Koichi Yoshiyama

Personalized peptide vaccination in patients with refractory non-small cell lung cancer.

Since the prognosis of non-small cell lung cancer (NSCLC) remains poor, the development of novel therapeutic approaches, including cancer vaccines, is highly desirable. In the current study, we conducted a phase II study of personalized peptide vaccination (PPV), in which a maximum of 4 peptides were selected based on pre-existing humoral immune responses and administered subcutaneously (weekly for 6 consecutive weeks and bi-weekly thereafter) in refractory NSCLC patients. Forty-one refractory NSCLC patients (4 stage IIIb, 22 stage IV and 15 recurrent), who had failed to respond to chemotherapy and/or targeted therapy (median number of regimens, 3; median duration, 10 months), were enrolled. Median overall survival (OS) was 304 days with a one-year survival rate of 42% in the enrolled patients. The main toxicity of PPV was skin reactions at the injection sites, but no serious adverse events were observed. In order to identify potential biomarkers for predicting OS, pre-vaccination and post-vaccination clinical findings and laboratory data were retrospectively assessed and evaluated by multivariate Cox regression analysis. Among the pre-vaccination factors examined, high C-reactive protein (CRP) level was a significant predictor of unfavorable OS [hazard ratio (HR)=10.115, 95% confidence interval (CI)=2.447-41.806, P=0.001]. Among the post-vaccination factors, high CRP level and low frequency of CD3⁺CD26⁺ cells were significant predictors of unfavorable OS (HR=23.127, 95% CI=2.919-183.233, P=0.003; HR=0.952, 95% CI=0.917-0.989, P=0.012). Taken together, our results suggest the feasibility of PPV for the treatment of refractory NSCLC. Evaluation of the identified factors before or at an early stage of vaccination could be potentially useful for selecting NSCLC patients who would likely have better prognosis following PPV.

PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer

PD‐1 expression in peripheral blood T‐cells has been reported in several kinds of cancers, including lung cancer. However, the relationship between PD‐1 expression in peripheral blood T‐cells and prognosis after treatment with a cancer vaccine has not been reported. To elucidate this relationship, we analyzed PD‐1 expression in the peripheral blood T‐cells of patients with non‐small cell lung cancer. The blood samples used in this study were obtained from patients enrolled in phase II clinical trials of a personalized peptide vaccine. Seventy‐eight samples obtained before and after a single vaccination cycle (consisting of six or eight doses) were subjected to the analysis. PD‐1 was expressed on lymphocytes in the majority of samples. The relative contents of PD1+CD4+ T‐cells against total lymphocytes before and after the vaccination cycle correlated with overall survival (OS) with a high degree of statistical significance (P < 0.0001 and P = 0.0014). A decrease in PD‐1+CD8+ T‐cells after one cycle of vaccination also correlated with longer OS (P = 0.032). The IgG response to the non‐vaccinated peptides suggested that the epitope spreading seemed to occur more frequently in high‐PD‐1+CD4+ T‐cell groups. Enrichment of CD45RA−CCR7− effector‐memory phenotype cells in PD‐1+ T‐cells in PBMCs was also shown. These results suggest that PD‐1 expression on the peripheral blood T‐cell subsets can become a new prognostic marker in non‐small cell lung cancer patients treated with personalized peptide vaccination.

Immunological evaluation of personalized peptide vaccination in refractory small cell lung cancer

Since the prognosis of small cell lung cancer (SCLC) remains poor, development of new therapeutic approaches, including immunotherapies, would be desirable. In the current study, to evaluate immunological responses in refractory SCLC patients, we conducted a small scale phase II clinical trial of personalized peptide vaccination (PPV), in which vaccine antigens are selected based on pre‐existing host immunity. Ten refractory SCLC patients, who had failed to respond to chemo‐ and/or chemoradiotherapies (median number of regimens, 2.5; median duration, 20.5 months), were enrolled. A maximum of four human leukocyte antigen (HLA)‐matched peptides showing higher antigen‐specific humoral responses were subcutaneously administered (weekly for six consecutive weeks and then bi‐weekly thereafter). PPV was terminated before the 3rd administration in four patients because of rapid disease progression, whereas the remaining six patients completed at least one cycle (six times) of vaccinations. Peptide‐specific immunological boosting was observed in all of the six patients at the end of the first cycle of vaccinations, with their survival time of 25, 24.5 (alive), 10 (alive), 9.5, 6.5, and 6 months. Number of previous chemotherapy regimens and frequency of CD3+CD26+ cells in peripheral blood were potentially prognostic in the vaccinated patients (hazard ratio [HR] = 2.540, 95% confidence interval [CI] = 1.188–5.431, P = 0.016; HR = 0.941, 95% CI = 0.878–1.008, P = 0.084; respectively). Based on the feasible immune responses in refractory SCLC patients who received at least one cycle (six times) of vaccinations, PPV could be recommended for a next stage of larger‐scale, prospective clinical trials. (Cancer Sci 2012; 103: 638–644)

