement (P = .17). Biopsy status had no significant correlation with other indicators of amyloid burden, GI symptoms or management. CONCLUSIONS & INFERENCES: Nearly one in six amyloid patients have GI symptoms, and half do not have GI amyloid. The type of symptom does not predict endoscopic findings. Most biopsy absent patients are not managed as a functional disorder despite no alternative etiology. Gastroenterologists may have an increased role to play in the care of systemic amyloidosis beyond performing endoscopies, such as evaluating cardiac amyloid patients for concurrent GI amyloid.

Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network.

Niemann-Pick type C (NPC) disease is a severe cell lipidosis characterized by the accumulation of unesterified cholesterol in the endosomal/lysosomal system. Recently the primary disease-causing gene, NPC1, was identified, but few clues regarding its potential function(s) could be derived from its predicted amino acid sequence. Therefore, efforts were directed at characterizing the subcellular location of the NPC1 protein. Initial studies with a FLAG-tagged NPC1 cDNA demonstrated that NPC1 is a glycoprotein that associates with the membranes of a population of cytoplasmic vesicles. Immunofluorescence microscopy using anti-NPC1 polyclonal antibodies confirmed this analysis. Double-label immunofluorescence microscopy and subcellular fractionation studies indicated that NPC1 associates predominantly with late endosomes (Rab9 GTPase-positive vesicles) and, to a lesser extent, with lysosomes and the trans-Golgi network. When cholesterol egress from lysosomes was blocked by treatment of cells with U18666A, the NPC1 location shifted from late endosomes to the trans-Golgi network and lysosomes. Subcellular fractionation of liver homogenates from U18666A-treated mice confirmed these observations. These data suggest that U18666A may inhibit the retrograde transport of NPC1 from lysosomes to late endosomes for subsequent transfer to the trans-Golgi network.

Differential gene expression in apoptosis: identification of ribosomal protein 23K, a cell proliferation inhibitor.

Gene expression during the camptothecin-induced apoptotic death of human leukemic U937 cells and mouse T-cell hybridoma QW4.1 cells was studied by the mRNA differential display technique. Ten clones were confirmed to be differentially expressed, nine of which encoded novel sequences. One clone, U3.2, was induced approximately 10-fold in camptothecin-treated cells and was found to be identical to a highly basic 23-kDa human protein which contains basic leucine zipper-like motifs and has recently been identified as the human homologue of the rat ribosomal protein L13a. Northern blot analysis revealed a major mRNA of approximately 0.9 kb and a minor mRNA of approximately 1.3 kb. Overexpression of a full-length 23K cDNA, tagged with a FLAG sequence, in COS-7 cells revealed a predominantly nucleolar localization and the absence of any 23K protein from the cytoplasm. Subsequent transfection studies, using antisense phosphorothioate-modified oligonucleotides, revealed that inhibition of 23K expression results in an increased cell proliferation and greater sensitivity of U937 cells to the effects of camptothecin-induced cell death. Upregulation of 23K expression using a cDNA construct resulted in a decrease in cell proliferation and growth arrest, suggesting a role for 23K protein as a proliferation checkpoint following a cellular insult.

Maximizing radiotracer delivery to experimental atherosclerotic lesions with high-dose, negative charge-modified Z2D3 antibody for immunoscintigraphic targeting.

