Kentaro Yoshimoto

Quantification of the impact of segmentectomy on pulmonary function by perfusion single-photon-emission computed tomography and multidetector computed tomography

OBJECTIVE The impact of segmentectomy for preservation of pulmonary function was quantified by using a co-registered perfusion single-photon-emission computed tomography and multidetector computed tomography (SPECT/CT). METHODS Pulmonary function tests and perfusion SPECT/CT were conducted before and after segmentectomy in 56 patients. Actual values of forced expiratory volume in 1 second (FEV(1)) after segmentectomy were compared with the FEV(1) after virtual lobectomy, which was calculated by SPECT/CT. The preoperative and postoperative FEV(1) of each lobe that had undergone segmentectomy was measured by SPECT/CT. RESULTS The mean percent of FEV(1) preserved after segmentectomy was significantly higher than the value after virtual lobectomy (88% +/- 9% vs 77% +/- 7%; P < .001). Whereas the mean value of the preoperative FEV(1) of each lobe that was undergoing segmentectomy was 0.51+/-0.21 L, segmentectomy could preserve 41% +/- 24% of it. The FEV(1) of each lobe after the resection of more than three segments (n = 4) was preserved in 17% +/- 12% of the preoperative values, which was significantly less than 49% +/- 23% and 35% +/- 22% after the resection of one (n = 29) and two (n = 23) segments (P = .02 and .08, respectively). The FEV(1) of the left upper lobe after the upper division segmentectomy (n = 8) was preserved in 21% +/- 11% of the preoperative values, which was significantly less than 35% +/- 12% after the lingular segmentectomy (n = 7) (P = .03). CONCLUSION Segmentectomy can preserve the pulmonary function more significantly than lobectomy, except for the resection of more than three segments or the left upper division segmentectomy.

Prediction of pulmonary function after lung lobectomy by subsegments counting, computed tomography, single photon emission computed tomography and computed tomography: a comparative study

OBJECTIVE The aim of the present study was to determine the optimal method of predicting postoperative pulmonary function (PPF) after lung lobectomy. METHODS The forced expiratory volume in 1s (FEV(1)) was measured in 37 patients before and after lobectomy, and the following three methods of predicting the PPF were evaluated: (1) the number of functioning subsegments to be resected were counted (subsegments counting [SC]); (2) the volume of the functioning lung was calculated using CT images (quantitative CT); and (3) perfusion scintigraphy was performed using co-registered single photon emission computed tomography and CT imaging (SPECT/CT). The FEV(1) values predicted using these three methods were then compared with the measured postoperative FEV(1), and the correlations and differences were analyzed. RESULTS While a paired t-test showed the SPECT/CT method to have the smallest difference between the measured and the predicted FEV(1) values (0.05 l, p=0.33), followed by the quantitative CT method (0.07 l, p=0.07), and finally the SC method (0.15 l, p<0.001), the difference between the two values was not significantly different between the quantitative CT and SPECT/CT method (p=0.22). CONCLUSIONS While the SC method is inferior to both the quantitative CT and the SPECT/CT methods for predicting the PPF after lobectomy, the latter two methods are almost equally accurate.

Peptides derived from human insulin-like growth factor-II mRNA binding protein 3 can induce human leukocyte antigen-A2-restricted cytotoxic T lymphocytes reactive to cancer cells

Insulin‐like growth factor‐II mRNA binding protein 3 (IMP‐3) is an oncofetal protein expressed in various malignancies including lung cancer. This study aimed to identify immunogenic peptides derived from IMP‐3 that can induce tumor‐reactive and human leukocyte antigen (HLA)‐A2 (A*02:01)‐restricted cytotoxic T lymphocytes (CTL) for lung cancer immunotherapy. Forty human IMP‐3‐derived peptides predicted to bind to HLA‐A2 were analyzed to determine their capacity to induce HLA‐A2‐restricted T cells in HLA‐A2.1 (HHD) transgenic mice (Tgm). We found that three IMP‐3 peptides primed HLA‐A2‐restricted CTL in the HLA‐A2.1 Tgm. Among them, human CTL lines reactive to IMP‐3 515NLSSAEVVV523 were reproducibly established from HLA‐A2‐positive healthy donors and lung cancer patients. On the other hand, IMP‐3 199RLLVPTQFV207 reproducibly induced IMP‐3‐specific and HLA‐A2‐restricted CTL from healthy donors, but did not sensitize CTL in the HLA‐A2.1 Tgm. Importantly, these two IMP‐3 peptide‐specific CTL generated from healthy donors and cancer patients effectively killed the cancer cells naturally expressing both IMP‐3 and HLA‐A2. Cytotoxicity was significantly inhibited by anti‐HLA class I and anti‐HLA‐A2 monoclonal antibodies, but not by the anti‐HLA‐class II monoclonal antibody. In addition, natural processing of these two epitopes derived from the IMP‐3 protein was confirmed by specific killing of HLA‐A2‐positive IMP‐3‐transfectants but not the parental IMP‐negative cell line by peptide‐induced CTL. This suggests that these two IMP‐3‐derived peptides represent highly immunogenic CTL epitopes that may be attractive targets for lung cancer immunotherapy. (Cancer Sci 2011; 102: 71–80)

