Novel prognostic prediction models for patients with stage IV colorectal cancer after concurrent curative resection.

BACKGROUND: We developed a prediction tool for recurrence and survival in patients with stage IV colorectal cancer (CRC) following surgically curative resection. PATIENTS AND METHODS: From January 1983 to December 2012, 113 patients with CRC and synchronous liver and/or lung metastatic CRC were investigated at the Osaka Medical Center for Cancer and Cardiovascular Diseases. All patients underwent curative resection of primary and metastatic lesions. In the group of patients who underwent surgery from 1983 to 2008, a Cox regression model was used to develop prediction models for 1-year, 3-year and 5-year cancer-specific survival (CSS) and relapse-free survival (RFS). In the other group of patients who underwent surgery from 2009 to 2012, the developed prediction model was validated. RESULTS: Univariate analysis of clinicopathological factors showed that the following factors were significantly correlated with CSS and RFS: preoperative serum carcinoembryonic antigen level, tumour location, pathologically defined tumour invasion and lymph node metastasis, and synchronous metastatic lesions. Using these variables, novel prediction models predicting CSS and RFS were constructed using the Cox regression model with concordance indexes of 0.802 for CSS and 0.631 for RFS. The prediction models were validated by external data sets in an independent patient group. CONCLUSIONS: We developed novel and reliable personalised prognostic models, integrating tumour, node, metastasis (TNM) factors as well as the preoperative serum carcinoembryonic antigen level, tumour location and metastatic lesions, to predict patients' prognosis following surgically curative resection. This individualised prediction model may help clinicians in the treatment of postoperative stage IV CRC following surgically curative resection.

Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR-activating and gatekeeper mutations.

Despite initial dramatic response, epidermal growth factor receptor (EGFR) mutant lung cancer patients always acquire resistance to EGFR-tyrosine kinase inhibitors (TKIs). Gatekeeper T790M mutation in EGFR is the most prevalent genetic alteration underlying acquired resistance to EGFR-TKI, and EGFR mutant lung cancer cells are reported to be addictive to EGFR/Akt signaling even after acquired T790M mutation. Here, we focused on Akt kinase-interacting protein1 (Aki1), a scaffold protein of PI3K (phosphoinositide 3-kinase)/PDK1 (3-phosphoinositide-dependent protein kinase)/Akt that determines receptor signal selectivity for non-mutated EGFR, and assessed its role in EGFR mutant lung cancer with or without gatekeeper T790M mutation. Cell line-based assays showed that Aki1 constitutively associates with mutant EGFR in lung cancer cells with (H1975) or without (PC-9 and HCC827) T790M gatekeeper mutation. Silencing of Aki1 induced apoptosis of EGFR mutant lung cancer cells. Treatment with Aki1 siRNA dramatically inhibited growth of H1975 cells in a xenograft model. Moreover, silencing of Aki1 further potentiated growth inhibitory effect of new generation EGFR-TKIs against H1975 cells in vitro. Aki1 was frequently expressed in tumor cells of EGFR mutant lung cancer patients (53/56 cases), including those with acquired resistance to EGFR-TKI treatment (7/7 cases). Our data suggest that Aki1 may be a critical mediator of survival signaling from mutant EGFR to Akt, and may therefore be an ideal target for EGFR mutant lung cancer patients, especially those with acquired EGFR-TKI resistance due to EGFR T790M gatekeeper mutation.

Interferon-α increases monocyte migration via platelet-monocyte interaction in murine intestinal microvessels.

The aim of this study was to investigate the effect of interferon (IFN)-α on recruitment of platelets and monocytes within the murine small intestinal venular endothelium. Monocytes were isolated from bone marrow of C57B6 mice. Platelets were collected from murine blood. Rolling and adhesion to submucosal microvessels in the small intestine were examined under an intravital fluorescence microscope after injection of fluorescein-labelled monocytes or platelets. In some mice, IFN-α (5×10(5) U/kg) was administered intraperitoneally. After treatment with an antibody against P-selectin, changes in monocyte and platelet migration were also investigated. Changes in monocyte migration under the condition of thrombocytopenia were also investigated. Platelets and monocytes interacted with murine intestinal microvessels, although only few platelets and monocytes showed migration behaviour. Intraperitoneal injection of IFN-α enhanced the migration of both platelets and monocytes in the intestinal microvessels. Pretreatment with anti-P-selectin attenuated the increase in migration of platelets and monocytes induced by administration of IFN-α. Thrombocytopenia decreased the rolling ratio of monocytes, suggesting that the effect of IFN-α on migration was P-selectin-dependent, derived from both the endothelium of microvessels and platelets. The results of this study suggest that IFN-α acts as a potent proinflammatory agent via its stimulatory effect on the endothelium-platelet-monocyte interaction in intestinal microvessels by a P-selectin-dependent mechanism.