BACKGROUND: Two factors that directly affect target/background ratio in immunoscintigraphy are the concentration of the antibody bound to the target and the concentration of the antibody in the circulation. High dosages of monoclonal antibody have been reported to be more efficacious in visualization of tumors. Although administration of a higher dosage of antibody increases the absolute target accumulation of the radiotracer, it also increases the background activity, which may offset this advantage. Negative charge-modified antibodies carry high specific radioactivity to the target sites without significantly increasing the background activity. Therefore we investigated whether higher dosages of negative charge-modified antibody can be used to improve imaging of experimental atherosclerotic lesions. METHODS AND RESULTS: Experimental atherosclerotic lesions were produced in 16 New Zealand White rabbits by balloon deendothelialization of the infradiaphragmatic aorta and hyperlipidemic diet for 12 weeks. Negative charge-modified Z2D3 antibody F(ab')2 specific for an antigen on proliferating smooth muscle cells of human atheroma labeled with (111)In was used for imaging experimental atherosclerotic lesions either at high (100 to 125 microg) or low (25 to 50 microg) dosages. A lower dosage of Z2D3 was labeled with 507 +/- 29.5 microCi (25 to 50 microg) (111)In label, compared with 2.9 +/- 0.24 mCi (100 to 125 microg) for the higher dosage. Although noninvasive visualization of atherosclerotic lesions was possible in all animals at 24 hours, high antibody dose allowed unequivocal visualization of the lesion as early as 3 hours after intravenous administration of the antibody. Eight animals were killed at 24 hours and the remaining eight animals at 48 hours. Mean radioactivity dose delivered per gram of lesion with the low-dose protocol at 24 hours was 0.46 +/- 0.09 microCi, which remained essentially unchanged at 48 hours (0.37 +/- 0.09 microCi; p = 0.51). With the high-dosage protocol, the total radioactivity (dose) per gram uptake in the lesion increased by about eightfold (3.49 +/- 0.58 microCi; p = 0.002) at 24 hours and was sixfold higher at 48 hours (2.21 +/- 0.45 microCi; p < 0.02). CONCLUSIONS: The study demonstrated that the increase in the dosage of negatively charge-modified antibody allows a very high delivery of specific radioactivity to the target, which in turn enables early visualization of experimental atherosclerotic lesions.

Noninvasive localization of experimental atherosclerotic lesions with mouse/human chimeric Z2D3 F(ab')2 specific for the proliferating smooth muscle cells of human atheroma. Imaging with conventional and negative charge-modified antibody fragments.

BACKGROUND: A murine monoclonal antibody designated Z2D3 (IgM) generated against homogenized human atherosclerotic plaques was demonstrated to be highly specific for proliferating smooth muscle cells. The primary clone subsequently was genetically engineered to provide a mouse/human chimeric antibody with human IgG1 constant region expressed in a rat myeloma cell line. The resulting Z2D3-73.30 chimeric retained the immunoreactivity relative to the parent Z2D3-IgM and was pepsin-digested to yield F(ab')2. 111In-labeled chimeric Z2D3 F(ab')2 was then used for noninvasive imaging of experimental atherosclerotic lesions. To improve the imaging characteristics, we modified chimeric Z2D3 F(ab')2 fragments to carry a high negative charge. Improved visualization of targets with 111In-labeled, negatively charged, polymer-modified antibodies most probably is the result of faster blood clearance and a decrease in nontarget background activity. METHODS AND RESULTS: Experimental atherosclerotic lesions were induced in rabbits by deendothelialization of the infradiaphragmatic aorta followed by a 6% peanut oil-2% cholesterol diet. After 12 weeks, localization of the conventionally labeled 111In-Z2D3 F(ab')2 (24 Mbq [650 microCi]/500 to 750 micrograms) (n = 4) was compared with 111In-labeled, negatively charged, polymer-modified Z2D3 F(ab')2 (24 Mbq [650 microCi]/25 to 50 micrograms) in eight atherosclerotic rabbits. Three control rabbits also received radiolabeled polymer-modified Z2D3. Ten rabbits with atherosclerotic lesions received 111In-labeled nonspecific human IgG1 F(ab')2 with (n = 6) or without (n = 4) negative charge modification. Atherosclerotic lesions were visualized in all rabbits with the conventional Z2D3 F(ab')2 at 48 hours. However, unequivocal lesion visualization was possible at 24 hours only with negatively charged, polymer-modified Z2D3 F(ab')2. Quantitative uptake of F(ab')2 fragments was essentially determined by the presence of atherosclerotic lesions (F1.37 = 69.8; P < .0001) and the specificity of the antibody (F1.37 = 36.6; P < .0001). Uptake of the conventional Z2D3 in atherosclerotic lesions (mean +/- SEM percent injected dose per gram, 0.112 +/- 0.024%) was six times higher than background activity in the normal aortic segments (nondenuded thoracic aorta; mean percent injected dose per gram, 0.019 +/- 0.003%). Uptake of the conventional Z2D3 was also significantly higher than that of nonspecific human IgG1 F(ab')2 (0.027 +/- 0.004%). Specific uptake of the conventional Z2D3 in the lesions was comparable to the charge-modified Z2D3 uptake (0.084 +/- 0.017; P = .20). Uptake of negative charge-modified Z2D3 in the lesions was significantly higher than in the corresponding background activity in normal thoracic aorta (0.021 +/- 0.002). Uptake of negative charge-modified Z2D3 F(ab')2 in the lesions was higher than the uptake of negative charge-modified nonspecific IgG1 F(ab')2 (0.020 +/- 0.002) in the lesions. Uptake of charge-modified Z2D3 in the atherosclerotic lesions was also significantly higher than the corresponding regions of the aorta of the control rabbits (0.017 +/- 0.002; F1.18 = 27.9; P = .0001). There was, however, no difference in the specific lesion uptake of negative charge-modified Z2D3 at 24 hours (0.079 +/- 0.014) and 48 hours (0.084 +/- 0.0017; P = .99) after intravenous administration. Nontarget organ activities were lower with negative charge-modified 111In-labeled Z2D3 F(ab')2 than with the conventional Z2D3 F(ab')2. Mean kidney activity was fourfold less with the modified (0.45 +/- 0.06) than with the conventionally radiolabeled (1.67 +/- 0.264; P = .001) Z2D3 F(ab')2.

