Takashi Nojiri

Predictive value of B-type natriuretic peptide for postoperative atrial fibrillation following pulmonary resection for lung cancer

OBJECTIVE To evaluate the usefulness of atrial natriuretic peptide (ANP) and brain B-type natriuretic peptide (BNP) for predicting postoperative atrial fibrillation (AF), we determined the changes in perioperative ANP and BNP levels in patients undergoing pulmonary resection for lung cancer. METHODS This prospective observational study was conducted during the 10-month period from July 2007 to April 2008. Eighty patients with lung cancer underwent lobectomy, segmentectomy or wedge resection. Preoperative evaluations included spirometry and examinations of plasma ANP and BNP-levels, which were also determined on postoperative days 1, 3 and 7. RESULTS Postoperative AF was identified in 22 (28%) of the patients, and those had significantly higher preoperative ANP and BNP levels as compared with patients without AF. During the postoperative course, patients with postoperative AF also had significantly higher ANP and BNP-levels. The area under the receiver-operating characteristic curve for BNP to predict postoperative AF following pulmonary resection for lung cancer was 0.90 (95% confidence interval (CI), 0.82-0.98; p<0.001). A BNP value of 30pgml(-1) had a sensitivity of 77% and a specificity of 93% for predicting postoperative AF following pulmonary resection for lung cancer. CONCLUSIONS Preoperative BNP level seems to be an appropriate predictor of AF after pulmonary resection.

Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells

Significance Postoperative cancer recurrence is a major problem following curative cancer surgery. Perioperative systemic inflammation induces the adhesion of circulating tumor cells released from the primary tumor to the vascular endothelium of distant organs, which is the first step in hematogenous metastasis. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here, we demonstrate that cancer recurrence after lung cancer surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). We show that ANP prevents cancer metastasis by suppressing the inflammatory reaction of endothelial cells, thereby inhibiting cancer cell adhesion to vascular endothelial cells. Most patients suffering from cancer die of metastatic disease. Surgical removal of solid tumors is performed as an initial attempt to cure patients; however, surgery is often accompanied with trauma, which can promote early recurrence by provoking detachment of tumor cells into the blood stream or inducing systemic inflammation or both. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here we demonstrate that cancer recurrence after curative surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). ANP is known to bind specifically to NPR1 [also called guanylyl cyclase-A (GC-A) receptor]. In mouse models, we found that metastasis of GC-A–nonexpressing tumor cells (i.e., B16 mouse melanoma cells) to the lung was increased in vascular endothelium-specific GC-A knockout mice and decreased in vascular endothelium-specific GC-A transgenic mice compared with control mice. We examined the effect of ANP on tumor metastasis in mice treated with lipopolysaccharide, which mimics systemic inflammation induced by surgical stress. ANP inhibited the adhesion of cancer cells to pulmonary arterial and micro-vascular endothelial cells by suppressing the E-selectin expression that is promoted by inflammation. These results suggest that ANP prevents cancer metastasis by inhibiting the adhesion of tumor cells to inflamed endothelial cells.

Predictive value of preoperative tissue Doppler echocardiographic analysis for postoperative atrial fibrillation after pulmonary resection for lung cancer

