Usefulness of antidiabetic alpha-glucosidase inhibitors: a review on the timing of administration and effects on gut hormones.

Elevation of postprandial plasma glucose is correlated with an increase in cardiovascular events, and alpha-glucosidase inhibitors (αGIs) are effective at reducing postprandial glucose levels. In Japan, the αGIs acarbose, voglibose, and miglitol have been available since 1993, 1994, and 2006, respectively. Dipeptidyl peptidase-4 (DPP-4) inhibitors are also effective at reducing postprandial glucose levels, and they have been available in Japan since 2009. A combination therapy of αGI, miglitol, and the DPP-4 inhibitor, sitagliptin, is more effective at decreasing postprandial glucose levels than monotherapy with either miglitol or sitagliptin. Moreover, the combination therapy of miglitol and sitagliptin is more effective at increasing postprandial active glucagon-like peptide-1 (GLP-1) levels than monotherapy. Peptide YY (PYY) has appetite-suppressing and gastric-emptying effects similar to GLP-1. In healthy individuals, miglitol increases the postprandial total PYY; however, combination therapy of miglitol and vildagliptin does not change postprandial total PYY levels. αGIs are typically prescribed to be taken just before a meal, which can result in decreased drug adherence. Different patterns of αGI intake were examined, and the results showed that miglitol or acarbose administration after a meal is effective. The effects of taking miglitol dissolved in water during a meal appeared to be similar to that of taking miglitol as a tablet just before a meal. The long-term effects of taking miglitol dissolved in water should be evaluated in future studies. αGIs may be effective even when they are not taken before a meal, and a more flexible administration may improve drug adherence.

Time-dependent change of blood flow in the prostate treated with high-intensity focused ultrasound.

Avascular areas on contrast-enhanced magnetic resonance imaging have been considered to be areas of localized prostate cancer successfully treated by high-intensity focused ultrasound. However, the optimal timing of magnetic resonance imaging has not been discussed. The thermal effect of high-intensity focused ultrasound is degraded by regional prostatic blood flow. Conversely, the mechanical effect of high-intensity focused ultrasound (cavitation) is not affected by blood flow, and can induce vessel damage. In this series, the longitudinal change of blood flow on contrast-enhanced magnetic resonance imaging was observed from postoperative day 1 to postoperative day 14 in 10 patients treated with high-intensity focused ultrasound. The median rates of increase in the non-enhanced volume of the whole gland, transition zone and peripheral zone from postoperative day 1 to postoperative day 14 were 36%, 39%, and 34%, respectively. In another pathological analysis of the prostate tissue of 17 patients immediately after high-intensity focused ultrasound without neoadjuvant hormonal therapy, we observed diffuse coagulative degeneration and partial non-coagulative prostate tissue around arteries with vascular endothelial cell detachment. These observations on contrast-enhanced magnetic resonance imaging support a time-dependent change of the blood flow in the prostate treated with high-intensity focused ultrasound. Additionally, our pathological findings support the longitudinal changes of these magnetic resonance imaging findings. Further large-scale studies will investigate the most appropriate timing of contrast-enhanced magnetic resonance imaging for evaluation of the effectiveness of high-intensity focused ultrasound for localized prostate cancer.

Clinical features of primary hyperthyroidism caused by Graves' disease admixed with resistance to thyroid hormone (P453T).

A 34-year-old Japanese woman was referred to the hospital because of general fatigue and palpitations. She was diagnosed as having resistance to thyroid hormone (RTH) and Hashimoto's thyroiditis at the age of 28. She felt general fatigue, palpitations, heat intolerance, and sweating for 6 months. Thyroid function tests demonstrated elevated levels of free triidothyronine (T3) and free thyroxine (T4) that were above detectable ranges and a completely suppressed level of TSH that was below the detectable range. Titers of anti-TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) were positive. A 20-minute Technetium-m99 pertechnetate thyroid uptake imaging study showed an elevated value of 39.53% and a normal-shaped thyroid gland. These results indicated that Graves' disease (GD) caused primary hyperthyroidism. Pituitary and peripheral tissues responded to the presence of excess thyroid hormone in the patient. Oral administration of methimazole was started and continued for 1 year 10 months, after which it was ceased. Two years after the cessation of methimazole treatment, level of free T4 was elevated compared to reference range, but levels of TSH and free T3 were within normal reference ranges. Titers of TRAb and TSAb remained negative for 2 years. These findings indicated that the patient's GD was in remission. In conclusion, it is difficult to make a differential diagnosis between GD with RTH and GD alone if RTH is not diagnosed before the onset of GD. An antithyroid drug is able to cause the remission of GD with RTH.

