Arihiro Shibata

Inhibition of NF-κB Activity Decreases the VEGF mRNA Expression in MDA-MB-231 Breast Cancer Cells

VEGF (vascular endothelial growth factor) secreted from tumor cells including breast cancer serves as a potent angiogenic factor which favors tumor growth and metastasis. Indeed, a higher concentration of serum VEGF has been shown to associate with a poorer prognosis in patients with breast cancer. On the other hand, constitutive expression of a transcription factor, NF-κB was correlated with progression and metastasis in a number of human breast cancers, suggesting a possible regulation of VEGF expression by NF-κB. We thus investigated the relationship between the expression of VEGF and constitutive NF-κB activity in three breast cancer cell lines, MCF-7, T47D, and MDA-MB-231. The basal levels of VEGF mRNA expression correlated with those of nuclear NF-κB activity in these cell lines. The highest NF-κB activity in MDA-MB-231 cells was associated with the highest expression of VEGF mRNA, while the activity and the mRNA levels were moderate in MCF cells and the lowest in T47D cells. In MDA-MB-231 cells, inhibition of NF-κB by adenovirus-mediated expression of a dominant negative NF-κB or by a proteasome inhibitor, MG132, decreased the VEGF mRNA. These results suggest that NF-κB is involved in the upregulation of VEGF mRNA and inhibition of the activity could be a new approach for the treatment of breast cancer by preventing angiogenesis.

Seaweed Prevents Breast Cancer

To investigate the chemopreventive effects of seaweed on breast cancer, we have been studying the relationship between iodine and breast cancer. We found earlier that the seaweed, wakame, showed a suppressive effect on the proliferation of DMBA (dimethylbenz(a)anthracene)‐induced rat mammary tumors, possibly via apoptosis induction. In the present study, powdered mekabu was placed in distilled water, and left to stand for 24 h at 4°C. The filtered supernatant was used as mekabu solution. It showed an extremely strong suppressive effect on rat mammary carcinogenesis when used in daily drinking water, without toxicity. In vitro, mekabu solution strongly induced apoptosis in 3 kinds of human breast cancer cells. These effects were stronger than those of a chemothera‐peutic agent widely used to treat human breast cancer. Furthermore, no apoptosis induction was observed in normal human mammary cells. In Japan, mekabu is widely consumed as a safe, inexpensive food. Our results suggest that mekabu has potential for chemoprevention of human breast

Wakame seaweed suppresses the proliferation of 7,12-dimethylbenz(a)-anthracene-induced mammary tumors in rats.

We examined the anti‐tumor proliferation effects of wakame seaweed on 7,12‐dimethylbenz(a)‐anthracene (DMBA)‐induced rat mammary tumor. DMBA was administered to 8‐week‐old female Sprague‐Dawley rats, and rats which developed mammary tumors were assigned randomly to three groups. Commercial rat feed was used in a control group (group I‐A), and two feed mixtures were prepared, which contained commercial rat feed blended with wakame at 1.0% (group I‐B) and 5.0% (group I‐C) by weight. The respective feeds were given to each group for 8 weeks, and changes in mammary tumor size were compared. At the end of the experiment, mammary tumors and thyroid glands were resected to compare their weights. Serum total iodine and thyroxin (T4) levels were measured. Immunohistochemical studies for bromodeoxyuridine (BrdU) labeling, transforming growth factor (TGF)‐β, and apoptosis were carried out in the resected tumor. Significant suppression of tumor growth was observed in groups I‐B and I‐C compared with I‐A. In groups I‐B and I‐C, the weights of resected mammary tumors were significantly lower and serum total iodine concentration was significantly higher than in I‐A. BrdU indices were significantly lower in groups I‐B and I‐C, compared with I‐A. TGF‐β and apoptotic index were inversely related to BrdU. These results suggest that iodine is transported from the serum into mammary tissues and induces apoptosis through the expression of TGF‐β. In conclusion, wakame suppressed the proliferation of DMBA‐induced mammary tumors.

