Evolution of Pleural Solitary Fibrous Tumors Causing Severe Hypoglycemia after Exceptionally Long Asymptomatic Periods: Report of Two Surgical Cases.

Non-islet cell tumor hypoglycemia (NICTH) is one of the paraneoplastic syndromes manifesting severe hypoglycemia caused by aberrant production of high-molecular-weight insulin-like growth factor 2 (big-IGF2). Two surgical cases of extremely large thoracic solitary fibrous tumors (SFT) with unusual history of NICTH are presented. One case manifested severe hypoglycemia after four years of the first complete surgical resection of the tumor with potential malignant transformation, and the other case showed severe hypoglycemia after ten years of the first detection of the tumor. Meticulous laboratory testing, including serum endocrinological tests and western immunoblotting before and after surgery was performed, and both cases were diagnosed as NICTH. Both patients underwent open thoracic surgery. The patients showed normal glucose and hormone levels immediately after the resection of responsible tumors with elevated blood insulin concentration. SFTs are generally considered benign; however, life-threatening hypoglycemia can happen regardless of treatment. Careful follow-up of the tumor growth is warranted.

Fulminant Type 1 Diabetes Mellitus Developed about Half a Year after Discontinuation of Immune Checkpoint Inhibitor Combination Therapy with Nivolumab and Ipilimumab: A Case Report.

The cytotoxic T-lymphocyte antigen-4 and programmed cell death 1 pathways are novel therapeutic targets in immune checkpoint inhibitor (ICI) therapy for cancer. However, they may cause endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis and type 1 diabetes mellitus (DM). Moreover, delayed immune-related adverse events (irAEs) after discontinuation of ICI therapy have been reported. Here we report a 60-year-old female patient with advanced renal cell carcinoma with brain metastasis who was treated with nivolumab, ipilimumab and prednisolone. At the 3rd course of combination therapy, the administration was discontinued due to the onset of colitis and the dosage of prednisolone was increased. About half a year after discontinuation, she was admitted to the hospital with general malaise, hyperglycemia (330 mg/dL) and diabetic ketoacidosis. Glycated hemoglobin level was 6.5%. Islet-related autoantibodies were negative. The glucagon tolerance test showed complete depletion of insulin. Therefore, we diagnosed fulminant type 1 DM and treated with multiple daily injections of insulin. The onset of type 1 DM was rapid in many cases treated with combination therapy of ICIs. The present case is a rare case in which fulminant type 1 DM developed about half a year after discontinuation of nivolumab and ipilimumab. The literature shows two cases of type 1 DM occurring 4 months after discontinuation of ICI therapy by nivolumab or atezolizumab. The present case indicates that regular monitoring is mandatory for fulminant type 1 DM and other delayed irAEs after discontinuation of ICI therapy even under the low-dose prednisolone treatment.

Sight-Threatening Graves' Ophthalmopathy during the Third Trimester of Pregnancy: A Case Report.

Dysthyroid optic neuropathy is a severe manifestation of Graves' ophthalmopathy that can result in permanent vision loss. We report a 37-year-old pregnant woman with Graves' ophthalmopathy which was deteriorated to dysthyroid optic neuropathy in the third trimester of pregnancy. Diplopia, bilateral eye lid retraction, lid edema and proptosis were observed in the 29th week of gestation. Thyroid-stimulating hormone (TSH) level was decreased with a normal level of free triiodothyronine (FT3) and an upper normal level of free thyroxine (FT4). Anti-TSH receptor antibodies (16.2 IU/L, reference range < 2.0 IU/L) and thyroid stimulating antibody (4,443%, reference range < 120%) were positive. Magnetic resonance imaging (MRI) demonstrated a significant enlargement of the extraocular muscles with a high signal intensity on T2-weighted image. She was diagnosed as Graves' ophthalmopathy and subclinical hyperthyroidism, and followed without treatment. In the 34th week of gestation, the symptom of color vision abnormality appeared, suggesting dysthyroid optic neuropathy. She delivered a female infant during the 36th week of gestation. Four days after delivery, she had a spontaneous orbital pain. MRI showed that the extraocular muscles were more enlarged than the findings in the 29th week of gestation. FT3 and FT4 levels were mildly elevated. Dysthyroid optic neuropathy was diagnosed. She was treated with methylprednisolone pulse therapy and retrobulbar injections of betamethasone valerate, and the ocular symptoms improved. The present case shows that the glucocorticoid therapy performed one week after delivery is effective against Graves' ophthalmopathy which was deteriorated to dysthyroid optic neuropathy during the third trimester of pregnancy.