Clinical experience of octreotide in the treatment of acromegaly.

To evaluate the efficacy and safety of octreotide (a somatostatin analogue) in the treatment of acromegaly, 10 patients were injected subcutaneously with octreotide, 50 micrograms, thrice daily before each meal for two days, followed by 100 micrograms thrice daily for six months. One case dropped out at the initial stage because of diarrhea, and another quit due to a lack of improvement in headaches after treatment for three months. Eight patients completed the study. The results showed that the circumference of the fourth finger and hand volume significantly decreased after treatment. Laboratory data demonstrated that serum growth hormone (GH) and somatomedin-C levels also decreased significantly. However, in six patients without a history of trans-sphenoidal adenomectomy, the serum GH and somatomedin-C levels returned to normal in only one case who had a serum GH level < 20 mU/L before treatment. In the oral glucose tolerance test, paradoxic elevation of GH subsided after treatment. In the TRH test, paradoxic elevation of GH improved after treatment. In the bromocriptine test, octreotide had a synergistic effect on the suppression of GH. All cases had the side effect of injection pain, especially at the initial stage. An increase in intestinal peristalsis and bowel movement occurred in the first week, but symptoms later subsided. Two out of these eight patients had gallbladder sludge after six months of treatment. In conclusion, octreotide is effective in the treatment of acromegaly; however, it is better used in patients who have serum GH levels < 20 mU/L, or after a trans-sphenoidal adenomectomy, and may be combined with bromocriptine to treat the patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cranial irradiation on hypothalamus-pituitary function: follow-up study one year after radiotherapy.