Adrenal Incidentaloma: Review of 197 Patients and Report of a Drug-Related False-Positive Urinary Normetanephrine Result

PurposeTo determine the incidence and importance of functioning tumors among incidentally discovered adrenal masses in the era of laparoscopic surgery.MethodsWe defined adrenal incidentaloma as a tumor detected during abdominal imaging for adrenal-unrelated reasons, and we reviewed 197 consecutive patients with adrenal incidentaloma diagnosed since we started laparoscopic adrenalectomy.ResultsIncidentaloma was discovered initially in 91 (46%) patients and pheochromocytoma was detected as an incidentaloma in 21 (39%) of 54 patients. One patient, a 21-year-old woman taking mesalamine for ulcerative colitis, had a remarkably elevated urinary normetanephrine level, which resulted in the initial misdiagnosis of a 10-cm right adrenal incidentaloma as a pheochromocytoma. Laparoscopic right adrenalectomy resulted in a pathological diagnosis of ganglioneuroma. A series of urinary normetanephrine measurements were taken in parallel with the mesalamine doses. We found that other patients medicated with mesalamine, without adrenal tumors, had elevated urinary normetanephrine levels, confirming that mesalamine metabolites interfere with urinary normetanephrine measurements.ConclusionsIt is essential to diagnose the functional potential of adrenal incidentaloma preoperatively, and not to perform laparoscopic adrenalectomy for adrenal incidentaloma without careful evaluation first.

Patterns of Lymph Node Metastases in Papillary Thyroid Carcinoma: Results from Consecutive Bilateral Cervical Lymph Node Dissection

BackgroundIn patients with papillary thyroid carcinoma (PTC), the appropriate extent of lymph node dissection has not yet been established due to lack of accurate patterns of lymph node metastases (LNM). The aim of this study was to clarify the LNM pattern in PTC patients based on our institution’s experience with a consistent technique of bilateral neck dissection, and to consider the rational extent of lymph node dissection.MethodsBetween 1990 and 1999, 152 consecutive patients with PTC who underwent curative total thyroidectomy and bilateral neck dissection as initial treatment were analyzed. The patterns of LNM according to clinicopathological classification were analyzed using the lymph node ratio (LNR; number of metastatic lymph nodes/number of dissected nodes) and frequency (FLNM; number of patients with LNM/number of dissected patients) in cervical compartments.ResultsRegardless of clinicopathological classification, LNR in the central compartment was consistently higher than in other compartments, and FLNM in the ipsilateral lateral compartment was consistently higher than in other compartments except for multifocal tumors. The LNR and FLNM in the contralateral lateral compartment were significantly higher in advanced (≥T3) cases than in cases with smaller tumors (T1) and were comparable to those in the ipsilateral lateral compartment in advanced (≥T3) cases.ConclusionsThe pattern of LNR provided a better reflection of the patterns of LNM. In terms of the LNR, central neck dissection is the basic extent of lymph node dissection for all clinically apparent PTC. In advanced patients, it is also advisable to include bilateral lateral neck dissection.

Expression of Adrenocorticotropin Receptor Gene in Adrenocortical Adenomas From Patients With Cushing Syndrome: Possible Contribution for the Autonomous Production of Cortisol

ObjectiveTo examine whether inhibition of endogenous adrenocorticotropin (ACTH) secretion in patients with Cushing syndrome affects the expression of the ACTH receptor (ACTH-R) gene in adrenocortical adenoma and attached atrophic normal gland. Summary Background DataACTH increases adrenal cell growth and steroidogenesis by means of ACTH-R. In vivo and in vitro studies have shown that expression of ACTH-R is upregulated by its own ligand ACTH in several species. In patients with Cushing syndrome resulting from adrenocortical adenoma, there is autonomous production of cortisol from the adenoma. This strongly inhibits endogenous ACTH secretion, giving rise to the speculation that the expression of the ACTH-R gene in these patients is also suppressed. However, previous studies have shown that administration of exogenous ACTH to these patients leads to a further increase in the production of cortisol, suggesting the expression of functional ACTH-R in the adenoma. The authors, therefore, examined the expression of the ACTH-R gene in these patients. MethodsFourteen patients with Cushing syndrome were studied. Glucocorticoid excess resulting from autonomous production from the adenomas was ascertained, and unilateral adrenalectomy was performed. The levels of ACTH-R and cytochrome P450 side chain cleavage enzyme (P450scc) mRNAs were determined by Northern blot analysis. The entire coding region of the ACTH-R gene in these patients was sequenced. ResultsACTH-R mRNA abundance in the attached atrophic normal adrenals was suppressed and invariably less than that in the normal gland obtained from a patient with renal cancer. However, the expression of ACTH-R mRNA was not suppressed in any of the adenomas. Expression of ACTH-R mRNA in the adenomas was four- to sixfold greater than that in the attached atrophic gland. No mutation in the coding sequence of the ACTH-R gene in the adenoma was detected in any of the patients. The mRNA in the adenomas appeared to be translated into functionally active receptor because intramuscular administration of ACTH resulted in significant increases in plasma cortisol before surgery but not 3 months after surgery. In addition, there was a positive linear correlation between the expressions of ACTH-R and P450scc mRNAs in the adenoma tissue. ConclusionsSuppressed ACTH secretion in patients with Cushing syndrome results in reduction of the ACTH-R mRNA expression in nonneoplastic adrenocortical cells. However, the regulatory mechanism of ACTH-R expression might be different in adenoma. Persistent expression in the adenoma of ACTH-R alone, even in the absence of ACTH, might result in increased basal adenyl cyclase activity, as observed in the case of thyroid-stimulating hormone receptor, and thereby might play a role in the autonomous production of cortisol.