Reducing the gender gap in academic activities: a 10-year progress report by the Japan Endocrine Society Women Endocrinologists Association (JES-We-Can).

The Japan Endocrine Society (JES) has the largest ratio of female membership among societies associated with Internal Medicine in Japan; half of female members are in their 20s or 30s at present. In 2009, JES organized the "JES-We-Can" committee to promote women's career development. To evaluate the effectiveness of JES-We-Can, we investigated the gender balance of various activities at JES in fiscal 2009 and 2017. Significant gender-differences were not observed in the acquisition rate of board-certified endocrinologists (BCEs) aged <40 y in 2009 and 2017. However, the acquisition rate of BCEs among women aged ≥40 y was significantly lower than men in 2009. In 2017, the gender-difference among BCEs in this group (currently aged ≥50 y) has considerably improved, but is not resolved. The acquisition rate of certificated endocrine educators (CEEs) among women was still significantly lower than men at all ages in 2017. Since the ratio of women oral speakers or poster presenters at annual academic meetings have grown to equal or surpass the membership ratio, female members make efficient contributions to JES. The numbers of women chairpersons, symposiasts, lecturers and invited speakers have increased, but remain limited. JES-We-Can was found to be effective in reducing the gender gap in academic activities at JES, but JES-We-Can should support women more intensely to raise the rate of CEEs among all ages and BCEs currently over 50 y, and to promote more women into higher positions in JES in the future. These actions are expected to introduce new and diverse perspectives into academia.

Painless Thyroiditis and Fulminant Type 1 Diabetes Mellitus in a Patient Treated with an Immune Checkpoint Inhibitor, Nivolumab.

The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. Nivolumab, an anti-PD-1 monoclonal antibody, blocks PD-1 and can restore anti-cancer immune responses by disrupting the signal that inhibits T-cell activation. Nivolumab may induce endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis, and type 1 diabetes mellitus. Here we report a 68-year-old female patient with advanced renal cell carcinoma who was treated with nivolumab. She had positive anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies with slightly elevated thyroid-stimulating hormone (9.048 µU/mL), and was diagnosed as chronic thyroiditis with subclinical hypothyroidism before nivolumab therapy. She developed painless thyroiditis after the first cycle of the therapy (Day 14). At the 7th cycle of nivolumab therapy (Day 98), hyperglycemia (473 mg/dL) was noted, whereas glycated hemoglobin level was 6.9%. Islet-related autoantibodies were all negative. The glucagon tolerance test showed complete depletion of insulin. Human leukocyte antigen typing showed haplotype DRB1*09:01-DQB1*03:03, which was reported to be closely associated with type 1 diabetes mellitus in Japan. Fulminant type 1 diabetes mellitus was diagnosed, and she was immediately treated with multiple daily injections of insulin. Fulminant type 1 diabetes mellitus is characterized by rapid-onset diabetic ketoacidosis, and negative islet-related autoantibodies, and was proposed as a novel subtype of non-autoimmune diabetes. Preceding painless thyroiditis with positive thyroid autoantibodies observed in the present case, however, raises the possibility that autoimmune mechanisms are involved in the pathogenesis of nivolumab-induced fulminant type 1 diabetes mellitus.

Usefulness of anti-rabphilin-3A antibodies for diagnosing central diabetes insipidus in the third trimester of pregnancy.

