Norifumi Tsubokawa

Multidisciplinary Team-Based Approach for Comprehensive Preoperative Pulmonary Rehabilitation Including Intensive Nutritional Support for Lung Cancer Patients

Background To decrease the risk of postoperative complication, improving general and pulmonary conditioning preoperatively should be considered essential for patients scheduled to undergo lung surgery. Objective The aim of this study is to develop a short-term beneficial program of preoperative pulmonary rehabilitation for lung cancer patients. Methods From June 2009, comprehensive preoperative pulmonary rehabilitation (CHPR) including intensive nutritional support was performed prospectively using a multidisciplinary team-based approach. Postoperative complication rate and the transitions of pulmonary function in CHPR were compared with historical data of conventional preoperative pulmonary rehabilitation (CVPR) conducted since June 2006. The study population was limited to patients who underwent standard lobectomy. Results Postoperative complication rate in the CVPR (n = 29) and CHPR (n = 21) were 48.3% and 28.6% (p = 0.2428), respectively. Those in patients with Charlson Comorbidity Index scores ≥2 were 68.8% (n = 16) and 27.3% (n = 11), respectively (p = 0.0341) and those in patients with preoperative risk score in Estimation of Physiologic Ability and Surgical Stress scores >0.3 were 57.9% (n = 19) and 21.4% (n = 14), respectively (p = 0.0362). Vital capacities of pre- and post intervention before surgery in the CHPR group were 2.63±0.65 L and 2.75±0.63 L (p = 0.0043), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6815). Forced expiratory volumes in one second of pre- and post intervention before surgery in the CHPR group were 1.73±0.46 L and 1.87±0.46 L (p = 0.0012), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6424). Conclusions CHPR appeared to be a beneficial and effective short-term preoperative rehabilitation protocol, especially in patients with poor preoperative conditions.

Prognostic value of the new IASLC/ATS/ERS classification of clinical stage IA lung adenocarcinoma

OBJECTIVES We analyzed and validated the prognostic utility of the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) for clinical stage IA lung adenocarcinoma (ADC) classification of adenocarcinoma (ADC). METHODS We retrospectively reviewed 347 patients with clinical stage IA nonmucinous ADC, who had undergone complete resection. The histological subtype was classified according to the predominant subtype, as proposed by the new IASLC/ATS/ERS ADC classification. RESULTS The histopathological subtypes, defined according to the new IASLC/ATS/ERS ADC classification, were ADC in situ (AIS) in 56 patients (16.1%), minimally invasive ADC (MIA) in 15 (4.3%), lepidic-predominant ADC in 109 (31.4%), papillary-predominant ADC in 70 (20.2%), acinar-predominant ADC in 61 (17.6%), solid-predominant ADC in 30 (8.6%), and micropapillary-predominant ADC in 6 (1.7%). The 5-year disease-free survival (DFS) rate was 100% for both AIS and MIA. All cases of recurrence involved invasive ADC. The 5-year DFS for lepidic-predominant ADC was 99.0%; acinar-predominant ADC, 82.4%; papillary-predominant ADC, 80.8%; solid-predominant ADC, 73.6%; and micropapillary-predominant ADC, 33.3%. The predominant subtype of ADC was significantly correlated with DFS (P<0.0001). Multivariate analysis indicated that the pathological stage was an independent predictor of DFS (P=0.031). Other independent predictors of increased risk of recurrence were the presence of vascular or lymphatic invasion (HR=4.96, P=0.001), and a pathological stage more advanced than IB (HR=2.87, P=0.010). The coincidence between the clinical stage and pathological stage was 79.8%. The stage migration was found in 53.3% of solid-predominat ADC and in 83.3% of micropapillary-predominant ADC. CONCLUSION The new IASLC/ATS/ERS ADC classification has prognostic value in predicting the recurrence and survival of patients with clinical stage IA ADC. The frequency of stage migration was found in more than half of solid and micropapillary predominant ADCs.