Small-cell carcinoma of the endometrium presenting as Cushing's syndrome.

Small-cell carcinoma (SCC) of neuroendocrine type is an uncommon tumor of the endometrium. No previous report has documented Cushing's syndrome due to ectopic ACTH production by SCC of the endometrium. We describe a 56-year-old Japanese woman with SCC of the endometrium and multiple lung metastases presenting as Cushing's syndrome. The patient was referred to our hospital because of general fatigue with facial and leg edema, and multiple nodular lesions in the bilateral lungs on chest X-ray examination. A physical examination revealed that the patient had moon face, buffalo hump, and truncal obesity. Endocrinological examinations confirmed ACTH-dependent Cushing's syndrome. Thoracic computed tomography imaging showed multiple nodular lesions in the bilateral lungs. Abdominal magnetic resonance imaging suggested a malignant tumor of the uterus. The patient received a lung tumor biopsy and surgical hysterectomy. The endometrial carcinoma was histologically a SCC admixed with endometrioid adenocarcinoma. The SCC of the endometrium showed immunoreactivity for pro-opiomelanocortin, ACTH, and vimentin, but not for thyroid transcription factor-1. The lung biopsy specimen had the same features. These findings indicated that the SCC originated from the endometrium, and the ectopic ACTH-producing tumor caused Cushing's syndrome. This study provides the evidence that SCC of endometrial origin was an ectopic ACTH-producing tumor causing Cushing's syndrome.

Positive Immunostaining for Succinate Dehydrogenase B (SDHB) in Paraganglioma Associated with Germline Mutation of SDHB, L157X and P236S.

PURPOSE: Pheochromocytoma (PCC) and paraganglioma (PGL) associated with the succinate dehydrogenase (SDH) germline mutations are characterized by negative results of immunohistochemistry tests for SDH subunit B (SDHB). Genetic testing for the SDH complex (SDHA, SDHB, SDHC, SDHD, and SDHAF2) is indicated only in patients with those diseases in whom immunohistochemistry tests for SDHB as a surrogate marker to detect the SDH complex mutation yield negative results. Two novel SDHB germline mutations, L157X and P236S, in PGL were previously reported. We therefore examined immunohistochemistry testing for SDHB in the PGLs with the SDHB germline mutations of L157X and P236S. METHODS: Immunohistochemistry for SDHB was performed in PGLs with the SDHB germline mutations of L157X and P236S. Five cases of sporadic PCC were subject to immunohistochemistry testing for SDHB. Normal tissue from the adrenal cortex adjacent to the sporadic PCC was used as the external positive control. RESULTS: Immunohistochemistry results were positive for SDHB in PGLs with the SDHB germline mutation of L157X and P236S, all five cases of sporadic PCC, and the adrenal cortex as the external positive control. CONCLUSION: Immunohistochemistry tests for SDHB showed positivity in PGLs associated with the SDHB germline mutations of L157X and P236S. Thus, immunohistochemistry testing for SDHB might not always reveal a surrogate marker in formal genetic testing of the SDH complex.

Effect of Lenvatinib on a Patient with Medullary Thyroid Carcinoma Liver Metastasis Caused by Multiple Endocrine Neoplasia Type 2A.

A 61-year-old female was diagnosed with multiple endocrine neoplasia type 2A (MEN2A), caused by a heterozygous point mutation in the RET gene (TGC to TAC at codon 634) resulting in the substitution of cytosine with leucine (C634Y). The patient had pheochromocytoma (PCC) in the left adrenal gland and medullary thyroid carcinoma (MTC) with liver metastasis. Primary hyperparathyroidism (PHP) was not evident. Family history data suggested that the RET gene mutation was inherited from the father. The PCC was removed laparoscopically, but the MTC was observed conservatively for 7 years because the status of the MTC was compatible with T1N1M1 and stage IVC; therefore, it was not curable with surgery. The MTC liver metastasis increased in size. Lenvatinib, an oral multi-tyrosine kinase inhibitor, was administered until the patient had received a total dose of 1336mg, and then administration was stopped because of nausea. The reduction rate of the MTC liver metastasis was 31%, which was considered partial response. At this point, the patient was doing well, suggesting that lenvatinib was effective in treating the MTC liver metastasis and may be one of the treatment for advanced MTC caused by C634Y mutation in the RET gene.