We report a 27-year-old pregnant woman with polyuria, polydipsia and headache in the third trimester of pregnancy. Hypernatremia (153 mEq/L), high plasma osmolality (300 mOsm/kgH2O) and low urinary osmolality (92 mOsm/kgH2O) were observed at the admission to our hospital. Plasma arginine vasopressin (AVP) level was inappropriately low (2.2 pg/mL) compared to the high plasma osmolality. Plasma AVP responses to hypertonic-saline infusion were blunted, and her urine osmolality increased in response to desmopressin. The diagnosis of central diabetes insipidus was made from these results. Magnetic resonance imaging (MRI) of hypothalamic-pituitary region demonstrated a significant enlargement of the pituitary stalk, suggesting the presence of hypophysitis. In addition, serum anti-rabphilin-3A antibodies that have been recently reported as a biomarker of lymphocytic infundibulo-neurohypophysitis, were positive. Diabetes insipidus continued after delivery, suggesting that polyuria was not mainly due to excessive vasopressinase activity or reduced renal sensitivity to AVP by prostaglandin E2 that can cause temporal polyuria during pregnancy. We therefore clinically diagnosed central diabetes insipidus due to lymphocytic infundibulo-neurohypophysitis, without performing invasive transsphenoidal pituitary biopsy. This case suggested the usefulness of anti-rabphilin-3A antibodies for the etiological diagnosis of central diabetes insipidus during pregnancy.

[A Case of Rectal Cancer with Lymphangiosis Carcinomatosa Successfully Treated with Chemotherapy Despite Anaphylactic Reaction to Oxaliplatin].

A 64-year-old man was admitted because of dyspnea. He was diagnosed with rectal cancer with lymphangiosis carcinomatosa and metastases in the liver and lymph nodes. The patient was treated with cetuximab and modified FOLFOX6 (mFOLFOX6). After treatment, the primary rectal cancer and metastases were considered to have achieved a partial response (PR) and the lymphangiosis carcinomatosa remarkably improved. However, anaphylactic shock occurred in the 6 courses of treatment, 5 minutes after the infusion of oxaliplatin, and the patient was treated.

Bromocriptine, a dopamine agonist, increases growth hormone secretion in a patient with acromegaly.

Bromocriptine, a potent D2-dopamine agonist, suppresses growth hormone (GH) secretion in most patients with acromegaly and has been approved for the treatment of acromegaly. Here we report a patient with acromegaly who showed increased GH secretion after administration of bromocriptine. A 70-year-old man with acromegalic manifestation was admitted to our hospital because of a pituitary tumor invading to the right cavernous sinus detected by brain magnetic resonance imaging. Serum GH and insulin-like growth factor-I (IGF-I) levels were elevated in several occasions (GH: 15.0-51.7 ng/mL, reference range: <2.47 ng/mL; and IGF-I: 776-856 ng/mL, reference range: 57-175 ng/mL). Effect of bromocriptine on serum GH levels was then studied because pre-operative treatment with a D2-dopamine agonist was planned in order to reduce the tumor size and serum GH levels before surgery. After oral administration of 2.5 mg of bromocriptine, serum GH levels were unexpectedly increased from 30.7 ng/mL to 189 ng/mL, despite the fact that the levels of prolactin (PRL) were decreased from 4.2 ng/mL to 0.6 ng/mL. By contrast, serum GH levels were decreased by a somatostatin analogue, octreotide. Transsphenoidal surgery of the pituitary tumor was performed after treatment of octreotide. Histological analysis and immunohistochemistry revealed a GH-producing pituitary adenoma positive for D2-dopamine receptor. This case of acromegaly suggests that the preliminary test with a single administration of a short-acting D2-dopamine agonist, bromocriptine, is mandatory before the long-term therapy with a D2-dopamine agonist in patients with GH-secreting pituitary tumors.

Papillary thyroid carcinoma in one of identical twin patients with Pendred syndrome.