Selection of Pulmonary Resection Procedures to Reduce Postoperative Complications in 200 Patients

PurposeWe previously demonstrated in a pilot study that postoperative cardiopulmonary complications could be reduced by selecting pulmonary resection procedures based on the results of a combination of specific preoperative cardiopulmonary function tests. The present study reports a re-examination of the criteria for preoperative screening and prospectively assessed whether the selected surgical procedures were appropriate in 200 patients who underwent the planned extent of pulmonary resection.MethodsIn 200 patients requiring lung tumor resection, five preoperative parameters (forced expiratory volume in 1 s on the intact side, maximal oxygen uptake, ejection fraction, occluded pulmonary artery pressure, and occluded total pulmonary vascular resistance index) were used to assign each patient to one of five risk categories in order to select the optimal resection procedure. Thereafter, the postoperative course was investigated to determine the value of this selection method.ResultsThoracotomy was performed in 195 of the 200 patients (97.5%). Two patients (1%) died; one patient succumbed to acute exacerbation of interstitial pneumonia and the other patient died from pulmonary embolism. Six patients (3.1%) developed major complications after surgery and 12 patients (6.2%) had mild complications, while 175 (89.7%) showed a good postoperative course.ConclusionThe use of five preoperative parameters to select the pulmonary resection procedure minimized postoperative death and major complications.

Factors Related to an Early Restoration of Exercise Capacity After Major Lung Resection

PurposeWe attempted to identify the factors related to an early restoration of the exercise capacity after lung resection.MethodsMajor lung resection was performed in 164 patients. Exercise testing and spirometry were performed before surgery, and 2 weeks and 1 month afterward. During exercise, the maximum oxygen uptake per minute per m2 of body surface area (V̇o2max/m2) was measured. The percent change of V̇o2max/m2 at 2 weeks and 1 month after surgery was calculated by setting the preoperative V̇o2max/m2 value as 100%. Patients were then assigned to the early restoration group or late restoration group according to their V̇o2max/m2 measured 2 weeks after surgery. Preoperative cardiopulmonary function, as well as various preoperative and intraoperative factors were compared between the two groups.ResultsAt 2 weeks after surgery, the mean V̇o2max/m2 was 80.9% compared with that before surgery, and was 88.1% at 1 month. A multivariate analysis showed that the surgical method used (thoracotomy and mediastinal lymph node dissection) had a significant effect on the postoperative restoration of the V̇o2max/m2.ConclusionAn early restoration of exercise capacity after lung resection is possible in patients without mediastinal lymph node dissection and in those who have a small thoracotomy wound.

Changes in the pleural cavity by pleurodesis using talc or OK-432: an experimental study.

PurposeTo define the changes in the pleural cavity after pleurodesis induced by talc or OK-432.MethodsA total of 30 rats were divided into three groups: a normal saline group (control group, n = 10), a group administered 400 mg/kg talc (talc group, n = 10), and a group administered 0.3 KE/kg OK-432 (OK-432 group, n = 10). Pleural cavities were examined and scored on the 30th day after the intrapleural administration of each agent.ResultsBoth the talc group and OK-432 group showed significantly higher macroscopic or microscopic pleurodesis scores than the control group (P < 0.05). Upon microscopic evaluation, the pleurodesis scores in the talc group were significantly higher than those in the OK-432 group (P < 0.01).The majority of the pleural thickness was found on the visceral pleura, and the parietal pleura was very thin. The thickness of the visceral pleura in the talc group was significantly higher than that in the OK-432 group (P < 0.005). Pathologically, the pleural thickening in the talc group consisted of fibrous tissue with injury of the pleural mesothelium, and talc particles were seen in the submesothelial fibrotic tissue and inside the alveoli.ConclusionsTalc pleurodesis induces more marked changes in the pleural cavity than OK-432-induced pleurodesis.