Aberrant methylation of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer

Genome-wide DNA hypomethylation and gene hypermethylation play important roles in instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. Slit homolog 2 (SLIT2), myelin and lymphocyte protein gene (MAL) and insulin-like growth factor binding protein 7 (IGFBP7) are known to be hypermethylated in various malignancies. The aim of the present study was to assess the precise methylation levels of LINE-1, SLIT2, MAL and IGFBP7 in non-small cell lung cancer (NSCLC) using a pyrosequencing assay. Methylation of all regions was examined in 56 primary NSCLCs using a pyrosequencing assay. Changes in mRNA expression levels of SLIT2, MAL and IGFBP7 were measured before and after treatment with a demethylating agent. Methylation of these genes was also examined in 9 lung cancer cell lines using RT-PCR and a pyrosequencing assay. Frequencies of hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7, defined by predetermined cut off values, were 55, 64, 46 and 54% in NSCLCs, respectively and exhibited tumor-specific features. The hypermethylation of all genes was well correlated with changes in expression. The methylation level and frequency of MAL were significantly higher in smokers and in patients without EGFR mutations. Through accurate measurement of methylation levels using pyrosequencing, hypomethylation of LINE-1 and hypermethylation of SLIT2, MAL and IGFBP7 were frequently detected in NSCLCs and associated with various clinical features. Analysis of the methylation profiles of these genes may, therefore, provide novel opportunities for the therapy of NSCLCs.

Long interspersed nucleotide element 1 hypomethylation is associated with poor prognosis of lung adenocarcinoma.

BACKGROUND Genome-wide DNA hypomethylation is known to play important roles in genomic instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. The aim of this study was to evaluate prognostic significance of LINE-1 hypomethylation in lung adenocarcinoma. METHODS A consecutive series of 211 lung adenocarcinoma patients who underwent curative resections without any preoperative chemotherapy or radiotherapy at Kumamoto University Hospital between April 2010 and December 2012 were included. The LINE-1 methylation levels were quantified in tumor and noncancerous tissue by Pyrosequencing assay. RESULTS Higher histologic grade and positive findings for vascular invasion were significantly associated with lower methylation levels. The disease-free survival in the hypomethylation group was significantly shorter than that of the non-hypomethylation group. The prognostic difference was more obvious in advanced cases (stage II, III) than in stage I cases. CONCLUSIONS The LINE-1 methylation level is associated with histologic grade and vascular invasion of lung adenocarcinoma. Additionally, LINE-1 hypomethylation is a useful biomarker to predict early recurrence of lung adenocarcinoma.

Postoperative change in pulmonary function of the ipsilateral preserved lung after segmentectomy versus lobectomy

OBJECTIVE Anatomical repositioning and expansion of the ipsilateral preserved lung after lung resection may influence postoperative pulmonary function. To study the postoperative changes in pulmonary function of the preserved lung after lobectomy compared with that after segmentectomy, the preoperative and postoperative forced expiratory volume in 1s (FEV(1)) of the ipsilateral non-operated lobe was measured using perfusion single-photon-emission computed tomography and computed tomography (SPECT/CT). METHODS Eighty-nine patients (n=24; lobectomy, n=65; segmentectomy) who were examined with pulmonary function test and perfusion SPECT/CT both before and after surgery were enrolled in this study. The FEV(1) values of the ipsilateral non-operated lobes before and after surgery were measured using perfusion SPECT/CT. RESULTS The FEV(1) of the ipsilateral non-operated lobe increased after segmentectomy of the right upper lobe (p=0.07) and after both lobectomy and segmentectomy of the left upper lobe (p=0.04 and 0.001, respectively), but decreased after lobectomy of the right upper lobe (p=0.06). In the right upper lobe, the percentage change in FEV(1) of the ipsilateral non-operated lobe after lobectomy was significantly lower than that after segmentectomy (p<0.001). The FEV(1) of the ipsilateral non-operated lobe had not significantly changed after surgery on the lower lobes. CONCLUSIONS The FEV(1) of the ipsilateral non-operated lobes increased after surgery on left upper lobe, whereas it decreased after right upper lobectomy. The surgery on lower lobe did not affect the FEV(1) of the ipsilateral non-operated lobes. Our data may facilitate determining the indications for lung cancer surgery, especially in patients with tumours involving the upper lobes.