Pendred syndrome is an autosomal recessive disorder characterized by sensorineural deafness, a partial defect in iodide organification, and dyshormonogenetic goiter. Several cases of Pendred syndrome with follicular thyroid carcinomas were reported previously. Here we report identical twin patients with Pendred syndrome, who had thyroid tumors with distinct histopathological findings. 34-year-old identical twins with congenital deafness and goiter were referred to our hospital with complaint of neck discomfort. The genetic testing showed that these twin patients were compound heterozygotes carrying the same two mutations in the Pendred's syndrome (PDS / SLC26A4) gene (c2168A > G and ins2110GCTGG), which confirmed the diagnoses of Pendred syndrome. They underwent thyroidectomy. Histological examination of the thyroid tumors resected from these twin patients revealed follicular variant of papillary thyroid carcinoma, and diffuse and nodular goiter without any evidence of malignancy, respectively. To our knowledge, the former is the first case of follicular variant of papillary thyroid carcinoma in Pendred Syndrome.

Prediction of late (24-hour) radioactive iodine uptake using early (3-hour) uptake values in Japanese patients with Graves' disease.

Measurement of 24-hour radioactive iodine uptake (RAIU), which is commonly used to calculate the dose of radioiodine (RI) therapy, cannot be accomplished in a single day. The purpose of this study was to predict 24-hour RAIU from 3-hour RAIU in Japanese patients with Graves' disease, and to investigate other factors that could be used to predict 24-hour RAIU. A total of 66 Japanese patients (14 men and 52 women; age, 17-83 years) with Graves' disease who had undergone both 3-hour and 24-hour ¹²³I RAIU measurements between January 2006 and September 2011 were included in this study. Stepwise multiple regression analyses were performed in order to identify factors that could be used to predict 24-hour RAIU. The investigated factors were gender, age, thyroid volume, TSH, free thyroxine (FT4), free triiodothyronine (FT3), serum creatinine, second generation assay TSH receptor antibody (TRAb2), antithyroid drugs discontinuation period (ADP), iodine restriction period and 3-hour RAIU. The ADP was converted to an ordinal scale ADP score (ADPS) for multiple regression analyses. Multiple regression analyses showed that 3-hour RAIU (P < 0.001), FT3 (P < 0.001) and ADPS (P < 0.001) were statistically significant predictive factors of 24-hour RAIU. The relationship between 24-hour RAIU (LU) and 3-hour RAIU (EU), FT3 and ADPS was: LU = 11.5 + 29.1 × log10 EU + 23.0 × log10 FT3 - 2.7 × ADPS (r = 0.82, P < 0.001). The present results indicate that prediction of LU from EU, FT3 and ADPS is feasible in Japanese patients with Graves' disease.

Type 1 diabetes mellitus following COVID-19 RNA-based vaccine.

The epidemic of coronavirus disease-2019 (COVID-19) is the major public health issue in the world. COVID-19 vaccines are one of the most effective strategies against COVID-19. Here we report a 36-year-old female patient who had thirst, polydipsia, polyuria, palpitations, loss of appetite, and fatigue 3 days after the first dose of COVID-19 RNA-based vaccines without a prior history of diabetes. Ten days after vaccination, she visited our hospital with diabetic ketoacidosis and was diagnosed with type 1 diabetes. Hyperglycemia (501 mg/dL), anion gap metabolic acidosis and ketonuria were observed. The glycated hemoglobin level was 7.0%. Islet-related autoantibodies were all negative. The glucagon tolerance test revealed attenuated secretion of insulin. Human leukocyte antigen was haplotype DRB1*0405-DQB1*0401, which was associated with type 1 diabetes in Japan. The present case suggests that COVID-19 RNA-based vaccines might trigger the onset of type 1 diabetes, even in subjects without prior histories of diabetes.

Studies on anti-rabphilin-3A antibodies in 15 consecutive patients presenting with central diabetes insipidus at a single referral center.