[Complete resection of Pancoast tumor following induction chemoradiotherapy improves survival].

OBJECTIVE: Pancoast tumors are some of the most challenging thoracic malignant diseases to treat because of their proximity to vital structures at the thoracic inlet. We retrospectively analyzed 23 patients with pT3-4, N0-3 Pancoast tumors who underwent combined chest wall resection including the 1st rib, and discuss the anatomical considerations, assessment of induction therapy, and surgical approaches for these cancers. METHODS: Between 1983 and 2006, 23 patients with Pancoast tumors underwent combined resection of the 1st rib at our institute. Of those, 21 were male and 2 were female, with an average age of 58 years. There were 10 each of squamous cell carcinoma and adenocarcinoma, 2 large cell carcinoma, and 1 adenosquamous carcinoma. Over the past decade, induction chemoradiotherapy (>40Gy) was employed before surgery. RESULTS: A posterior approach was employed in 14 patients, an anterior approach in 7, and a combined anterior and posterior approach in 2. Sixteen patients underwent complete resection. One of 7 patients undergoing incomplete resection (4.3%) died on the 45th postoperative day. The 3- and 5-year survival rates were 50 and 22%, respectively, for patients with complete resection. No case survived for more than 8 months out of the 7 patients with incomplete resection. Fourteen patients with pN0 showed significantly better survival than those with pN1-3 (p = 0.0053). CONCLUSION: Recent literature and our results suggest that patients with pN0 and/or a pathological complete response (pCR) after induction chemoradiotherapy could achieve long-term survival after complete resection.

[Surgical treatment for the second double lung cancers following chemotherapy for small cell lung cancer].

We report a case with surgery for the 2nd primary double lung cancers-adenocarcinoma and squamous cell carcinoma which developed in the right upper lobe after 5 years successful control by chemotherapy for small cell lung cancer in the left upper lobe. Long term survivors with small cell lung cancer have recently increased as a result of progress of chemotherapy. Therefore, 2nd primary lung cancer is not rare after the treatment for the initial small cell lung cancer. Although several causes have been proposed on the development of 2nd primary lung cancer after small cell lung cancer treatment, smoking history was strongly suggested as a cause in this case. Careful follow-up especially focusing on 2nd primary lung cancer development is necessary for patients after successful treatment for small cell lung cancer.

[Extrapleural pneumonectomy for relapsed solitary fibrous tumors of the pleura with pleural dissemination].

We report a case of a 62-year-old female with a prior thoracotomy for solitary fibrous tumor of the diaphragmatic pleura. There was no clear evidence of malignant solitary fibrous tumor of the pleura (SFTP). In the 19th postoperative month, she had a disseminated recurrence of SFTP in the left thoracic cavity. There was no evidence of metastasis from medical imaging. Accordingly, a left extrapleural pneumonectomy was performed. Pathological examination revealed a disseminated recurrence of malignant SFTP, showing a higher grade of malignancy, because the resected specimen was identical to the only section suspicious of malignancy in the previous tumor. She had no complaint and kept better performance status until the 7th postoperative month after the re-resection, when she had a recurrence in the left thoracic cavity and dissemination in the peritoneal cavity. She died of the recurrence 15 months after the re-resection and 34 months after the prior thoracotomy.

[Survey of surgical treatment of malignant pleural mesothelioma in Japan].