Resistance to thyroid hormone accompanied by atrial fibrillation

Resistance to thyroid hormone (RTH), which is primarily caused by mutations in the thyroid hormone (TH) receptor beta (THRB) gene, is dominantly inherited syndrome of variable tissue hyposensitivity to TH. We herein describe a case involving a 22-year-old Japanese man with RTH and atrial fibrillation (AF) complaining of palpitation and general fatigue. Electrocardiography results revealed AF. He exhibited elevated TH levels and an inappropriately normal level of thyroidstimulating hormone (TSH). Despite being negative for anti-TSH receptor antibody, thyroid-stimulating antibody and anti-thyroperoxidase antibody, the patient was positive for anti-thyroglobulin (Tg) antibody. Genetic analysis of the THRB gene identified a missense mutation, F269L, leading to the diagnosis of RTH. Normal sinus rhythm was achieved after 1 week of oral bisoprolol fumarate (5 mg/day) administration. After 3 years on bisoprolol fumarate, the patient had been doing well with normal sinus rhythm, syndrome of inappropriate secretion of TSH (SITSH) and positive titer of anti-Tg antibody. Learning points: •• Atrial fibrillation can occur in patients with RTH. •• Only a few cases have been reported on the coexistence of RTH and atrial fibrillation. •• No consensus exists regarding the management of atrial fibrillation in patients with RTH. •• Administration of bisoprolol fumarate, a beta-blocker, can ameliorate atrial fibrillation in RTH.

Novel application of three-dimensional shear wave elastography in the detection of clinically significant prostate cancer.

The present study evaluated three-dimensional shear wave elastography (3D SWE) in the detection of clinically significant prostate cancer. Clinically significant prostate cancer was defined by a minimum of one biopsy core with a Gleason score of 3+4 or 6 with a maximum cancer core length >4 mm. Patients with serum prostate-specific antigen levels of 4.0-20.0 ng/ml who were suspected of having prostate cancer from multi-parametric magnetic resonance imaging (mpMRI) were prospectively recruited. The 3D SWE was performed pre-biopsy, after which patients underwent MRI-transrectal ultrasound image-guided targeted biopsies for cancer-suspicious lesions and 12-core systematic biopsies. The pathological biopsy results were compared with the mpMRI and 3D SWE images. A total of 12 patients who were suspected of having significant cancer on mpMRI were included. The median pre-biopsy PSA value was 5.65 ng/ml. Of the 12 patients, 10 patients were diagnosed as having prostate cancer. In the targeted biopsy lesions, there was a significant difference in Young's modulus between the cancer-detected area (median 64.1 kPa, n=20) and undetected area (median 30.8 kPa, n=8; P<0.0001). On evaluation of receiver operating characteristics, a cut-off value of the Young's modulus of 41.0 kPa was used for the detection of clinically significant cancer, with which the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of cancer detection were 58, 97, 86 and 87%, respectively. When combining this cut-off tissue elasticity value with Prostate Imaging Reporting and Data System (PI-RADS) scores, the sensitivity, specificity, positive predictive value and negative predictive value of cancer detection were improved to 70, 98, 91 and 92%, respectively. In the cancer-detected lesions, a significant correlation was identified between the tissue elasticity value of the lesions and Gleason score (r=0.898, P<0.0001). In conclusion, PI-RADS combined with measurement of Young's modulus by 3D SWE may improve the diagnosis of clinically significant prostate cancer.

Evaluation of thyroid hormone action in a case of generalized resistance to thyroid hormone with chronic thyroiditis: discovery of a novel heterozygous missense mutation (G347A).

Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone (TH). Its characteristics are a high level of TH and inappropriate lack of TSH suppression. RTH is mainly categorized as generalized RTH (GRTH), pituitary RTH (PRTH), and peripheral tissue RTH (PTRTH). Untreated subjects with GRTH usually achieve a normal metabolic state. We describe a 21-year-old Japanese woman with GRTH and coincidental chronic thyroiditis. Physical examination revealed palpable goiter, congenital alopecia on top of the head, and short stature. She showed elevated levels of free triiodothyronine (FT3) and free thyroxine (FT4), and an inappropriately normal level of TSH. Anti-thyroglobulin and anti-thyroid peroxidase antibodies were positive. A TRH stimulation test showed a normal TSH response. The patient received the standardized diagnostic protocol, administration of incremental doses of liothyronine (L-T3). The peak TSH level after the TRH stimulation test gradually decreased. The patient showed low sensitivity to TH in terms of bone metabolism, protein catabolism, lipid metabolism, and urine magnesium metabolism. Sequence analysis of the TR beta gene was performed with informed consent, and this revealed a novel heterozygous mutation at codon 347 resulting in a GGG (glycine) to GCG (alanine) substitution (G347A). The patient was diagnosed as having GRTH with chronic thyroiditis, and carrying a novel mutation, G347A, of the TR beta gene.

Dysadherin: expression and clinical significance in thyroid carcinoma.

Dysadherin is a cancer-associated cell membrane glycoprotein. Its cDNA encodes 178 amino acids, including a putative signal sequence, a potential O-glycosylated extracellular domain, a single transmembrane domain, and a short cytoplasmic tail. Dysadherin is believed to down-regulate the expression of E-cadherin, the prime mediator of cell-cell adhesion in epithelial cells, by a posttranscriptional mechanism and promote the metastasis of carcinoma cells. To evaluate the association between dysadherin expression and E-cadherin expression in thyroid carcinoma, immunostaining for dysadherin and E-cadherin was performed in 51 papillary, 10 follicular, and 31 undifferentiated carcinomas. Immunoreactivity for dysadherin, localized at cell-cell boundaries, was detected in 39 of the 51 papillary carcinomas and all 31 undifferentiated carcinomas but not in the follicular carcinomas or normal thyroid tissue controls. Dysadherin expression was significantly higher in undifferentiated carcinoma than in papillary carcinoma and follicular carcinoma and showed significant negative correlation with E-cadherin expression. The degree of dysadherin expression was significantly associated with the prognosis, occurrence of secondary undifferentiated carcinomas, size of the primary tumor, and metastasis to the regional lymph nodes and lungs. In conclusion, a process involving increased dysadherin expression may lead to an adverse clinical outcome.

Expression and significance of c-met protein in papillary thyroid carcinoma.

The c-met protein, encoded by the c-met oncogene and its ligand, the hepatocellular growth factor/scatter factor, are known to be responsible for the motility and mitogenesis of epithelial cells including cancer cells. Recent studies have reported the prognostic significance of the c-met protein in malignant tumors. Papillary thyroid carcinoma, the most common histological type of thyroid carcinoma, can easily metastasize to regional lymph nodes, reflecting the activated motility and invasiveness of the carcinoma cells. We examined the expression of c-met protein in papillary thyroid carcinomas to assess its significance. Immunohistochemical staining of the c-met protein was performed on archival materials. The c-met protein was expressed in 10 cases of papillary thyroid carcinoma with recurrence, and in 5 of 10 cases without recurrence. Normal thyroids were negative for c-met protein. Expression of the c-met protein was statistically associated with recurrence of the thyroid carcinoma (p = 0.016). It is suggested that expression of the c-met protein plays a role in the recurrence of papillary thyroid carcinoma.

[Incidentaloma of the thyroid].

Thyroid incidentalomas are common, often less than 1.5 cm in size, and frequently benign. It is recommended that low-risk patients with incidentalomas be followed up ultrasonographically in 6 to 12 months and not be subjected to routine testing with ultrasonographically guided fine-needle aspiration biopsy (US-FNA). In patients who have nodules larger than 1.5 cm in size, a history of head and neck irradiation, a strong family history of thyroid carcinoma, or ultrasonographic findings that suggest malignancy, US-FNA should be done. A patient with hypercalcemia caused by ectopic production of parathyroid hormone in papillary thyroid carcinoma was reported. It is known that medullary thyroid carcinoma rarely shows production of adrenocorticotropic hormone or serotonin. However, ectopic hormone productive tumors in the thyroid are extremely rare.