Difference of Sentinel Lymph Node Identification Between Tin Colloid and Phytate in Patients With Non–Small Cell Lung Cancer

BACKGROUND The advantages and disadvantages of technetium Tc 99m tin colloid and technetium Tc 99m phytate as tracers for sentinel node (SN) identification in patients with clinical stage I non-small cell lung cancer were examined retrospectively. METHODS Sentinel node identification was conducted using tin colloid and phytate, respectively, in 73 and 74 patients with clinical stage I non-small cell lung cancer. We compared these two tracers in terms of identification rates, numbers of SNs, characteristics of patients whose SNs could not be identified, and the pathologic results of SNs. RESULTS The tin colloid tracer identified SNs in 54 of the 73 patients (74%), which was significantly lower than the 89% (66 of 74 patients) in the phytate group (p = 0.02). The number of SNs per patient was 1.7 +/- 0.8 in the tin colloid group, which was significantly less than the 2.4 +/- 1.5 in the phytate group (p = 0.002). Although patients in the tin colloid group whose SNs could not be identified had a significantly lower forced expiratory volume in 1 second to forced vital capacity ratio than those whose SNs could be identified (p = 0.04), the phytate group did not show such a difference. Eleven of 120 patients whose SNs could be identified had pathologic N1 or N2 disease, but neither group showed any false-negative results for SN identification. CONCLUSIONS Both tin colloid and phytate are reliable tracers for identifying SNs in non-small cell lung cancer. The advantage of phytate is that SNs can be detected more frequently than with tin colloid, even in patients with a low forced expiratory volume in 1 second to forced vital capacity ratio. However, tin colloid requires fewer nodes than phytate to identify SNs.

Size of Metastatic and Nonmetastatic Mediastinal Lymph Nodes in Non-small Cell Lung Cancer

Objective: To determine the optimum selection of mediastinal lymph nodes for biopsy in non-small cell lung cancer (NSCLC), lymph nodes with or without metastasis at each mediastinal station were ranked in size in patients with pathological N2 disease. Methods: Twenty-five NSCLC patients with pathological N2 disease who underwent pulmonary resection with complete mediastinal lymph node clearance were examined. Of 114 mediastinal lymph node stations dissected, 47 had metastases and 67 did not. The sizes of 259 nodes in the 47 positive lymph node stations were measured. Of these 259 nodes, 137 had metastases and 122 did not. The short- and long-axis diameters of the 259 lymph nodes were ranked in each lymph node station. Results: Mean short- and long-axis diameters of lymph nodes with metastases were significantly greater than those without (p < 0.001). In 47 metastatic lymph node stations, the short- and long-axis diameters were greatest in a metastatic node in 44 (94%) and 42 (89%) respectively, whereas in the remaining 3 (6%) and 5 (11%), the second largest but not the largest node was positive. None of the largest lymph nodes with metastasis were smaller than the second largest lymph node at each station. Four of the 10 patients with adenocarcinoma (40%) had metastasis in the second largest but not in the largest node measured by long-axis diameter, a significant difference from one in eight (12.5%) among the squamous cell carcinoma cases (p = 0.04). Conclusion: For mediastinal lymph node biopsy, both the largest and the second largest node at each station should be sampled, especially in adenocarcinoma. If only the largest lymph node is selected, false-negative results will occur at a rate of about 10%.

Is completion lobectomy merited for unanticipated nodal metastases after radical segmentectomy for cT1 N0 M0/pN1-2 non-small cell lung cancer?

OBJECTIVE To examine the role of radical segmentectomy, defined as a segmentectomy with extensive hilar/mediastinal lymph node dissection and a sufficient surgical margin, for local control in cT1 N0 M0/pN1-2 non-small cell lung cancer (NSCLC), we examined the following: (1) whether metastases were observed in specimens additionally resected by completion lobectomy undertaken after segmentectomy because of pN1-2 disease and (2) prognostic outcome in patients whose operations were completed with segmentectomy regardless of pN1-2. METHODS Of 275 patients with cT1 N0 M0 NSCLC who were scheduled to undergo radical segmentectomy, 15 (6%) had a diagnosis of pN1 or N2 disease. Of these patients, 10 were additionally treated with completion lobectomy, whereas the operations of the remaining 5 were completed with segmentectomy. RESULTS None of the 10 patients who underwent completion lobectomy showed residual metastases in the specimens additionally resected by completion lobectomy. Two of the 5 patients whose operations were completed with segmentectomy, regardless of N1 or N2 disease, had tumor recurrence, but their first recurrence was not local. CONCLUSIONS Radical segmentectomy, with extensive hilar/mediastinal lymph node dissection and a sufficient surgical margin, may play a role in local control in patients with cT1 N0 M0/pN1-2 NSCLC.

Positron emission tomography in lung cancer

Recent advances in positron emission tomography (PET) with 2-deoxy-2-fluoro [F-18]-d-glucose (FDG) has enabled not only the diagnosis and staging of lung cancer but also the prediction of its malignancy grade. However, FDG-PET has been known to have several pitfalls for imaging of lung cancer. For the effective clinical use of FDG-PET in lung cancer, we reviewed the pitfalls of using FDG-PET in the diagnosis of pulmonary nodules, semiquantitative analysis of FDG-uptake, N-staging, prediction of tumor aggressiveness, prognostic significance, and prediction of pathological response after chemoradiotherapy.