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Purpose: To investigate the efficacy and safety of proton beam therapy (PBT) for the treatment of stage I non-small cell lung cancer (NSCLC)., Methods and Materials: Six hundred sixty-nine patients with 682 tumors histologically or clinically diagnosed stage I NSCLC according to the seventh edition of Union for International Cancer Control who received passive-scattering PBT from April 2004 and December 2013 in Japan were retrospectively reviewed to analyze survival, local control, and toxicities., Results: Of 669 patients, 486 (72.6%) were men, with a median age of 76 years (range, 42-94 years). NSCLC was histologically confirmed in 440 patients (65.7%). Clinical T stages included T1a (n = 265; 38.9%), T1b (n = 216; 31.7%), and T2a (n = 201; 29.4%). The total irradiation doses of PBT ranged from 74.4 to 131.3 biological effective dose GyE (median, 109.6 biological effective dose GyE). The median follow-up period was 38.2 months (range, 0.6-154.5 months) for all patients. The 3-year overall survival and progression-free survival rates for all patients were 79.5% and 64.1%, respectively. For patients with stage IA tumors, the 3-year overall survival and progression-free survival rates were 82.8% and 70.6%, respectively, and the corresponding rates for patients with stage IB tumors were 70.8% and 47.3%, respectively. The 3-year local progression-free rates for all, stage IA, and stage IB patients were 89.8%, 93.5%, and 79.4%, respectively. The incidence of grade 2, 3, 4, and 5 pneumonitis was 9.8%, 1.0%, 0%, and 0.7%, respectively. The incidence of grade ≥3 dermatitis was 0.4%. No grade 4 or severe adverse events, other than pneumonitis, were observed., Conclusions: PBT appears to yield acceptable survival rates, with a low rate of toxicities., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the safety and efficacy of a mixture of indigo carmine and lipiodol (MIL) as a marker of pulmonary nodule before video-assisted thoracic surgery (VATS)., Materials and Methods: One hundred sixty-eight sessions of pulmonary marking were performed using MIL before VATS for 184 nodules (mean size, 1.2 ± 0.6 cm; range, 0.3-3.6 cm) on 157 patients (83 men and 74 women; median age, 66 years). The mean distance between the lung surface and the nodule was 0.8 ± 0.7 cm (range, 0-3.9 cm). MIL was injected near the nodule using a 23-gauge needle. Mean number of 1.2 ± 0.4 (range, 1-3) punctures were performed in a session for the target nodules, with mean number of 1.1 ± 0.3 (range, 1-3). Successful targeting, localization, and VATS were defined as achievement of lipiodol accumulation at the target site on computed tomography, detection of the nodule in the operative field by fluoroscopy or visualization of dye pigmentation, and complete resection of the target nodule with sufficient margin, respectively., Results: The successful targeting rate was 100%, and the successful localization rate was 99.5%, with dye pigmentation for 160 nodules (87.0%) and intraoperative fluoroscopy for 23 nodules (12.5%). Successful VATS was achieved for 181 nodules (98.4%). Two nodules (1.1%) were not resectable, and surgical margin was positive in 1 nodule (0.5%). Complications requiring interventions occurred in 5 sessions (3.0%) and included pneumothorax with chest tube placement (n = 3) and aspiration (n = 2). No complication related to the injected MIL occurred., Conclusions: MIL was safe and useful for preoperative pulmonary nodule marking., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Our previous report suggested that fluorescence thoracoscopic anatomical segmentectomy (TAS) using intravenous (IV) indocyanine green (ICG) injection is safe, feasible, and efficacious for identifying segmental boundaries. However, contrast visualization in the conventional indocyanine green mode (CIM) remains relatively obscure in smoking-related comorbidities. Our aim was to evaluate the safety and efficacy of recently released Spectra-A with CIM by simultaneous observation., Materials and Methods: We postoperatively analyzed captive imaging using histogram counts in 29 patients who underwent TAS and previously reported that Δ indicates the index of visualization obtained by subtraction from its representative illuminated signal quantities of maximum pixels so that light-shade, intensity-removed image signals are obtained., Results: Sixteen (55.2%) patients were male, and 13 (44.8%) were female. Segmental boundaries were successfully visualized in all patients (100%). The histogram count widths in dim and bright segments with CIM were 13.3 ± 3.8 and 52.5 ± 12.2, and those with Spectra-A were 19.4 ± 6.1 and 118.1 ± 37.4, respectively. The mean value was 4.3-fold higher for ΔSpa-A (61.4 ± 33.2) than for ΔCIM (14.2 ± 8.5) (P < 0.01). In 14 (48.3%) patients, the segmental boundary could not be clearly visualized using CIM but was explicitly identified using Spectra-A., Conclusions: Spectra-A is a safe and promising noninvasive alternative like CIM, and more effective because of overcoming the limitation of CIM, but its use should be studied further to determine its usefulness in identifying segmental boundaries., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To identify risk factors for symptomatic radiation pneumonitis (RP) after stereotactic radiation therapy (SRT) for lung tumours., Methods: We retrospectively evaluated 68 lung tumours in 63 patients treated with SRT between 2011 and 2015. RP was graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0. SRT was delivered at 7.0-12.0 Gy per each fraction, once daily, to a total of 48-64 Gy (median, 50 Gy). Univariate analysis was performed to assess patient- and treatment-related factors, including age, sex, smoking index (SI), pulmonary function, tumour location, serum Krebs von den Lungen-6 value (KL-6), dose-volume metrics (V5, V10, V20, V30, V40 and VS5), homogeneity index of the planning target volume (PTV), PTV dose, mean lung dose (MLD), contralateral MLD and V2, PTV volume, lung volume and the PTV/lung volume ratio (PTV/Lung). Performance of PTV/Lung in predicting symptomatic RP was also analysed using receiver operating characteristic (ROC) analysis., Results: The median follow-up period was 21 months. 10 of 63 patients (15.9%) developed symptomatic RP after SRT. On univariate analysis, V10, V20, PTV volume and PTV/Lung were significantly associated with occurrence of RP  ≥Grade 2. ROC curves indicated that symptomatic RP could be predicted using PTV/Lung [area under curve (AUC): 0.88, confidence interval (CI: 0.78-0.95), cut-off value: 1.09, sensitivity: 90.0% and specificity: 72.4%]., Conclusion: PTV/Lung is a good predictor of symptomatic RP after SRT. Advances in knowledge: The cases with high PTV/Lung should be carefully monitored with caution for the occurrence of RP after SRT.