Hypothalamic pituitary functions were studied in 24 patients before, 6 months after and 1 year after cranial irradiation with or without radiosensitizing chemotherapy for nasopharyngeal carcinoma (NPC). The estimated average total dose was 5,000 cGy to the hypothalamus and pituitary gland. The radiosensitizing chemotherapy used was endoxan, 4,900 +/- 873 mg (mean +/- SD) and/or methotrexate, 113 +/- 30 mg. All patients had normal pituitary function before radiotherapy. There was a progressive increase in baseline serum thyrotropin (TSH) after radiotherapy. The basal serum follicle stimulating hormone (FSH) was significantly increased 6 months after radiotherapy and remained so at 1 year after radiotherapy. The TSH response to thyrotropin-releasing hormone (TRH) also progressively increased after radiotherapy, suggesting primary hypothyroidism due to neck irradiation. The peak serum TSH response to TRH became delayed after radiotherapy, suggesting a defect in TRH release. In male patients who did not receive chemotherapy, the LH response to luteinizing hormone-releasing hormone (LHRH) decreased after radiotherapy. After an initial rise in the FSH response to LHRH 6 months after radiotherapy, there was a reduction in the FSH response at 1 year. This suggests a defect in LHRH pulsatile release. However, in male patients who received radiosensitizing chemotherapy, both the FSH and LH responses to LHRH had declined at 1 year after radiotherapy, as compared with their responses at 6 months. However, these were still higher than those obtained before radiotherapy. This suggests further GnRH neuron damage, which was previously masked by chemotherapy-induced primary hypogonadism. The adrenocorticotropic hormone (ACTH) response to ovine corticotropin-releasing hormone (CRH) had not changed further at 1 year after radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Sonographic presentation in autoimmune thyroiditis.

We used real-time ultrasonography to examine 60 patients with autoimmune thyroiditis, then correlated the ultrasonic pictures with thyroid function, thyroid autoantibodies and fine needle aspiration cytology. In these 60 patients, 45 (75%) showed diffuse goiter, 6 (10%) showed multinodular goiter, and 9 (15%) had a solitary thyroid nodule sonographically. One of the 9 patients with a solitary nodule was a case of autoimmune thyroiditis combined with papillary carcinoma. The echogenicity of the thyroid was more than, the same as, or less than that of the adjacent muscles in 17, 22, and 21 patients, respectively. The groups were classified as hyperechoic, isoechoic, and hypoechoic, respectively. The mean serum T4 level was significantly lower in the hypoechoic group than in the hyperechoic or isoechoic groups (p less than 0.01 and p less than 0.05, respectively), and the incidence of hypothyroidism was significantly higher in the hypoechoic group than in the hyperechoic or isoechoic groups (p less than 0.001 and p less than 0.005, respectively). In addition, high titers of the antithyroid microsomal antibody (greater than or equal to 1280) were present more frequently in the hypoechoic group than in the hyperechoic or isoechoic groups (p less than 0.01 and p less than 0.05, respectively). There was no significant correlation between the cytomorphology and echogenicity of the thyroid in these cases. We conclude that sonography has two major uses in evaluating autoimmune thyroiditis: First, it is useful in excluding the coexistence of thyroid nodules; and second, marked hypoechogenicity of the thyroid implies an active cytotoxic autoimmune process and possibly a hypothyroid state.

Albright's syndrome with acromegaly and Hashimoto's thyroiditis: report of a case.

The case of a 35-year-old woman with Albright's syndrome, acromegaly and Hashimoto's thyroiditis is presented. She had noted deformity of the left mandible and chest from childhood. She developed persistent galactorrhea and amenorrhea after the delivery of her second child. X ray of the skull, and a head CT, revealed a pituitary tumor and fibrous dysplasia of the left mandible, sphenoid, zygomatic bone and pteryoid plate. Serum GH and PRL levels were markedly elevated. She received recontouring surgery of the left mandible, and a pathological examination confirmed the diagnosis of fibrous dysplasia. Chest X ray also showed fibrous dysplastic change of the left 4th, 5th, 6th and 7th ribs and left clavicle. Because of poor response to bromocriptine, she received a craniotomy to remove the pituitary macroadenoma. Pathological examination of the tumor revealed an acidophilic tumor. Postoperative radiotherapy was given for residual active tumor. She developed adrenal crisis two months after radiotherapy when she discontinued replacement therapy. The diagnosis of Hashimoto's thyroiditis was arrived at by palpation of the goiter, elevated thyroid antibodies, ultrasound pictures of the thyroid, fine needle aspiration cytology and hypothyroidism. To our knowledge, this is the first report of Albright's syndrome with Hashimoto's thyroiditis. The hypothesis of autoimmune disease is proposed to explain the hypofunction of the endocrine glands associated with Albright's syndrome.