The current status of tailor-made medicine with molecular biomarkers for patients with clear cell renal cell carcinoma.

Appropriate use of multiple reliable molecular biomarkers in the right context will play a role in tailormade medicine of clear cell renal cell carcinoma (RCC) patients in the future. A total of 11,056 patients from 53 studies were included in this review. The article numbers of the each evidence levels, using the grading system defined by the Oxford Centre for Evidence-based Medicine, in 1b, 2a, 2b, and 3b were 5 (9%), 18 (34%), 29 (55%), and 1 (2%), respectively. The main goal of using biomarkers is to refine predictions of tumor progression, pharmacotherapy responsiveness, and cancer-specific and/or overall survival. Currently, carbonic anhydrase (CA9) and vascular endothelial growth factor (VEGF) in peripheral blood and p53 in tumor tissues are measured to predict metastasis, while VEGF-related proteins in peripheral blood are used to assess pharmacotherapy responsiveness with sunitinib. Furthermore, interleukin 8, osteopontin, hepatocyte growth factor, and tissue inhibitors of metalloproteinases-1 in peripheral blood enable assessment of responsiveness to pazopanib treatment. Other reliable molecular biomarkers include von Hippel­Lindau gene alteration, hypoxia-inducible factor-1a, CA9, and survivin in tumor tissues and VEGF in peripheral blood for predicting cancer-specific survival. In the future, studies should undergo external validation for developing tailored management of clear cell RCC with molecular biomarkers, since individual institutional studies lack the generalization and consistency required to maintain accuracy among different patient series.

A novel mutation (P236S) in the succinate dehydrogenase subunit B gene in a Japanese patient with a posterior mediastinal paraganglioma.

Succinate dehydrogenase subunit B gene (SDHB) is associated with the development of hereditary paraganglioma (PGL) and pheochromocytoma (PCC). Here we describe a novel germline mutation in SDHB in a 69-year-old Japanese woman with a posterior mediastinal PGL. We summarize the clinical presentation, diagnostic work-up, and pathological features of a patient with a posterior mediastinal PGL and review the pertinent literature. Direct sequencing of SDHB and SDHD was performed. The patient presented with a posterior mediastinal tumor and was normotensive. She underwent abdominal tumor resection at the age of 38 years, but clinical and pathological diagnoses were unknown. She had no family history of hypertension, PGL, or PCC. Imaging studies suggested that the tumor was neurogenic. Endocrinological examinations showed normal plasma catecholamine levels. The tumor was completely removed without metastasis. Pathological findings confirmed PGL. Immunohistochemical staining showed that the tumor cells were positive for chromogranin A, synaptophysin, and CD56, and the Ki67 index was low (<1 %). The patient has not experienced recurrence or metastasis for the last 5 years. DNA sequencing revealed a novel P236S (c.843 C > T) mutation in SDHB. The P236S germline mutation in SDHB was associated with posterior mediastinal PGL. Strict follow-up of the patient is necessary because the SDHB mutation may be related to malignancy.

Value of metastin receptor immunohistochemistry in predicting metastasis after radical nephrectomy for pT1 clear cell renal cell carcinoma.

KISS-1 is a metastasis-suppressor gene of human melanoma, and encodes metastin, which was identified as the ligand of a G-protein-coupled receptor (metastin receptor). The precursor protein is cleaved to 54 amino acids, which may be further truncated into carboxy-terminal fragments. Previous studies showed that lack of metastin receptor in clear cell renal cell carcinoma (RCC) is associated with tumor progression, but the prediction of metastasis in patients with pT1 clear cell RCC after radical nephrectomy is difficult. The objective of this study was to evaluate the usefulness of metastin receptor immunohistochemistry in predicting metastasis after nephrectomy for pT1 clear cell RCC. After verification of the correlation between immunostaining and mRNA expression, we evaluated the clinical value of metastin receptor immunohistochemistry. Fifty-four patients were enrolled in this study; following radical nephrectomy, seven patients were found to have lung metastasis. The sensitivity, specificity, positive predictive value, and negative predictive value with negative immunostaining of metastin receptor were 85.7, 97.6, 46.2, and 97.6 %, respectively. Metastasis-free survival rates were significantly higher in patients with positive staining (97.6 %) than in patients with negative staining (53.8 %) (P < 0.001). In univariate analysis for metastasis-free survival, negative immunostaining of metastin receptor was a significant risk factor for metastasis (P = 0.001). Furthermore, negative immunostaining of metastin receptor was an independent predictor for metastasis in multivariate analysis (hazard ratio, 3.735; 95 % CI 0.629-22.174; P = 0.002). In conclusion, our study suggests that negative expression of metastin receptor in clear cell RCC is significantly related to metastasis.