Objectives: The eighth tumor-node-metastasis (TNM) classification system for lung cancer has been used since January 2017 and must be applied to an individual institution's database., Methods: We analyzed pathological stage data of 2756 patients who underwent resection of non-small-cell lung cancer, particularly in terms of the degree of visceral pleural invasion and involved neighboring structures., Results: Few patients had stage IIA disease (103, 4%); stratification between stages IB and IIA was insufficient (p = 0.129). When T2a tumors were divided into PL1 and PL2 subgroups based on the degree of pleural invasion, there was a significant prognostic difference between the subgroups (p < 0.001). By incorporating T2a tumors with PL2 (T2a-PL2) into the T2b category, modified stages IB, IIA (234, 8%), and IIB were well stratified (IB vs. IIA, p < 0.001; IIA vs. IIB, p = 0.011). Focusing on T3 tumors with PL3 (T3-PL3) invading neighboring structures, multivariate analysis for surveying pT3N0-2M0 tumors revealed that completeness of resection (p = 0.002), implementation of any postoperative therapies (p = 0.003), and subcategorization of whether only the pleura was infiltrated or other deeper structures were also invaded (p = 0.024) were significant and crucial predictors. N2 disease showed worse outcome than N0-1 diseases, with marginal difference (p = 0.054)., Conclusion: T2a-PL2 tumors could be categorized into a worse prognostic T2b category. For T3-PL3 tumors involving resectable neighboring organs, subcategorization of whether there is only pleura infiltration (T3a) or other deeper structure invasion (T3b) could be a practical consideration., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Non-small cell lung cancer (NSCLC) patients at cN1 have unfavorable outcomes. It has been reported that a substantial proportion of cN1 patients have occult mediastinal disease, and treatment guidelines suggest invasive preoperative mediastinal evaluation. However, the population that would most benefit from invasive staging has not been defined. The aims of this study are to identify factors predicting mediastinal metastasis and outcomes in cN1 NSCLC patients to select appropriate candidates for invasive mediastinal evaluation., Methods: We retrospectively studied 164 patients with radiologically diagnosed cN1 NSCLC. Clinicopathological factors including radiological nodal findings were reviewed. Factors predicting the pN2 status, disease-free survival (DFS), and overall survival (OS) were investigated., Results: Among 164 patients with cN1 disease, pN2 was diagnosed in 43 (26.4%). This pN2 subgroup included a higher proportion of cases with adenocarcinoma (AD) histology than the pN0/1 subgroup (60.5 vs. 38.8%, p = 0.012). Logistic regression analyses revealed AD as an independent predictor of the pN2 status, while radiological nodal findings were unrelated. Cox regression analyses identified lower preoperative serum CEA, non-AD, and pN0/1 status as favorable factors of DFS and adjuvant therapy to be associated with OS. Five-year DFS was much lower in the pN2 subgroup than the pN0/1 subgroup of AD patients (p < 0.001), while DFS was independent of pN status in non-AD patients., Conclusions: Adenocarcinoma is predictive of pN2 and poor prognosis in radiologically diagnosed cN1 NSCLC. Accurate mediastinal staging may be more beneficial for prognoses and optimal treatment planning in NSCLC patients with AD histology.