Influence of stapling the intersegmental planes on lung volume and function after segmentectomy

OBJECTIVES Dividing the intersegmental planes with a stapler during pulmonary segmentectomy leads to volume loss in the remnant segment. The aim of this study was to assess the influence of segment division methods on preserved lung volume and pulmonary function after segmentectomy. METHODS Using image analysis software on computed tomography (CT) images of 41 patients, the ratio of remnant segment and ipsilateral lung volume to their preoperative values (R-seg and R-ips) was calculated. The ratio of postoperative actual forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) per those predicted values based on three-dimensional volumetry (R-FEV1 and R-FVC) was also calculated. Differences in actual/predicted ratios of lung volume and pulmonary function for each of the division methods were analysed. We also investigated the correlations of the actual/predicted ratio of remnant lung volume with that of postoperative pulmonary function. RESULTS The intersegmental planes were divided by either electrocautery or with a stapler in 22 patients and with a stapler alone in 19 patients. Mean values of R-seg and R-ips were 82.7 (37.9-140.2) and 104.9 (77.5-129.2)%, respectively. The mean values of R-FEV1 and R-FVC were 103.9 (83.7-135.1) and 103.4 (82.2-125.1)%, respectively. There were no correlations between the actual/predicted ratio of remnant lung volume and pulmonary function based on the division method. Both R-FEV1 and R-FVC were correlated not with R-seg, but with R-ips. CONCLUSIONS Stapling does not lead to less preserved volume or function than electrocautery in the division of the intersegmental planes.

Ectopic Cervical Thymoma Excised through a Transcervical Approach Combined with Video-assisted Thoracoscopic Surgery: A Case Report

Ectopic cervical thymoma (ECT) is a rare tumor. We present a case of 56-year-old woman with an ECT in the anterior neck that was correctly diagnosed preoperatively. The patient had no symptoms of myasthenia gravis or other immune disorders, and the tumor was not invading any adjacent structures. We performed tumor resection and thymectomy through a transcervical approach using video-assisted thoracoscopic surgery with a multi-access single port. To our knowledge, this is a novel combined technique for the resection of an ECT.

Feasibility Study of Personalized Peptide Vaccination for Advanced Small Cell Lung Cancer

Introduction The prognosis of patients with small cell lung cancer (SCLC) remains very poor. Therefore, the development of new therapeutic approaches, including immunotherapies, is desirable. Patients and Methods We conducted a phase II study of personalized peptide vaccination (PPV), in which a maximum of 4 human leukocyte antigen‐matched peptides were selected from 31 pooled peptides according to the pre‐existing peptide‐specific IgG responses before vaccination. The PPV was subcutaneously administered. Results Forty‐six patients were enrolled (median age, 63 years; 40 patients were men). Grade 1 (n = 13), 2 (n = 10), or 3 (n = 1) skin reactions at the injection sites were observed; however, no other severe adverse events related to the PPV were observed. The median survival time was 466, 397, 401, and 107 days in the subgroups with 0 (n = 5), 1 (n = 15), 2 (n = 12), and ≥ 3 (n = 14) previous chemotherapy regimens, respectively. Peptide‐specific IgG responses to the vaccinated peptides were augmented in 70% and 95% of patients after 1 and 2 vaccination cycles, respectively. The overall survival (OS) of patients with augmented IgG responses to a greater number of nonvaccinated peptides after the second cycle of vaccination was significantly longer (median survival time, 1237 days vs. 382 days; P = .010). In addition, augmentation of IgG responses specific to 6 peptides, including Lck‐derived peptides, was significantly related to better OS (P < .05, in each peptide). Conclusion These results suggest the feasibility of PPV for SCLC patients from the viewpoints of safety, immune boosting, and possible prolongation of OS. Therefore, further evaluation of PPV for advanced SCLC in prospective randomized trials is warranted. Micro‐Abstract We conducted a phase II study of personalized peptide vaccination (PPV) for 46 patients with advanced small cell lung cancer (SCLC). We observed immune boosting and possible prolongation of overall survival after PPV without severe adverse events. These results suggest that PPV has potential as a new treatment modality for SCLC.

Neutrophil elastase activity in pulmonary venous blood during lung resection

OBJECTIVES Neutrophil elastase has been reported to play an important role in acute lung injury, which is a major cause of postoperative mortality after pulmonary resection. Neutrophil elastase released in the lungs reaches the peripheral circulation via the pulmonary veins. This study was performed to compare neutrophil elastase activity in pulmonary venous blood (collected during lobectomy) with that in the peripheral blood, and to determine the perioperative changes of neutrophil elastase activity. METHODS In 34 patients undergoing lobectomy with mediastinal lymph node dissection, the leucocyte count, neutrophil count, neutrophil elastase activity and levels of tumour necrosis factor-α, interleukin-6 and interleukin-8 were measured in the pulmonary venous blood and peripheral arterial blood before and after surgery. Then, these parameters were compared between before and after surgery with peripheral and pulmonary blood. RESULTS Neutrophil elastase activity was found to be significantly higher in pulmonary venous blood at the completion of surgery than at the start (during thoracotomy), while the neutrophil elastase activity of peripheral arterial blood showed no significant change between the start and completion of surgery. CONCLUSIONS In conclusion, measurement of neutrophil elastase activity in pulmonary venous blood revealed changes associated with lobectomy.