Syndrome of inappropriate secretion of antidiuretic hormone caused by pituitary macroadenoma with hemangiomatous stroma.

A 55-year-old Japanese man was referred to our hospital because of disturbance of consciousness and hyponatremia. He had been aware of general fatigue, nausea, and headache for two weeks. Tests revealed hyponatremia, plasma hypoosmolarity with urine hyperosmolarity, an elevated level of urine sodium excretion, and normal functions of the kidney, adrenal gland, and thyroid. These findings were compatible with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Head magnetic resonance imaging (MRI) demonstrated a pituitary tumor measuring 20 x 22 x 21 mm that pushed the pituitary stalk upward. Endocrinological evaluations suggested that the pituitary adenoma was non-functional. The pituitary adenoma was surgically removed, and histological examination revealed a biphasic appearance characterized by endocrine cells and a hemangiomatous stroma. After surgery, the patient developed pituitary hypothyroidism, pituitary adrenal insufficiency, and pituitary gonadal failure. Therefore, levothyroxine sodium, 50 µg per day, and hydrocortisone, 10 mg per day, were administered orally. Androgen depot, 250 mg every two months, was also injected intramuscularly. The hyponatremia did not recur, and the patient has done well for the last five years. The pituitary adenoma in this case showed two features: one was the cause of SIADH, and the other was a biphasic histological picture of endocrine cells with a hemangiomatous stroma.

Surgical management of metastatic adrenal tumors: Decision-making factors in imaging.

The present study aimed to clarify decision-making factors based on imaging for laparoscopic adrenalectomy (LA) or open adrenalectomy (OA) for adrenal metastasis (AM) based on our previous experience. From November 2003 to November 2006, 11 adrenalectomies were performed for AM for malignancies such as lung cancer, renal cell carcinoma (RCC) and breast cancer at Tokai University Hospital. A diagnosis of AM for these malignancies was suspected whenever a newly diagnosed adrenal mass was located, characterized by a basal computed tomography (CT) density superior to 10 Hounsfield units, strong or heterogeneous vascular enhancement following contrast injection and/or increasing size in sequential imaging studies. There was no evidence of extra-AM. The approach to surgical management using LA or OA was determined on the basis of CT and/or magnetic resonance imaging. The patients were reviewed every 2 or 3 months by physical examination and systemic CT. We analyzed the decision-making factors based on imaging for surgical management with LA or OA from the results of oncological outcome, imaging, intraoperative and pathohistological findings. In this study, 9 patients underwent 11 adrenalectomies (9 laparoscopic and 2 open procedures). Non-small cell lung cancer was the most common primary malignancy (5 adrenalectomies of 4 patients), followed by RCC (4 adrenalectomies of 4 patients) and breast cancer (2 adrenalectomies of 1 patient). The median tumor size for the LA group was 3.1±0.7 cm (range 2.1-4.3) and for the OA group, 6.1±0.8 cm (5.5 and 6.7 cm) (p=0.001). The operative time for the LA group was 127±42 min (range 90-215) and for the OA group, 224±47 min (190 and 257 min) (p=0.018). Blood loss for the LA group was 49±63 g (range 3-207) and for the OA group, 340±10 g (333 and 347 g) (p<0.001). No complications were noted and no conversion of LA to OA occurred. All 9 adrenal tumors selected for LA were removed safely without strong adhesion to the surrounding tissue. Two adrenal tumors removed by OA had a strong adhesion to the surrounding tissue. All 9 patients had complete resection, without capsular disruption and a negative margin in the pathological findings. No port-site and local recurrences occurred. No patients presented with local relapse or port-site metastasis. Disease-free survival rate for the LA group was 57% and for the OA group, 50% (p=0.661). LA is a less invasive treatment than OA for AM. However, for complete resection, OA should be selected for cases where resection by LA is difficult. Therefore, in the decision making towards the appropriate surgical management with LA or OA, it is important to closely assess pre-operative imaging. Imaging features supporting OA include no detection of fatty tissue between the tumor and proximal organs, tumors with an irregular contour, large tumors and tumors with a cystic component.