Surgical results of patients with malignant pleural mesothelioma (MPM) in Japan was surveyed from the results of a questionnaire sent to members of the Japan Lung Cancer Society. and a total of 132 surgical cases of MPM from 1997 to 2002 were analyzed. They consisted of 112 males and 20 females. By histological type, 87 cases had epithelial type, 10 had sarcomatous type, 26 had mixed type and 2 had uncommon type of MPM (the histology of 7 cases was not indicated). As to the surgical mode, extrapleural pneumonectomy (EPP) was performed in 73 cases, and limited surgery such as decortication and tumorectomy was performed in 59 cases. The tumor was potentially completely resected in 83 cases. Postoperative adjuvant therapy was performed in 56 cases. The 1-, 2- and 3-year survival rates of the present cases were 54, 33 and 21%, respectively, and the perioperative mortality rate was 5%. These survival and mortality rates in the present series were almost similar to those of the MPM cases in the previously reported series from 1987 to 1996 by Takagi et al. According to Cox regression analysis, prognostic factors for survival included postoperative adjuvant therapy (p=0.003) and complete resection (p=0.037) significantly, and International Mesothelioma Interest Group (IMIG) stage (p=0.051) and performance status (p=0.086) with a marginal significance, indicating that complete surgical resection of the tumor and perioperative adjuvant therapy could be effective treatment for MPM in Japan. Thus, the development of multimodality therapy including surgical treatment for this disease may be required to improve surgical results of MPM patients.

Pros and cons of chest wall reconstruction using prosthetic meshes in a two-layer fashion.

A 46-year-old woman with giant chondrosarcoma of the sternum underwent wide full-thickness resection of the anterior chest wall, which included the pericardium and lung. The free rectus abdominus musculocutaneous flap was transplanted onto prosthetic meshes placed in two layers. While stability and esthetic effect were both good, the subsequent infection in the space between the two meshes prolonged for one month. As a result, the space was closed with an omentum flap. As a consequence, we recommend one-stage omentopexy to prevent the space problem between the two meshes.

Thymidylate synthase and dihydropyrimidine dehydrogenase activities in non-small cell lung cancer tissues: relationship with in vitro sensitivity to 5-fluorouracil.

We examined enzymatic activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in non-small cell lung cancer (NSCLC) tissues to determine the relationship to tumor sensitivity to 5-fluorouracil (5-FU). TS and DPD activities were measured in 60 surgically resected primary NSCLC tissues using a TS-binding assay and a radioenzyme assay, respectively. In vitro tumor sensitivity to 5-FU was assayed using a collagen gel droplet embedded culture drug test (CD-DST). DPD activities slightly correlated with in vitro sensitivity to 5-FU (r=0.402,P=0.013), such that tumors with higher DPD activity were more resistant to 5-FU. In contrast, no correlation was observed in TS activities. Thus, it was suggested that only DPD activity in NSCLC tissues is a potential indicator in predicting tumor sensitivity to 5-FU. Based on these results, further study is needed to evaluate the clinical significance of these enzymes in 5-FU-based chemotherapy for patients with NSCLC.

Role of aquaporin-2 gene expression in hyponatremic rats with chronic vasopressin-induced antidiuresis.

BACKGROUND: In a state of chronic arginine vasopressin (AVP) excess, the action of antidiuresis has been attenuated, resulting in some water diuresis. This state has been termed an "AVP escape" phenomenon. The present study was designed to determine what mechanisms underlie this attenuation in renal concentrating ability, which is found in chronic AVP excess, both in the presence and absence of volume expansion. METHODS: Two groups of experimental rats were established. One group received solid chow with water ad libitum. The second group received chow, which was offered as a liquid diet. Both groups received subcutaneous administration of 1-deamino-8-D-arginine vasopressin (dDAVP) at 5 ng/h for the entire observation period of one week. Over the course of the observation period, tissue levels of aquaporin-2 (AQP-2) mRNA and protein were measured. Levels of AVP V2 receptor were monitored, both by measuring mRNA levels and by ligand-binding studies using [3H]AVP. Tissue levels of cAMP also were determined. RESULTS: Experimental rats with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) had severe hyponatremia below 120 mmol/L, and impaired urinary concentrating ability, during the seven-day observation period. In contrast, the dDAVP-excess rats, given solid chow, maintained maximally concentrated urine and normal levels of serum sodium. The down-regulation of AVP V2 receptor function was comparable in the two groups. The maximal binding capacity (Bmax) fell to the nadir on day 2 and was thereafter suppressed at approximately 60% of control rats during the experiment. Up-regulation of AQP-2 mRNA expression was found, but this up-regulation was significantly less in the SIADH rats compared with the dDAVP-excess rats (153.5 +/- 29.8% vs. 323.7 +/- 23.8% on day 7, P < 0.05). This differential response between these two groups was affirmed by measured differences in AQP-2 protein levels, both in tissue and in urinary excretion. CONCLUSIONS: These results indicate that the attenuated regulation of the AQP-2 gene leads to the decrease in urinary concentrating ability in the experimental SIADH rats, suffering from hypervolemic state, compared with the normonatremic rats receiving AVP. Either hypervolemia or hypotonicity may diminish the post-receptor signaling of AVP in renal collecting duct cells, under the chronic AVP excess state found in SIADH.