Idiopathic hypothalamic hypogonadism with polyostotic fibrous dysplasia: report of a case.

A 48-year-old man with Albright's syndrome and hypogonadism is presented. Eunuchoid status, hypogenitalia and hypogonadotropinemia were associated with pathological fracture and deformity of bones. GnRH test revealed minimal LH response and delayed FSH peak. After pulsatile GnRH priming, the LH response to GnRH increased. Results of other provocative hypothalamic-pituitary tests were consistent with hypothalamic lesions. To the best of our knowledge, this is the first report of a male patient with Albright's syndrome and idiopathic hypothalamic hypogonadism. The hypothesis of endocrinopathy and its relation to other components of this syndrome were reviewed.

Effect of cranial irradiation on hypothalamus and pituitary functions.

Hypopituitarism can occur after cranial irradiation for tumors distant from the pituitary gland. Recent studies have suggested that this is hypothalamic in origin. Hypothalamic and pituitary functions were studied in 11 patients, 4 men and 7 women, 4.5 years or more after radiotherapy for nasopharyngeal carcinomas. The estimated average total dose was 5000 cGys for the hypothalamus and pituitary gland. Except for 2 women with amenorrhea and 4 men with impotency, the patients did not have evident endocrine deficiency. Baseline hormone profiles revealed normal T4, T3 and cortisol levels, 6 with elevated prolactin, 3 with reduced testosterone and 3 with slightly elevated basal TSH. The four menopausal women had impaired gonadotropin response to LHRH (100 micrograms, i.v.). Four (1 menstruating, 1 amenorrheic, 2 menopausal) women did not reach peak FSH response 4 hours after LHRH injection. The other amenorrheic woman had minimal FSH and LH response to LHRH which persisted even after 8 days of pulsatile infusion of LHRH (1 microgram/90min). TSH response to TRH (400 micrograms, i.v.) was delayed in 7 patients. GH response to human GRH (1 microgram/kg, i.v.) was impaired in 6 patients (maximal GH less than 5 mU/l). ACTH response to ovine CRH (1 microgram/kg, i.v.) was impaired in 3 patients (less than 50% elevation from baseline). Three patients who had normal GRH tests had impaired GH response to insulin hypoglycemia. Six patients had an empty sella on CT scan. From this study the following conclusions are drawn: (1) Among the four axes, GH is the most vulnerable. (2) The insulin tolerance test is still the best single test for evaluation of hypothalamic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaplastic thyroid carcinoma: review of 24 cases, with emphasis on cytodiagnosis and leukocytosis.