OBJECTIVE The objective of the present study was to evaluate the utility of tissue Doppler imaging for predicting the development of postoperative atrial fibrillation. METHODS In this prospective observational study, we evaluated 126 patients with lung cancer who underwent a lobectomy during the 18-month period from August 2007 to January 2009. Preoperative evaluations for all patients included tissue Doppler imaging in addition to conventional echocardiographic analysis. The study end point was the development of postoperative atrial fibrillation. RESULTS Postoperative atrial fibrillation was identified in 29 (23%) patients, in whom significantly higher early transmitral velocity/tissue Doppler mitral annular early diastolic velocity values were noted compared with those seen in patients without atrial fibrillation (9.76 ± 2.3 vs 7.14 ± 1.7, P < .0001). The area under the receiver operating characteristic curve for early transmitral velocity/tissue Doppler mitral annular early diastolic velocity to predict postoperative atrial fibrillation after pulmonary resection for lung cancer was 0.83 (95% confidence interval, 0.74-0.92; P < .001). An early transmitral velocity/tissue Doppler mitral annular early diastolic velocity value of greater than 8 had a sensitivity of 90% and a specificity of 73% for predicting postoperative atrial fibrillation. CONCLUSIONS Postoperative atrial fibrillation after pulmonary resection might be associated with left ventricular diastolic dysfunction before surgical intervention revealed by using tissue Doppler imaging. Additional studies to establish the significance of tissue Doppler imaging as a tool to predict postoperative atrial fibrillation could contribute to improvements in lung cancer treatments.

Effect of low-dose human atrial natriuretic peptide on postoperative atrial fibrillation in patients undergoing pulmonary resection for lung cancer: a double-blind, placebo-controlled study.

OBJECTIVES We previously reported that patients with preoperative B-type natriuretic peptide levels of 30 pg/mL or more have increased risk of postoperative atrial fibrillation after pulmonary resection. This study evaluated the effects of human atrial natriuretic peptide on postoperative atrial fibrillation in patients undergoing pulmonary resection for lung cancer. METHODS A prospective, randomized study was conducted with 40 patients who had preoperative elevated B-type natriuretic peptide (≥ 30 pg/mL) and underwent a scheduled pulmonary resection for lung cancer. Results were compared between patients who received low-dose human atrial natriuretic peptide and those who received a placebo. The primary end point was the incidence of postoperative atrial fibrillation during the first 4 days after surgery. RESULTS The incidence of postoperative atrial fibrillation was significantly lower in the human atrial natriuretic peptide group than in the placebo group (10% vs 60%; P < .001). Patients in the human atrial natriuretic peptide group also showed significantly lower white blood cell counts and C-reactive protein levels after surgery. CONCLUSIONS Continuous infusion of low-dose human atrial natriuretic peptide during lung cancer surgery had a prophylactic effect against postoperative atrial fibrillation after pulmonary resection in patients with preoperative elevation of B-type natriuretic peptide levels. A larger sample size is needed to establish the safety and efficacy of this intervention.

B-Type Natriuretic Peptide as a Predictor of Postoperative Cardiopulmonary Complications in Elderly Patients Undergoing Pulmonary Resection for Lung Cancer

BACKGROUND The objective of the present study was to evaluate the utility of B-type natriuretic peptide for prediction of postoperative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. METHODS A prospective observational study was performed involving 80 consecutive patients aged 75 years or older who underwent a scheduled pulmonary resection for lung cancer in two specialized thoracic centers between January 2008 and June 2010. Baseline clinical details were obtained, and spirometry and examination of serum B-type natriuretic peptide levels were performed before surgery. The primary endpoint was the incidence of postoperative cardiopulmonary complications. RESULTS Postoperative cardiopulmonary complications were identified in 34 (43%) patients; these patients had significantly higher preoperative B-type natriuretic peptide levels than those without cardiopulmonary complications (84.0±93.7 pg/mL vs 22.0±18.2 pg/mL; p<0.0001). The area under the receiver operating characteristic curve for B-type natriuretic peptide to predict postoperative cardiopulmonary complications after pulmonary resection for lung cancer was 0.85 (95% confidence interval 0.76 to 0.94; p<0.0001). A B-type natriuretic peptide value of 30 pg/mL had a sensitivity of 79% and a specificity of 83% for predicting postoperative cardiopulmonary complications after pulmonary resection for lung cancer. The incidences of both cardiovascular and respiratory complications were significantly higher in patients with preoperative B-type natriuretic peptide levels of 30 pg/mL or more. CONCLUSIONS Preoperative B-type natriuretic peptide level could be a useful predictor of postoperative cardiopulmonary complications in elderly patients after pulmonary resection for lung cancer.