Negative prognostic influence of micropapillary pattern in stage IA lung adenocarcinoma

OBJECTIVES There is uncertainty as to which factors determine the aggressiveness of lung adenocarcinoma with a micropapillary pattern (MPP). The present study aimed to clarify the influence of a MPP on the malignant aggressiveness of clinical stage IA lung adenocarcinoma. METHODS We retrospectively examined 347 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete resection. We defined MPP-positive as accounting for ≥5% of the entire tumour. RESULTS Forty-eight (14%) and 299 (86%) patients were MPP-positive and negative, respectively. Lymphatic (P = 0.003) and vessel (P = 0.029) invasion as well as lymph node metastasis (P = 0.002) were more frequent in the MPP-positive than negative group. Five-year disease-free survival (DFS) rates were significantly lower in the MPP-positive than negative group (69.7 vs 89.3%, P < 0.001). Multivariate analysis for DFS showed that MPP (P = 0.048), lymphatic invasion (P = 0.003) and vessel invasion (P = 0.002) were independent poor prognostic factors. In addition, higher proportions (<5%, 5-30% and ≥30%) of MPP were associated with a poorer prognosis (89.3, 76.0, and 48.1%, respectively; P < 0.001). The prognosis of patients with MPP-positive tumours and negative tumours harbouring lepidic and solid predominant growth patents did not differ (100 vs 96.8%, P = 0.564; 66.7 vs 62.5%, P = 0.791, respectively). On the other hand, the prognosis tended to be poorer for patients with papillary predominant MPP-positive tumours than for those with negative tumours (62.5 vs 82.5%, P = 0.075). CONCLUSIONS MPP has an effect on tumour malignancy and patients with tumours harbouring a higher ratio of MPP or papillary predominant subtypes have worse survival.

Laparoscopic Thoracic Duct Clipping for Persistent Chylothorax After Extrapleural Pneumonectomy

We describe a 68-year-old man who was treated by laparoscopic thoracic duct clipping for persistent chylothorax after an extrapleural pneumonectomy for malignant pleural mesothelioma. Initial conservative treatment did not resolve the postoperative chylothorax. A second surgery through the thoracic approach was considered invasive and difficult after extrapleural pneumonectomy. A laparoscopic approach proved effective and resolved the chylothorax. Thus, laparoscopic thoracic duct clipping is considered very useful for treating chylothorax.

Post-thoracotomy pain and long-term survival associated with video-assisted thoracic surgery lobectomy methods for clinical T1N0 lung cancer: a patient-oriented, prospective cohort study

OBJECTIVES To provide a less-invasive procedure for video-assisted thoracic surgery (VATS), we prospectively evaluated the feasibility of two existing VATS approaches. METHODS We conducted a prospective cohort study to determine the feasibility of two strictly defined types of VATS lobectomy. Based on free decisions made by patients after hearing similar preoperative explanations using the same table, either one modality was adopted. The perioperative variables, including operation time, blood loss, morbidity, mortality and particularly post-thoracotomy pain and long-term survival, were evaluated for the assisted VATS and the complete VATS groups. RESULTS We reviewed 104 consecutive patients who had clinical T1N0M0 non-small-cell lung cancer. Twenty-six patients (ASSIST group) chose lobectomy performed via an anterolateral small thoracotomy by using a rib spreader with a combination of thoracoscopic and direct views. Seventy-eight patients (PURE group) chose complete VATS in which only a monitor was used during smaller-access thoracotomy without a rib spreader. All clinical parameters that were scheduled to be measured during the perioperative period were found to be acceptable using both approaches. The ASSIST group had a significantly high odds ratio of using additional painkillers except epidural anaesthesia when compared with the PURE group, as shown by multivariate logistic regression analysis. Patients in the PURE group exhibited early recovery from surgery, but their operation time was longer. Disease-free and overall 5-year survival rates were equivalent between the two groups. CONCLUSIONS Both procedures are feasible with regard to perioperative factors and long-term survival rates. Patients undergoing complete VATS required less medication than those undergoing assisted VATS.