Nanomedicine allows achievement of tumor-selective drug delivery because of the enhanced permeability and retention (EPR) effect of solid tumors. We report here the first clinical application of a new agent-HPMA copolymer-conjugated pirarubicin (P-THP)-with a molecular size of about 8 nm, or 38.5 kDa. A patient had advanced prostate cancer with multiple metastases in the lung, pelvis, femur, and perhaps the sacrum. In April 2013, this 60-year-old patient started treatment with leuprorelin and estradiol, which continued until July 2014, but the patient became refractory to this treatment. So the patient underwent proton beam radiotherapy targeted to the primary prostate cancer, and P-THP was administered for numerous metastatic tumor nodules concomitantly with radiotherapy. This combination therapy had remarkable results, with complete remission of multiple metastases in the lung and bone. The prostate-specific antigen (PSA) value was decreased from about 1000 ng/mL on April 30, 2013, to about 100 ng/mL on June 24, 2013, with hormone therapy, but rose again to 964.2 ng/mL and then to 1472 ng/mL in July 2013, during leuprorelin administration. P-THP treatment administered concomitantly with proton beam irradiation was started in August 2013. The PSA value was decreased to 102 ng/mL on August 26, 2013, and then to 0.971 ng/mL on October 8, 2013, and 0.277 ng/mL on January 15, 2015. The P-THP doses ranged from 30 to 75 mg of free THP equivalent/patient every 2-3 weeks without signs of serious toxicity, such as cardiovascular side effects or a reduction in quality of life. No evidence of relapse was found more than 20 months after P-THP administration. This case demonstrates the value of hydrazone-bonded polymeric drugs in multimodal therapy.