Metastin has potential as a suitable biomarker and novel effective therapy for cancer metastasis (Review).

Cancer metastasis is a leading cause of death in cancer patients and is a multistep process involving complex interactions between tumor and host cells. To metastasize, tumor cells must invade or migrate from the primary tumor and be transported to close or distant secondary sites. A tumor cell should successfully accomplish each step of the pathway or metastasis may not develop. KiSS-1 is a human metastasis suppressor gene that inhibits metastasis of human melanomas and breast carcinomas without affecting tumorigenicity. KiSS-1 encodes a carboxy-terminally amidated peptide with 54 amino-acid residues. The peptide was isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor and termed 'metastin'. The literature reports metastin related to human carcinoma, such as melanoma, thyroid cancer, esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma, pancreatic carcinoma, as well as breast, ovarian, bladder and kidney cancer. These malignancies are difficult to treat and, even in early-stage cancer, a number of patients develop metastasis shortly after surgery. Studies have suggested that metastin inhibits tumor invasion or migration through focal adhesion kinase, paxillin, MAP kinase or Rho A. Additionally, metastin may be a biomarker in ESCC, pancreatic carcinoma and bladder cancer. Metastin has potential as a suitable biomarker in the identification of tumors with high metastatic potential and as a novel effective treatment modality for patients with metastasis.

L157X nonsense mutation of the succinate dehydrogenase subunit B gene in a Japanese patient with right paraaortic paraganglioma.

Nuclear genes succinate dehydrogenase B subunit and succinate dehydrogenase D subunit, which encode two mitochondrial complex II subunits, are associated with the development of familial paraganglioma (PGL). Succinate dehydrogenase B subunit gene mutation is highly associated with extraadrenal PGL and subsequent distant metastasis. We describe the case of a 29-year-old Japanese man with a 3-year history of hypertension, headache, and palpitation. Endocrinological examinations showed that the patient had elevated levels of catecholamines, and imaging studies revealed a right paraaortic PGL without distant metastases. The PGL was surgically removed. Genetic analysis of the patient showed a heterozygous thymine deletion at position 470 (c.470delT) in exon 5 of the succinate dehydrogenase B subunit gene complementary DNA. This thymine deletion changed TTG (leucine) to TGA (stop codon) at codon 157 (L157X). It remains unclear whether this mutation was associated with PGL malignancy because the patient has had no metastases for the past 3 years. It has been recently reported that L157X is associated with malignant paraaortic PGL. Thus, strict follow-up is required because this succinate dehydrogenase B subunit gene's nonsense mutation (L157X) may be related to the malignancy.

Black adrenal adenoma causing preclinical Cushing's syndrome.

Functioning black adrenal adenoma (BAA) rarely causes preclinical Cushing's syndrome (CS). In the present case, a 46-year-old Japanese Peruvian woman presented with left flank pain and hypertension. Abdominal computed tomography showed that she had a 15-mm in diameter, round, left adrenal adenoma. She had no physical features of CS, such as moon face, buffalo hump, truncal obesity, or purple striae. Endocrinological examination showed that the plasma adrenocorticotropic hormone (ACTH) level was below the detectable level, despite a serum cortisol level within the normal range. A normal cortisol circadian rhythm was not present. Dexamethasone (1 mg and 8 mg) suppression testing did not decrease serum cortisol levels to the reference levels. These findings were compatible with preclinical CS. The left adrenal adenoma was laparoscopically removed. Examination of the surgical specimen revealed unilateral double adrenal adenomas of the left adrenal gland, one of which was a BAA. The BAA measured 20 × 11 × 10 mm. Microscopically, the BAA showed proliferation of compact cells containing numerous brown-pigmented granules. There were also foci of myelolipomatous degenerative changes in the tumor. The compact cell zones remained in the adrenal cortex adjacent to the BAA showed atrophic change. These findings indicated that BAA appeared to have caused preclinical CS in this patient.