Comparison of Postoperative Pain after Different Thoracic Surgery Approaches as Measured by Electrical Stimulation

BACKGROUND Postoperative pain is commonly evaluated using the numerous rating scale (NRS), visual analogue scale, or pain scale; however, these assessments are easily affected by various subjective factors. We measured the degree of postoperative chest pain among different thoracic surgery approaches using NRS and electrical stimulation measurements. METHODS Seventy patients who underwent lobectomy or segmentectomy were enrolled. Concomitant with NRS, pain scores were quantitatively measured on postoperative day 2 using an electrical neurostimulator to compare the degree of pain among three different surgical approaches: pure video-assisted thoracic surgery (VATS), hybrid VATS, and conventional thoracotomy. The risk factors associated with postoperative pain were also analyzed. RESULTS Thirty patients underwent lung resection with pure VATS, while 30 had hybrid VATS, and 10 had conventional thoracotomy. Among the three surgical approaches, analyzing the pain score indicated statistically significant differences (pure, 159.50 ± 26.22; hybrid, 269.36 ± 30.49; thoracotomy, 589.40 ± 141.11; p = 0.003); however, NRS did not obtain a statistically significant difference between the three approaches (pure, 4.26 ± 0.27; hybrid, 4.96 ± 0.30; thoracotomy, 5.50 ± 0.68; p = 0.105). A multivariate analysis showed that the surgical approach was an independent risk factor for postoperative pain as determined by the pain score (pure vs. hybrid, p = 0.076; pure vs. thoracotomy, p < 0.001). CONCLUSION For lung surgery, the differences in surgical approach were an independent risk factor for postoperative pain. In the early postoperative period, pure VATS was shown to be the least painful of the three surgical approaches.

Role of Positron Emission Tomography/Computed Tomography Findings for Adjuvant Chemotherapy Indications in Stage T1b-2aN0M0 Lung Adenocarcinoma

BACKGROUND This study aimed to determine the significance of the maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) images on postoperative adjuvant chemotherapy for lung adenocarcinoma. METHODS We assessed recurrence-free interval (RFI) and overall survival (OS) based on SUVmax values derived from preoperative FDG-PET/CT images in 174 consecutive patients with completely resected pathologic stage T1b-2aN0M0 lung adenocarcinoma. RESULTS Ninety patients received adjuvant chemotherapy and 84 did not. Adjuvant chemotherapy conferred benefits on RFI and OS when compared with observation (p=0.007 and p=0.004, respectively). Multivariate Cox regression analyses revealed SUVmax as an independent prognostic factor for RFI. RFI and OS were significantly longer for patients who received adjuvant chemotherapy compared with those who did not in the group with SUVmax greater than or equal to 2.6 (p<0.001 and p<0.001, respectively). However, RFI and OS did not differ significantly between such patients in the group with SUVmax less than 2.6 (p=0.421 and p=0.452, respectively). CONCLUSIONS Preoperative SUVmax determined from FDG-PET/CT images reflected the effect of adjuvant chemotherapy after complete resection in patients with pathologic stage T1b-2aN0M0 lung adenocarcinoma. Indications for postoperative adjuvant chemotherapy among patients with lung adenocarcinoma might be more precisely determined using SUVmax derived from FDG-PET/CT images together with tumor size.