Central diabetes insipidus (CDI) is a rare condition caused by various underlying diseases including inflammatory and autoimmune diseases, and neoplasms. Obtaining an accurate definitive diagnosis of the underlying cause of CDI is difficult. Recently, anti-rabphilin-3A antibodies were demonstrated to be a highly sensitive and specific marker of lymphocytic infundibuloneurohypophysitis (LINH). Here, we report a detailed case series, and evaluated the significance of anti-rabphilin-3A antibodies in differentiating the etiologies of CDI. A prospective analysis was conducted in 15 consecutive patients with CDI from 2013 to 2020 at a single referral center. Anti-rabphilin-3A antibodies were measured and the relationship between antibody positivity and the clinical/histopathological diagnoses was evaluated. Among 15 CDI patients, the positive anti-rabphilin-3A antibodies were found in 4 of 5 LINH cases, 3 of 4 lymphocytic panhypophysitis (LPH) cases, one of 2 sarcoidosis cases, and one intracranial germinoma case, respectively. Two Rathke cleft cyst cases and one craniopharyngioma case were negative. This is the first report of anti-rabphilin-3A antibodies positivity in CDI patients with biopsy-proven LPH. Measurement of anti-rabphilin-3A antibodies may be valuable for differentiating CDI etiologies.

ACTH response to desmopressin in a patient with acromegaly; expression of corticotropin-releasing factor, urocortins and vasopressin V1b receptor in GH-producing pituitary adenoma.

GH-producing pituitary adenomas frequently co-produce other certain anterior pituitary hormones, such as prolactin (PRL). In contrast, GH-producing adenomas which express all of corticotropin-releasing factor (CRF), urocorin1 (Ucn1) and urocortin3 (Ucn3) have not been reported. A 39-year-old woman was admitted for evaluation of the pituitary tumor. The diagnosis of acromegaly was confirmed by elevated serum GH and IGF-I levels, and the absence of GH suppression by oral glucose tolerance test. ACTH response to desmopressin (DDAVP) was observed (plasma ACTH levels increased from 13.9 to 50.4 pg/ml at 90 min). Although it is known that ACTH response to DDAVP is considerably useful for the diagnosis of ACTH-dependent Cushing's syndrome, the diagnosis of Cushing's disease was not supported by the criteria. The patient underwent transsphenoidal resection of the pituitary tumor. Immunohistological examination confirmed a GH- and PRL-producing adenoma, whereas ACTH was negative. ACTH response to DDAVP disappeared after tumor removal. To determine the cause of preoperative ACTH response to DDAVP, we examined expression of CRF family peptides and vasopressin V1b receptor in the pituitary adenoma by immunohistochemistry. Immunohistochemistry revealed positive immunostaining for CRF, Ucn1, Ucn3 and vasopressin V1b receptor in the adenoma. These observations raised the possibility that DDAVP caused an ACTH response, perhaps via the paracrine effects of tumor-derived CRF and Ucn1. When ACTH response to DDAVP is observed in patients with pituitary tumor, not only the direct effect of DDAVP on ACTH secretion, but also a possible involvement of CRF and/or urocortins expressed in the pituitary adenoma, should be considered.

Sunitinib-induced thyrotoxicosis followed by persistent hypothyroidism with shrinkage of thyroid volume.

Sunitinib, a tyrosine kinase inhibitor, has been approved for the treatment of cancers, such as advanced renal cell carcinoma (RCC). On the other hand, sunitinib treatment is known to induce thyroid dysfunction in a substantial proportion of patients treated for advanced RCC; in fact, hypothyroidism is a frequent complication. However, little is known about sunitinib-induced thyrotoxicosis and destructive thyroiditis. Here, we report a patient with RCC who developed transient overt thyrotoxicosis followed by hypothyroidism due to sunitinib treatment. A 58-year-old woman, who had been treated with chronic thyroiditis, was diagnosed as having left RCC with bone metastasis to the rib. The patient underwent resection of the left kidney and the bone metastasis lesion. However, 3 months later, bone metastasis to the rib recurred, and sunitinib treatment was started. At 6 weeks of sunitinib therapy, the patient developed transient thyrotoxicosis, followed by persistent hypothyroidism. In the thyrotoxic phase, the patient was diagnosed as having destructive thyroiditis based on an increased thyroglobulin level, a low radioactive iodine uptake, increased free thyroxine level, and suppressed thyroid-stimulating hormone level. The thyroid volume in the hypothyroid phase was 68% of that in the thyrotoxic phase. In conclusion, the present report suggests that sunitinib-induced persistent hypothyroidism may be a consequence of preceding destructive thyroiditis with transient thyrotoxicosis. The decreased volume of the thyroid during the hypothyroid phase indicates irreversible organ damage in the present patient, thereby resulting in persistent hypothyroidism. Thus, periodic surveillance of thyroid function is mandatory during sunitinib therapy.