Neutral endopeptidase/CD10 and aminopeptidase N/CD13 gene expression as a prognostic factor in non-small cell lung cancer.

OBJECTIVES: Neutral endopeptidase modulates the growth of lung cancer, while aminopeptidase N degrades the extracellular matrix and is involved in cell motility. We studied the metastasis mechanism to detect novel metastasis-associated molecules and to evaluate them for clinical application. METHODS: We studied the relationship between the expression of neutral endopeptidase and aminopeptidase N by quantitative reverse transcript-polymerase chain reaction analysis in 132 patients with non-small cell lung cancer undergoing radical surgery from 1991 to 1996. RESULTS: Patients with neutral endopeptidase-positive and aminopeptidase N-negative tumors were defined as group A, those with neutral endopeptidase-positive and aminopeptidase N-positive or neutral endopeptidase-negative and aminopeptidase N-negative tumors as group B, and those with neutral endopeptidase-negative and aminopeptidase N-positive tumors as group C. The 5-year survival of group A patients (92.9%) was significantly better than that of group B patients (64.7%) and much better than that of group C patients (38.2%) (P = 0.0011). Neutral endopeptidase and aminopeptidase N thus have statistically significant P in overall survival in Cox regression (P = 0.019). CONCLUSION: Neutral endopeptidase and aminopeptidase N gene expressions are significant indicators of prognosis.

Urinary excretion of the aquaporin-2 water channel exaggerated in pathological states of impaired water excretion.

OBJECTIVE: The present study was undertaken to determine whether the hydro-osmotic action of arginine vasopressin (AVP) is exaggerated in pathological states of impaired water excretion by measuring urinary excretion of the aquaporin-2 (AQP-2) water channel. PATIENTS AND MEASUREMENTS: Eighteen hyponatraemic patients with impaired water excretion and 12 control subjects were studied during an acute oral water load (20 ml/kg body weight). RESULTS: In the patient group plasma AVP levels were 1.6 pmol/l, relatively high compared to plasma osmolality of 279.8 mmol/kg. Urinary excretion of AQP-2 under ad libitum water drinking was 41.1 fmol/micromol creatinine in the patient group, a value significantly greater than that of 21.7 fmol/micromol creatinine in the control subjects. The acute water load verified the impairment in water excretion in the patient group, as the excretion of the water load was only 28.2% (control, 77.3%, P < 0.001) and the minimum urinary osmolality was as high as 437.3 mmol/kg (control, 122.9 mmol/kg, P < 0.001). Also, the minimum urinary excretion of AQP-2 was significantly greater in the patient group than that in the control. There was a positive correlation between plasma AVP levels and urinary excretion of AQP-2 in the control subjects (r = 0.56, P < 0.01). In contrast, the urinary excretion of AQP-2 was exaggerated compared to the respective plasma AVP levels in the patient group, and thus the positive correlation disappeared. CONCLUSION: These results indicate that hydroosmotic action of AVP is exaggerated more than that expected from plasma AVP levels in pathological states of impaired water excretion, with non-suppressible, but normal, arginine vasopressin levels in spite of the hypo-osmotic condition.

Interferon gamma-producing ability in blood lymphocytes of patients with lung cancer through activation of the innate immune system by BCG cell wall skeleton.