Laparoscopic adrenalectomy for incidentaloma and bilateral adrenal disease.

Adrenalectomy is ideally suited to minimally invasive surgery based on the characteristics of adrenal tumours, which are usually small and benign. The aim of this study was to verify that laparoscopic adrenalectomy is minimally invasive and to assess the indication of laparoscopic adrenalectomy for incidentaloma. From October 1995 through August 2002, 133 patients underwent adrenal surgery at the Department of Surgery II, Nagoya University School of Medicine. Of these, 111 underwent laparoscopic adrenalectomy. All laparoscopic adrenalectomies were performed using the transabdominal lateral approach. In 50 of 133 patients, the adrenal tumours were incidentally discovered. There were 27 non-functioning adrenal tumours and six of seven preclinical Cushings test syndrome cases incidentally discovered. Six of 27 non-functioning adrenal tumour patients underwent open adrenalectomy because of large tumour size or malignancy. Based on the present criteria for laparoscopic adrenalectomy, 15 of 133 patients were retrospectively considered to have required open adrenalectomy. The average size of a non-functioning adrenal tumour was 5.8 cm in diameter, which was equal to the average size of a phaeochromocytoma. A simultaneous bilateral laparoscopic adrenalectomy was performed in a patient in poor condition with advanced Cushings syndrome due to adrenocorticotrophic hormone-independent macronodular adrenocortical hyperplasia (AIMAH). The adrenal glands were successfully removed without fragmentation in this patient, and the postoperative course was uneventful, thanks to the minimally invasive surgery. The laparoscopic technique assures less morbidity and faster recovery, and appears to be equally effective in eradicating functioning and non-functioning adrenal masses. The benefits of the laparoscopic approach to adrenalectomy should not result in a more aggressive attitude toward the excision of clinically silent, benign-appearing adrenal incidentalomas.

Section 3. Adrenal: Laparoscopic bilateral adrenalectomy for Cushing’s syndrome due to ACTH-independent macronodular adrenocortical hyperplasia

We performed simultaneous bilateral laparoscopic total adrenalectomy in two patients with Cushings syndrome due to ACTH-independent macronodular adrenocortical hyperplasia (AIMAH). Preoperative serum cortisol in the patients was 29.5 and 53.2 microg/dl, respectively. The clinical symptoms of the latter patient were advanced, and respiration was labored with orthopnea. Laparoscopic adrenalectomies were performed transabdominally in the sequential lateral decubitus positions with extension of the lateral abdominal wall of the affected side. Three 12-mm and three 5-mm trocars were positioned, and two trocar sites in the midline were used on both sides. The flexible fiberscope was inserted through the umbilical port. The adrenal glands were large, fragile, and multinodular. The maximal diameters of the removed glands were 7.8 and 8.7 cm, respectively. In both patients, the adrenal glands were successfully removed without fragmentation. The operation times were 505 and 320 min, and the estimated blood loss was 150 and 5 ml, respectively. Neither intraoperative nor postoperative complications occurred, although the latter patient required muscle training before ambulation on postoperative day 42. The procedures resulted in marked clinical improvements. Compliance with the substitutive therapy remained excellent, and the patients expressed a very high degree of satisfaction with the laparoscopic adrenal surgery. The procedures of bilateral laparoscopic adrenalectomy were successful, and provided increased experience with the laparoscopic techniques.

Mesh Plug Repair for a Small Incisional Hernia in a Cirrhotic Patient with Ascites:Report of a Case

We report herein the case of a patient with severe liver ascites due to cirrhosis in whom a small incisional hernia on a midline incision was successfully treated by a mesh plug repair, a method most commonly employed for groin hernia repair. The hernia sac was dissected and inverted into the abdominal cavity by the mesh plug under epidural anesthesia. The patient’s recovery was quick and relatively painless, and there has been no recurrence after 1 year of followup. This case report demonstrates that the method of mesh plug repair may be appropriate for small incisional hernias as well as groin hernias, performed under epidural anesthesia.