Use of Edoxaban for the Treatment of Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a life-threatening adverse drug reaction of heparin therapy, which increases a patient's risk of developing venous and/or arterial thromboembolism. HIT should be treated through discontinuation of heparin and administration of nonheparin anticoagulants such as argatroban. For long-term anticoagulation, parenteral nonheparin anticoagulants are generally converted to oral treatment with a vitamin K antagonist such as warfarin. Although administration of warfarin is recommended to overlap with a nonheparin anticoagulant for a minimum of 5 days, overlapping with argatroban and warfarin presents high risks of bleeding. We describe a case of HIT treated with edoxaban. A 78-year-old man underwent surgery for esophageal cancer and was administered heparin perioperatively. After surgery, he was diagnosed with HIT and venous thromboembolism. We immediately stopped heparin and initiated parenteral argatroban. The patient was subsequently started on edoxaban without any overlap between the two drugs. The treatment was successful. The treatment of edoxaban following argatroban for HIT could reduce bleeding complications and shorten the length of hospital stay. To the best of our knowledge, this is the first report of the use of edoxaban for HIT treatment.

Acromegaly with normal IGF-1 levels probably due to poorly controlled diabetes mellitus.

Acromegaly is characterized by the somatic disfigurement and excessive production of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Here we report a patient with aromegaly and diabetes mellitus, who showed normal IGF-1 levels in spite of elevated GH levels. The patient was a 52-year-old woman with acromegalic manifestations. Serum GH level was elevated (32.4 ng/mL) with hyperglycemia (fasting plasma glucose, 277 mg/dL) and an extremely high level of glycosylated hemoglobin (HbA1c 17.7%), whereas serum IGF-1 level was within normal range (110 ng/mL, normal range 37-266). Brain magnetic resonance imaging detected a pituitary tumor, with involvement of the right cavernous sinus. Oral glucose tolerance test (OGTT) showed no suppression of serum GH. Thyrotropin-releasing hormone test showed paradoxical increases in serum GH. We therefore diagnosed acromegaly accompanied with diabetes mellitus. A large amount of insulin (34 units/day) was required to control the blood glucose level. The patient was treated with octreotide, a somatostatin analogue, followed by transsphenoidal surgery. After the surgery, serum GH levels were suppressed by OGTT, although basal serum GH levels remained to be high. Basal serum GH levels, however, were normalized 5 months later. Blood glucose became well controlled by the diet alone. In contrast, serum IGF-1 increased to the range of 219-233 ng/mL. Pre-operative serum IGF-1 levels were low probably due to poorly controlled diabetes mellitus. In conclusion, the presence of normal serum IGF-1 levels cannot exclude the diagnosis of acromegaly especially when the patient is accompanied by diabetes mellitus.

Induction of endothelin-1 production in endothelial cells via co-operative action between CD40 and lectin-like oxidized LDL receptor (LOX-1).

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein in endothelial cells, mediates the interaction between activated platelets and endothelial cells. Stimulation of LOX-1 causes various functional changes in endothelial cells relevant to 'endothelial dysfunction'. This study investigated the cellular responses to platelet binding via LOX-1, comparing it with CD40, which also mediates platelet-binding in endothelial cells. Activated platelets, which bind both LOX-1 and CD40, induced endothelin-1 production via co-operation of LOX-1 and CD40. Stimulation of LOX-1 by oxidized low-density lipoprotein induced the expression of CD40 as well as LOX-1 itself, and stimulation of CD40 by CD40L induced the expression of LOX-1 as well as CD40. Activated platelets induced both LOX-1 and CD40 expression via these two systems in endothelial cells. Application of superoxide dismutase suppressed LOX-1-mediated, but not CD40-mediated, induction of endothelin-1. LOX-1 and CD40 synergistically, but through a distinct pathway, work to induce endothelin-1 expression in endothelial cells. This co-operative action between LOX-1 and CD40 might play a key role in the induction of endothelial dysfunction.