Postoperative complications and prognosis after lobar resection versus sublobar resection in elderly patients with clinical Stage I non-small-cell lung cancer

OBJECTIVES The study aimed to investigate the outcomes of sublobar resection in elderly patients with non-small-cell lung cancer. METHODS A total of 205 patients aged ≥75 years were identified from 794 consecutive patients who underwent complete surgical resection for clinical Stage I non-small-cell lung cancer. The outcomes of lobectomy and sublobar resection were compared. Propensity scores were estimated for multivariable analyses and matching. RESULTS Sublobar resection (n = 99) was more frequently performed than lobectomy (n = 106) in older patients (P = 0.027) and those with lower maximum standardized uptake on positron emission tomography (P < 0.001), lower T stage (P < 0.001), lower %vital capacity (P = 0.007) and lower %diffusing capacity of the lungs for carbon monoxide (P = 0.025). Severe (≥Grade IIIa) postoperative complications occurred more frequently with lobectomy (11 of 106 procedures, 10.4%) than with sublobar resection (5 of 99, 5.1%; P = 0.16). In propensity score-adjusted multivariable analysis, lobectomy was an independent predictive factor for severe postoperative complications (odds ratio 3.49, 95% confidence interval 1.01-12.05; P = 0.048). Overall survival (OS) was not significantly different following lobectomy (5-year OS 67.2%) or sublobar resection (5-year OS 73.9%; P = 0.93). In multivariable analysis, the surgical procedure was not an independent predictive factor for OS (lobectomy: hazard ratio 1.03, 95% confidence interval 0.49-2.16; P = 0.94). CONCLUSIONS Sublobar resection may be the optimal procedure in elderly patients with clinical Stage I non-small-cell lung cancer and is associated with less severe postoperative complications than lobectomy and similar OS.

The differences in histological changes among pulmonary vessels divided with an energy device

OBJECTIVES Histological changes after division of the pulmonary artery (PA) and the pulmonary vein (PV) using a vessel-sealing device are not fully understood. The goal of the present study was to clarify histologically and immunohistochemically how division with the device affects the wall layers of the pulmonary vasculature. METHODS This prospective cohort study analysed outcomes of 20 patients who underwent anatomical lung resection. After a single proximal ligation, the PA and the PV (diameter 2-7 mm) were divided using a LigaSure Blunt Tip (LSB). Histological findings and thermal damage were evaluated in vascular specimens from resected lungs. RESULTS The PA has a well-developed media with rich elastic fibres and a thin adventitia, whereas the PV has a thinner media and a thicker adventitia with abundant collagen fibres. Vascular division of the PAs and PVs appeared complete to the naked eye. However, in all divided PAs, the area adjacent to the sealed zone comprised only adventitia and thin disrupted media. Additionally, thermal energy generated by the LSB resulted in a wide area of thermal necrosis over the histologically fragile region in all cases. Conversely, the wall layers of all divided PVs were completely fused without disruption. Thermal spread and disruption did not significantly differ between small (2-4 mm) and large (5-7 mm) PAs [187 (150-253) vs 236 (190-275) μm, P = 0.22; 180 (138-200) vs 210 (161-305) μm, P = 0.22]. Histological changes differed significantly between the pulmonary vessels after division using the LSB. CONCLUSIONS Surgeons should consider that dividing the pulmonary vessels with a vessel-sealing device might have more histological impact on the layers of the wall of the PA than on those of the PV, although it remains unclear whether these findings constitute a clinical risk.

Therapeutic strategies and genetic profile comparisons in small cell carcinoma and large cell neuroendocrine carcinoma of the lung using next-generation sequencing

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of target therapy has not been established in these tumors. This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, and explore the possibility of target therapy using next-generation sequencing. In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected. As therapeutically targetable variants, mutations in EGFR (L858R), KRAS (G12D, G12A, G12V), and PIK3CA (E545K) were detected in 5 cases. The case harboring EGFR mutation showed response to EGFR-tyrosine kinase inhibitor. However, there are no clinicopathological features associated with therapeutically targetable cases. And there was no significant genetic feature between SCLC and LCNEC or pure and combined types. In conclusion, although patients with SCLC and LCNEC may benefit from target therapy, they were not identifiable by clinicopathologic background. And there was not significant genetic difference between SCLC and LCNEC, including between pure and combined types. Classifying SCLC and LCNEC in same category is reasonable. However, distinguishing the pure type from combined type was not validated. Comprehensive genetic analysis should be performed to detect targetable variants in any type of SCLC and LCNEC.