An in vitro assay system was developed to assess the potency of the human innate immune system by measurement of IL-12, IL-18, IL-10 and IFNgamma in the supernatants of bacillus Calmette-Guerin cell wall skeleton (BCG-CWS)-stimulated blood samples. BCG-CWS is a ligand for Toll-like receptor (TLR) 2 and 4, and activates monocytes to macrophages (Mphi), and immature dendritic cells to mature antigen-presenting cells (APC). This system was found to allow the discrimination of immune suppressive states in patients with lung cancer from normal immune states in light of the cytokine profile. The following results were deduced from analyses of BCG-CWS-stimulated blood samples of lung cancer patients with reference to normal subjects. (1) The levels of production of IFNgamma and IL-10 by lymphocytes were decreased. (2) IL-12 p40 production by monocytes/Mphi was upregulated, while that of IL-10 was downregulated. (3) IL-18 was detected in all patients in a range similar to normal subjects. (4) Responses of lymphocytes to IL-2 and IL- 18 in terms of IFNgamma production were diminished. (5) The upregulated IL-12 levels were recovered to within the normal range in most patients after tumor resection. (6) Male patients showed more severe suppression of IL-12/IL-18-mediated IFNgamma production than female patients. Thus, the lesser IFNgamma production observed in patients' blood with high IL-12 p40 levels in response to BCG-CWS may reflect the production of p40 dimers or IL-23 instead of p70, or the presence of some unknown pathways to prohibit the interface between the innate and acquired immune systems. BCG-CWS-mediated Toll signaling may participate in IFNgamma induction for lymphocytes through Mphi/APC IL-12/I-18 modulation.

Transmediastinal approach to exploring the lung contralateral to the thoracotomy site.

OBJECTIVE: The approach to contralateral lung through the mediastinum is assumed useful in managing oddly distributed bilateral lung tumors. SUBJECTS AND METHODS: To remove a tumor located in the contralateral lung, a transmediastinal approach from the thoracotomy site to the contralateral lung was used in 6 patients having oddly distributed bilateral lung tumors, 1 of which was located in the contralateral lung close to the anterior or posterior mediastinum. RESULTS: All cases were treated successfully. One patient required an additional small incision on the contralateral anterior chest wall to insert an endoscopic stapler without intraoperative postural change. The postoperative course was uneventful and, to date, no local recurrence has been seen at the resected margin of the contralateral lung. CONCLUSION: This novel approach is useful, offering the advantages of reduced invasiveness and pain, shorter surgical duration, and favorable cosmetic results for patients with a tumor close to the mediastinum in the contralateral lung.

Chronic hypernatremia derived from hypothalamic dysfunction: impaired secretion of arginine vasopressin and enhanced renal water handling.

We analyzed the disorder of water metabolism in a 32 year-old female with chronic hypernatremia. She had meningitis at 4 years, and ventriculo-peritoneal shunt operation at 13 years because of normal pressure hydrocephalus. At 14 years hypernatremia of 166 mmol/l was initially found and thereafter hypernatremia ranging from 150 to 166 mmol/l has been persisted for the last 18 years. Physical and laboratory findings did not show dehydration. Urine volume was 750-1700 ml per day and urinary osmolality (Uosm) 446-984 mmol/kg, suggesting no urinary concentrating defect. Plasma arginine vasopressin (AVP) levels ranged from 0.4 to 1.2 pmol/l despite hyperosmolality of 298 through 343 mmol/kg under ad libitum water drinking. There was no correlation between plasma osmolality (Posm) and plasma AVP levels, but Uosm had a positive correlation with Posm (r=0.545, P < 0.05). Hypertonic saline (500 NaCl) infusion after a water load increased Uosm from 377 to 679 mmol/kg, and plasma AVP from 0.2 to 1.3 pmol/l. There was a positive correlation between Posm and plasma AVP levels in the hypertonic saline test (r=0.612, P<0.05). In contrast, an acute water load (20 ml/kg BW) verified the presence of impaired water excretion, as the percent excretion of the water load was only 8.5% and the minimal Uosm was as high as 710 mmol/kg. Urinary excretion of aquaporin-2 remained low in concert with plasma AVP levels. No abnormality in pituitary-adrenocortical function was found. These results indicate that marked hypernatremia is derived from partial central diabetes insipidus and elevated threshold of thirst, and that enhanced renal water handling may contribute to maintenance of body water in the present subject.

Clinical implication of serial leptin measurement in subjects with type 2 diabetes mellitus.