Efficacy of low-dose landiolol, an ultrashort-acting β-blocker, on postoperative atrial fibrillation in patients undergoing pulmonary resection for lung cancer.

PurposePostoperative atrial fibrillation is the most common complication encountered during the early postoperative period following a pulmonary resection procedure. Landiolol is a newly developed, ultrashortacting, β-adrenoceptor antagonist. The objective of the present study was to evaluate the efficacy and safety of low-dose landiolol for postoperative atrial fibrillation in patients undergoing pulmonary resection for lung cancer.MethodsOf 553 patients who underwent an elective pulmonary resection procedure for lung cancer at National Toneyama Hospital from January 2005 to December 2009, this analysis involved 30 consecutive patients who developed atrial fibrillation after surgery and needed treatment. These patients were divided into two groups: the landiolol group (n = 15) and the historical control group (treated with a combination of verapamil and digoxin, n = 15). Hemodynamic changes before and 30 min, 2 h, and 12 h after medication, the time required to restore sinus rhythm, and adverse events were evaluated.ResultsThere were no significant differences between the two groups regarding blood pressure before and after medication. Heart rate was reduced immediately in both groups after medication and was significantly lower in the landiolol group than in the control group. The time to restore sinus rhythm was significantly shorter in the landiolol group than in the control group (8.1 ± 11.0 h vs. 23.0 ± 26.0 h, P < 0.05). In none of the subjects with the landiolol infusion was it discontinued because of side effects.ConclusionLow-dose landiolol can be effective quickly and used safely in patients who develop atrial fibrillation after pulmonary resection for lung cancer.

Low-dose human atrial natriuretic peptide for the prevention of postoperative cardiopulmonary complications in chronic obstructive pulmonary disease patients undergoing lung cancer surgery

OBJECTIVES Lung cancer patients with chronic obstructive pulmonary disease are at an increased risk of respiratory and cardiovascular complications after pulmonary resection. The objective of the present study was to evaluate the clinical effects of low-dose human atrial natriuretic peptide (hANP) on postoperative cardiopulmonary complications in untreated chronic obstructive pulmonary disease patients undergoing lung cancer surgery. METHODS Of 824 patients who underwent an elective pulmonary resection procedure for lung cancer in two specialized thoracic centres between 2008 and 2011, 202 consecutive patients who had airflow limitation before surgery were included in this retrospective study. The results were compared between patients who did and those who did not receive hANP during the perioperative period. The primary endpoint was the incidence of postoperative cardiopulmonary complications. Postoperative haemodynamics, white blood cell (WBC) counts and C-reactive protein (CRP) levels were also examined. Furthermore, propensity score matching analysis was used to reduce treatment selection bias from patient characteristics. RESULTS The incidence of postoperative cardiopulmonary complications was significantly lower in the hANP group than in the control group (14 vs 36%, P < 0.01). The propensity score matching analysis confirmed the significantly decreased frequency of postoperative cardiopulmonary complications in the hANP group. Patients in the hANP group showed significantly lower WBC counts and serum CRP levels postoperatively. CONCLUSIONS Treatment with hANP during the perioperative period had a prophylactic effect against postoperative cardiopulmonary complications in chronic obstructive pulmonary disease patients undergoing lung cancer surgery.