Objectives: The pleural invasion (PL) score is a useful prognostic indicator in lung cancer. However, in many cases, the cancer may exfoliate itself into the pleural cavity and may progress to a malignant pleural effusion without invading the parietal pleura. This stage is not currently evaluated, but it is detectable by means of the pleural lavage cytology (PLC). However, PLC's contribution to TNM staging has not yet been clarified. The purpose of this investigation was to demonstrate the usefulness of PLC in the precise staging of patients with such an occult pleural dissemination., Methods: A total of 3231 patients who were included in a multi-institutional database were studied retrospectively. PLC was performed by washing the thoracic cavity with a small amount of physiological saline immediately after opening the thoracic cavity during lung cancer surgery., Results: The incidence of positive PLC findings was 4.58%. In comparison with the negative group, the survival curves were significantly worse (P < 0.001) and the incidence of recurrence with pleuritis carcinomatosa was significantly higher (P < 0.001). According to the subset analysis, the survival difference was prominent in earlier stage groups and lower PL score groups. The positive findings were confirmed to be a significantly poor prognostic indicator (P = 0.016) by multivariate analysis using the Cox proportional hazard model (Cox analysis). However, integration of the positive findings with the PL score was attempted for the convenience of TNM staging. To find the accurate PL score for positive PLC findings, the Cox analysis was re-estimated using the PL score upgraded stepwise. The most reliable model with the highest score for the likelihood ratio χ(2) statistic was obtained by scoring positive findings as PL3. So, it was considered to be the most reliable conversion., Conclusions: Examining PLC in clinical practice is useful for detecting occult pleural dissemination before the appearance of a malignant pleural effusion. Evidence of positive findings should be treated as supplemental information to the precise diagnosis of TNM staging. Scoring positive PLC findings as PL3 (=T3) was appropriate.

Epithelioid haemangioendothelioma of the lung was found in a 9-year-old female dog. The tumour occurred bilaterally in the form of multiple, discrete, small nodular lesions with a similar histological appearance. The lesions were characterized by a hypocellular sclerotic core surrounded by a more cellular peripheral zone, from which the tumour tissue extended into the adjacent alveolar spaces and bronchioles in a micropolypoid manner, filling their lumina. In addition, invasion of the pulmonary vessels was frequently observed within, around, and at a distance from the nodular neoplastic lesions. Most of the tumour cells had abundant eosinophilic cytoplasm, large, round or oval nuclei, and occasional intracytoplasmic vacuoles containing red blood cells. By means of immunolabelling, factor VIII-related antigen, a marker for endothelial cells, was detected within the cytoplasm of a small proportion (< 5%) of the tumour cells. This appears to be the first report of such a tumour in an animal other than man.

We encountered three patients with synchronous double cancers in the lung and stomach. Although the gastric cancers were resected curatively in all three patients, the lung cancers were resected palliatively because they were too advanced for curative resection. In the Japanese literature we found 25 operated cases of synchronous double cancers and 24 operated cases of metachronous double cancers in the lung and stomach. Early diagnosis and curative resection of both cancers improve the survival rate of these primary double cancers.

During the period from 1973 to 1986, 230 patients with lung cancer were operated on at our Surgical Clinic of Kagoshima University Hospital. There were fourteen patients (6.1%) with lung cancer in the right middle lobe. There were 13 male and 1 female patients. The histological types were adenocarcinoma (10), squamous cell carcinoma (4). Five-year survival rate of 14 patients was 34.9%. Statistically, it was similar to that of the patients with lung cancer in the other lobes. As concerns with the histological type of lung cancer in the right middle lobe, the case of squamous cell carcinoma revealed poorer prognosis than those of adenocarcinoma, because there were many cases of advanced cancer in the former case.

A 62 year-old woman was admitted to our clinic for the treatment of lung cancer. Right middle and lower lobectomy was performed. Histological diagnosis was well differentiated adenocarcinoma in the right lower lobe (yp-T2N1M0, stage II). Forty-seven months before the pulmonary resection (at the age of 57 year-old), she had undergone hysterectomy for squamous cell carcinoma of the uterus (carcinoma in situ). Forty-three months after the pulmonary resection (at the age of 65 year-old), two minute thyroid cancer were resected. Twenty-one resected cases of triple cancer including lung cancer have been reported in Japanese literature.