[A case of advanced gastric cancer showing pylorus stenosis with multiple liver metastases, that respond remarkably to neoadjuvant chemotherapy of combined TXL and low-dose FP].

We report a 65-year-old man with advanced gastric cancer that showed a remarkable response to treatment with a new combination of paclitaxel (TXL) and low-dose 5-fluorouracil and cisplatin (FP) as neoadjuvant chemotherapy (NAC). The patient was admitted to our hospital complaining of epigastric discomfort. Endoscopic examination revealed type 3 advanced gastric cancer, which was confirmed to be adenocarcinoma by biopsy. Tumor markers of serum carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) were elevated to 768.7 ng/ml and 2,782.8 U/ml, respectively. Computed tomography (CT) showed multiple liver metastases, and metastases to group 3 lymph nodes. After three courses of NAC, the CEA and AFP levels decreased to 245.0 ng/ml and 754.0 U/ml, respectively. Computed tomography revealed marked reduction of the primary tumor, liver metastases, and lymph nodes. Shrinkage of the primary tumor was also shown by gastrography and endoscopy. Distal gastrectomy was then performed because of pylorus stenosis. The resected specimen showed tub 2, pSS, pN3, ly2, v2 and Grade 2 histological responses. About half of the nodal metastatic lesions were degenerated. The patient is doing well and undergoing treatment with hepatic arterial infusion chemotherapy as an outpatient. TXL + low-dose FP as NAC may be one of the new tactics against advanced gastric cancer.

Involvement of p38alpha mitogen-activated protein kinase in lung metastasis of tumor cells.

To study the role of p38 mitogen-activated protein kinase (p38) activity during the process of metastasis, p38alpha(+/-) mice were subjected to an in vivo metastasis assay. The number of lung colonies of tumor cells intravenously injected in p38alpha(+/-) mice was markedly decreased compared with that in wild-type (WT) mice. On the other hand, the time-dependent increase in tumor volume after subcutaneous tumor cells transplantation was comparable between WT and p38alpha(+/-) mice. Platelets of p38alpha(+/-) mice were poorly bound to tumor cells in vitro and in vivo compared with those of WT mice. E- and P-selectin mRNAs were markedly induced in the lung after intravenous injection of tumor cells. However, the induction of these selectin mRNAs in p38alpha(+/-) mice was weaker than that in WT mice. Furthermore, the resting expression levels of E-selectin in lung endothelial cells and P-selectin in platelets of p38alpha(+/-) mice were suppressed compared with those of WT mice. The number of tumor cells attached on lung endothelial cells of p38alpha(+/-) mice was significantly reduced compared with that of WT mice. The transmigrating activity of tumor cells through lung endothelial cells of p38alpha(+/-) mice was similar to that of WT mice. These results suggest that p38alpha plays an important role in extravasation of tumor cells, possibly through regulating the formation of tumor-platelet aggregates and their interaction with the endothelium involved in a step of hematogenous metastasis.

Stress and vascular responses: endothelial dysfunction via lectin-like oxidized low-density lipoprotein receptor-1: close relationships with oxidative stress.

Endothelial dysfunction is associated with pathological vascular conditions including atherosclerosis, hypertension, and diabetes. The oxidatively modified form of low-density lipoprotein (LDL) is recognized as a major cause of endothelial dysfunction in atherogenesis. As the receptor for oxidized LDL in endothelial cells, we have identified the lectin-like oxidized LDL receptor-1 (LOX-1). LOX-1 is up-regulated by products of oxidative stresses and the molecules that induce oxidative stresses. Activation of LOX-1 induces the generation of reactive oxygen species and decreases NO released from endothelial cells. LOX-1 activation further induces the expression of endothelin-1, AT(1) receptor, and cell adhesion molecules. Together with these properties, LOX-1 works as an adhesion molecule for activated platelets and neutrophils. Thus, LOX-1, within the close relationships between oxidative stress generation and response, enhances functional changes in endothelial cells that are relevant to the disturbed vascular homeostasis under pathological settings.