Effects of low-dose human atrial natriuretic peptide for preventing post-operative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer

OBJECTIVES The objective of the present study was to evaluate the clinical effects of human atrial natriuretic peptide (hANP) on post-operative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. METHODS A retrospective study involving 44 consecutive patients aged ≥75 years who had elevated pre-operative B-type natriuretic peptide levels (≥30 pg/ml) and underwent a scheduled pulmonary resection for lung cancer in two specialized thoracic centres between April 2008 and March 2010. Results were compared between the patients who did and did not receive hANP during the perioperative period. The primary endpoint was the incidence of post-operative cardiopulmonary complications. Post-operative haemodynamics, white blood cell (WBC) counts and C-reactive protein (CRP) levels were also examined. RESULTS The incidence of post-operative cardiopulmonary complications was significantly lower in the hANP group than that in the control group (26 vs. 86%, P < 0.0001). Patients in the hANP group showed significantly lower WBC counts and serum CRP levels post-operatively. CONCLUSIONS Continuous infusion of low-dose hANP during lung cancer surgery had a prophylactic effect on post-operative cardiopulmonary complications in elderly lung cancer patients. ( TRIAL REGISTRATION NUMBER JPRN-UMIN000003631).

Protective effects of ghrelin on cisplatin-induced nephrotoxicity in mice.

Cisplatin is a potent chemotherapeutic agent that has activity against malignant tumors. However, cisplatin causes various adverse effects, such as nephrotoxicity, which are associated with high morbidity and mortality. Recent studies have revealed that the mechanism of cisplatin nephrotoxicity includes a robust inflammatory response. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin might have protective effects against cisplatin nephrotoxicity. Mice were randomly divided into three groups: control, cisplatin with vehicle, and cisplatin with ghrelin. Ghrelin (0.8μg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started one day before cisplatin injection. At 72h after cisplatin administration (20mg/kg, intraperitoneally), we measured serum blood urea nitrogen and creatinine, urine albumin/creatinine, renal mRNA levels of monocyte chemoattractant protein-1, interleukin-6, tumor necrosis factor-α, interleukin-1β, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin by real-time polymerase chain reaction, and histological changes. Ghrelin significantly attenuated the increase in serum blood urea nitrogen and creatinine induced by cisplatin. Ghrelin tended to attenuate the increase in urine albumin/creatinine, although not significantly. Cisplatin-induced renal tubular injury and apoptosis were significantly attenuated by ghrelin pretreatment. Consequently, ghrelin significantly attenuated renal mRNA levels of monocyte chemoattractant protein-1, interleukin-6, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin. In conclusion, ghrelin produces protective effects in cisplatin-induced nephrotoxicity through inhibition of inflammatory reactions. Pretreatment with ghrelin may become a new prophylactic candidate for cisplatin-induced nephrotoxicity.

Clinical predictor of pre- or minimally invasive pulmonary adenocarcinoma: possibility of sub-classification of clinical T1a

OBJECTIVES A new pathological classification for pre- and minimally invasive adenocarcinoma has been established, with distinction prior to surgery crucial because of the extremely good prognosis. METHODS Of 412 patients who underwent surgery for lung cancer from 2008 to 2011, 110 classified as c-stage I had each of the following four parameters assessed for predictive power for pre- or minimally invasive adenocarcinoma and relapse-free survival (RFS): (i) whole tumour size (WS) shown by computed tomography (CT) , (ii) size of the solid (SS) component in CT findings, (iii) maximum standard uptake value in fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan images (SUVmax) and (iv) serum level of carcinoembryonic antigen. RESULTS For prediction of pre- or minimally invasive adenocarcinoma, the area under the receiver-operating curve was >0.7 for all the four parameters, while only SS was found to be an independent factor in multivariate logistic regression analysis. In Cox proportional hazard model analysis, SS and SUVmax were statistically significant, and SS was exclusively independent in multivariate analysis. Differences in RFS between T1a and T1b were more pronounced when using SS compared with WS. In the sub-classification of T1a, we used a breakpoint of 1.0 cm in SS (T1a-α and T1a-β), which resulted in a 2-year RFS rate of 1.00 for T1a-α (n=21), 0.89 for T1a-β (n=27) and 0.68 for T1b (n=26) (P=0.002 between T1a-β and T1b). CONCLUSIONS The SS parameter was useful to distinguish pre- and minimally invasive adenocarcinoma from other types of lung cancer, and set a T1a sub-classification.