Twenty-four cases of anaplastic thyroid carcinoma seen in the National Taiwan University Hospital from 1980 to 1988 were reviewed. The median age was 61.5 years. The ratio of men to women was 1:1.4. A preceding history of long-standing goiter could be obtained in 14 patients (58.3%) with a median duration of 20 years. Twenty patients (83.3%) presented with a rapid-growing neck mass with a median duration of 1.3 months. Nine out of 19 patients (47.4%) had white blood cell (WBC) counts over 10,000/microliters, which were closely related to the presence of fever (p less than 0.02). Serial follow-up showed that WBC and platelets gradually increased but red blood cells and hemoglobin decreased. Fever was noted at the time of diagnosis in 8 out of 24 patients (33.3%), and was closely related to the presence of abundant neutrophils in the cytologic smears of thyroid aspirates (p less than 0.01). Fever was not due to bacterial infection. Three out of 10 patients (30.0%) had calcification in the thyroid shown on neck X ray, and 7 out of 18 patients (38.9%) had lung metastasis shown on chest X ray. The ultrasonographic images of thyroid anaplastic carcinoma done in 6 patients were heterogeneous and hypoechoic. Fine-needle aspiration cytology was done in 20 patients. Anaplastic thyroid carcinoma was easily diagnosed in 18 patients (90.0%). One was misdiagnosed as acute thyroiditis. Another one was diagnosed as papillary carcinoma cytologically, which combined with anaplastic carcinoma shown on histology. The median survival was 2.2 months, ranging from 0.2 to 25.3 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum prolactin and growth hormone response to thyrotropin-releasing hormone in patients with pituitary adenomas.

The dynamics of growth hormone (GH) and prolactin (PRL) secretion in response to intravenous 400 micrograms thyrotropin-releasing hormone (TRH) in 13 untreated patients with pituitary adenomas (6 women, 7 men; ages 20-64 years; 8 patients with acromegaly, 3 prolactinomas and 2 non-functional adenomas) were correlated with the results of immunohistochemical studies of GH and PRL in the adenoma cells. The basal serum GH concentrations were abnormally high in 6 and normal in 2 cases of acromegaly. In 5 of 6 acromegalic patients with pure GH-containing adenomas, TRH stimulated GH release by less than 100%. One patient with acromegaly and pancreatic islet cell carcinoma had the maximum increment for GH by 303%. TRH stimulated GH release by more than 100% in 2 acromegalic patients with mixed GH/PRL-containing adenomas. In 3 patients with prolactinoma and in 2 patients with non-functional adenoma the basal GH levels were 0.5 mU/L or undetectable and there was no GH response to TRH. The peak serum PRL levels after TRH were less than 100 ng/ml in 6 acromegalic patients with pure GH-containing tumors and in 2 patients with non-functioning pituitary tumors, and were more than 230 ng/ml in 3 patients with prolactinoma and in 2 acromegalic patients with mixed GH/PRL-containing tumors. It is suggested that the TRH test may help clinically in establishing the diagnosis of prolactinoma, pure GH-secreting tumors and mixed GH/PRL-containing tumors.

Cell kinetics, DNA content and TSH receptor-adenylate cyclase system in differentiated thyroid cancer.

The purpose of this study was to elucidate the changes of the TSH receptor-adenylate cyclase system in differentiated thyroid carcinomas, and their relationships with nuclear DNA content, cell kinetics and clinical stage. The results showed that the papillary carcinomas had an impaired TSH receptor-adenylate cyclase system. The production of cAMP stimulated by TSH was decreased when compared with non-cancerous tissue and high-affinity TSH receptors were reduced in number or even completely lost (nine in 24 cases). Follicular carcinomas also showed a reduction in, or even complete loss, of high-affinity TSH receptor (one in five cases). However, the responses to the stimulation of TSH, Gpp (NH)p and forskolin were not different from those in non-cancerous tissue. Papillary and follicular cancer cells showed more proliferative activity than those in non-cancerous tissue. Follicular carcinomas contained more hyperploid cells (DNA content greater than 2.5 C) than papillary carcinomas. There were no differences in cell kinetics, DNA content or the effects of Gpp (NH)p or forskolin on adenylate cyclase activity between those papillary carcinomas with high-affinity TSH receptor and those without. However, the presence of high-affinity TSH receptors had higher cAMP generation stimulated by TSH. The patients having papillary carcinomas in the absence of high-affinity TSH receptors were all in clinical stage III. These studies suggest that TSH receptors are the major sites influenced in the TSH receptor-adenylate cyclase system in papillary carcinomas. The TSH receptor-adenylate cyclase system of papillary carcinomas differs more from normal than does that of follicular carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)