Plasma leptin concentration is closely associated with body fat in humans, with energy restriction inducing a greater decrease in plasma leptin than in body fat. Since adequate energy restriction is mandatory in diet therapy of diabetes mellitus especially in obese subjects, the present study was undertaken to evaluate the clinical implication of serial leptin measurement in the management of diabetic patients. Fifty-four consecutive subjects with type 2 diabetes, who were subjected to adjusted energy restriction during hospitalization, were enrolled in the study. During their hospitalization period (24+/-4 days), plasma leptin concentrations decreased from 6.9+/-0.7 to 5.7+/-0.6 microg/l (P<0.0001) in the overall subjects, and the %change in plasma leptin (-13.9%) was greater than the %changes in body mass index (BMI) and percent body fat (-1.7% and -4.7%, respectively). The %change in plasma leptin was positively correlated with the %changes in BMI and plasma C-peptide (r=0.526, P<0.0001 and r=0.446, P<0.002, respectively) and negatively with a %change in plasma ketone bodies (r=-0.516, P<0.005). Multiple regression analysis revealed that the %changes in BMI and plasma C-peptide were independent determinants of the %change in plasma leptin. In addition, 38 subjects were followed up after discharge. Three months after discharge, plasma leptin concentrations significantly increased by 25.6%, which was again much greater than the %change in BMI (+0.9%). In 28 subjects who showed increase in plasma leptin levels after discharge, BMI was also increased. In contrast, the remaining 10 subjects without the increase in plasma leptin kept their BMI unchanged. Throughout the observation period, the changes in plasma leptin were prominent in the subjects with BMI greater than 25 kg/m2. In conclusion, plasma leptin concentrations showed greater changes than the alterations in anthropometric indexes during the observation period. Serial leptin measurement may be useful to estimate adherence to energy restriction especially in obese subjects with type 2 diabetes.

Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning.

OBJECTIVE: This study was undertaken to investigate the value of the ground-glass opacity (GGO) area found on high-resolution computed tomography (HRCT) scanning as a preoperative prognostic indicator. PATIENTS AND METHODS: We studied 104 patients with small-sized lung adenocarcinoma, 20 mm or less in diameter, between 1995 and 1999. Three independent radiologists semi-quantitatively scored the extent of GGO on HRCT as greater than or less than 50%. Three independent pathologists semi-quantitatively scored the extent of the bronchioloalveolar carcinoma (BAC) component of the tumor on histologic examination as greater than or less than 50%. As no relapse occurred in patients with GGO greater than 50%, multivariate analysis of this prognostic factor was not possible. RESULTS: Fifty patients were scored as having both BAC and GGO greater than 50%, 36 as both BAC and GGO less than 50%, and 16 as BAC greater than 50% and GGO less than 50%. In only two patients (1.9%), BAC less than 50% was overestimated on HRCT as GGO greater than 50%. The sensitivity and specificity of GGO to BAC were 76 and 95%, respectively. The 3 year-relapse-free survival rates in each group of 52 patients with GGO greater than and less than 50% were 100 and 72%, respectively, after a median follow-up of 24 months. Univariate analysis indicated that both GGO and BAC areas were significantly correlated with cancer relapse (P=0.005 and P=0.002). The multivariate analysis revealed an independent prognostic influence of the BAC area on relapse-free survival (P=0.015, relative risk=0.07). CONCLUSIONS: To date there has been no relapse among the 52 patients with GGO greater than 50%. This novel classification based on the semiquantitative analysis of GGO area on HRCT should become an useful independent preoperative indicator when deciding on operative procedure, and to predict the potential of relapse in patients with small adenocarcinoma arising from the peripheral lung.

Close association of urinary excretion of aquaporin-2 with appropriate and inappropriate arginine vasopressin-dependent antidiuresis in hyponatremia in elderly subjects.

The present study was undertaken to determine whether urinary excretion of aquaporin-2 (AQP-2) participates in the involvement of arginine vasopressin (AVP) in hyponatremia less than 130 mmol/L in 33 elderly subjects (> or =65 yr old) during the last 5-yr period. Subjects were separated into euvolemic hyponatremia groups: 13 with hypopituitarism, 8 with syndrome of inappropriate secretion of antidiuretic hormone (SIADH), 8 with mineralocorticoid-responsive hyponatremia of the elderly, and 4 with miscellaneous diseases. Approximately 40% of those with hyponatremia was derived from hypopituitarism, but severe hyponatremia was found in the patients with SIADH and mineralocorticoid-responsive hyponatremia of the elderly. Plasma AVP levels remained relatively high despite hypoosmolality and were tightly linked with exaggerated urinary excretion of AQP-2 and antidiuresis in the 3 groups of patients, except for one miscellaneous one. An acute water load test verified the impairment in water excretion, because the percent excretion of the water load was less than 42% and the minimal urinary osmolality was not sufficiently diluted. Also, plasma AVP and urinary excretion of AQP-2 were not reduced after the water load. The inappropriate secretion of AVP was evident in the patients with SIADH and hypopituitarism, and hydrocortisone replacement normalized urinary excretion of AQP-2 and renal water excretion in those with hypopituitarism. In contrast, the appropriate antidiuresis seemed to compensate loss of body fluid in the patients with mineralocorticoid-responsive hyponatremia of the elderly, who lost circulatory blood volume by 7.3% (mean). Fludrocortisone acetate increased renal sodium handling and body fluid, resulting in the reduction in AVP release and urinary excretion of AQP-2 in mineralocorticoid-responsive hyponatremia of the elderly. These findings indicate that urinary excretion of AQP-2 may be a more sensitive measure of AVP effect on renal collecting duct cells than are plasma AVP levels, and that increased urinary excretion of AQP-2 shows exaggerated AVP-induced antidiuresis in hyponatremic subjects in the elderly. In addition, mineralocorticoid-responsive hyponatremia of the elderly has to be carefully differentiated from SIADH in elderly subjects.

Isolation of a novel human lung-specific gene, LUNX, a potential molecular marker for detection of micrometastasis in non-small-cell lung cancer.

We have isolated a novel human lung-specific gene, LUNX (lung-specific X protein), by differential-display mRNA analysis. The full-length cDNA contained 1,015 nucleotides including an open reading frame of 768 nucleotides encoding 256 amino acids. We localized the gene to chromosomal region 20p11.1-q12 by radiation hybrid mapping. Using an RT-PCR assay specific for LUNX mRNA, 35 non-small-cell lung-cancer (NSCLC) tumors and 0 of 16 normal lymph nodes were positive. Furthermore, LUNX mRNA expression was enhanced in 26 (84%) of 31 NSCLC tumors vs. corresponding cancer-free lung tissues by semi-quantitative analyses with multiplex RT-PCR. We assessed the possibility of LUNX mRNA as a molecular marker for detection of micrometastasis in dissected lymph nodes obtained from 20 patients with NSCLC tumors. LUNX mRNA was detected in 16 (80%) of 20 histologically positive lymph nodes and 21 (25%) of 84 histologically negative lymph nodes. Comparative analyses of the conventional histological examination and the RT-PCR detection assay for LUNX mRNA showed that the detection rate of metastases in lymph nodes by the RT-PCR assay was higher in 12 and consistent in 6 of the total 20 NSCLC patients. We demonstrate that the LUNX RT-PCR assay is a potential diagnostic method for detection of micrometastases in lymph nodes of NSCLC patients.

Arginine vasopressin inhibits apoptosis of rat glomerular mesangial cells via V1a receptors.

Arginine vasopressin (AVP) promotes proliferation of glomerular mesangial cells. We examined whether AVP modulates an apoptosis of cultured rat glomerular mesangial cells at 3-17th passages. The agarose gel electrophoresis demonstrated that AVP attenuated a ladder formation stimulated by the serum deprivation. The quantitation of oligonucleosomes by ELISA also showed that AVP suppressed the serum deprivation-induced apoptosis. Such an antiapoptotic effect of AVP was dose-dependent. An AVP V1a receptor antagonist, d(CH2)5Tyr(Me)AVP, abolished the antiapoptotic effect of AVP. The inhibitory effect of AVP on the apoptosis was reduced by staurosporine and mimicked by phorbol-12-myristate-13-acetate. These results suggest that AVP inhibits serum deprivation-induced apoptosis of glomerular mesangial cells via V1a receptor-protein kinase C pathway.