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Background: Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a high-grade malignant neoplasm with a poor prognosis. Most cases of SMARCA4-UT have extensive chest wall and mediastinum involvement. The efficacy of surgical resection has not been clearly established. Here, we report two surgical cases of SMARCA4-UT with chest wall invasion after chemoradiotherapy. Case presentation: The first patient was a 40-year-old man with back pain. Computed tomography revealed a 6.8 cm mass in contact with the thoracic vertebrae near the intervertebral foramen, which was suspected to involve the third to fifth ribs. The patient was diagnosed with SMARCA4-UT with clinical T3N0M0 stage IIB. The tumor shrank after chemoradiotherapy, and conversion surgery combined with partial vertebrectomy was performed. Histopathological findings revealed 30% residual tumor in the tumor bed. Thirty-six days after surgery, the patient developed multiple liver metastases and peritoneal dissemination. Chemotherapy combined with immune checkpoint inhibitor treatment was performed, resulting in tumor shrinkage. However, peritoneal dissemination recurred within a short interval. The patient died 5 months postoperatively. The second patient was a 74-year-old man with chest pain. Computed tomography revealed a 7.4-cm mass in the left upper lobe with invasion of the third and fourth ribs. The patient was initially diagnosed with non-small cell lung cancer with clinical T4N1M0 stage IIIA. The tumor shrank after induction chemoradiotherapy, and a left upper lobectomy combined with the chest wall resection was performed. Based on histopathological findings, the patient was diagnosed with SMARCA4-UT. The residual tumor percentage was 3%. The patient was followed up for 12 months postoperatively without recurrence. Conclusions: We performed the complete resection of SMARCA4-UT following chemoradiotherapy. The two surgical cases had different postoperative courses. Radical surgery after chemoradiotherapy is effective for local control. However, its long-term prognostic efficacy remains unclear. Multidisciplinary approaches and further investigations of novel therapeutic options are required. [ABSTRACT FROM AUTHOR]

Pathological germline variants (PGVs) of RAD51D increase the risk of breast and ovarian cancer. In East Asia, c.270_271dup is the most frequently detected PGV of RAD51D; however, only a few cases have been reported in Japan. We report four cancer cases with a germline RAD51D c.270_271dup PGV. Three of them (lung cancer: 2, oral cancer: 1) were incidentally identified by whole genome sequencing in patients negative for the associated cancer histories, homologous recombination (HR) deficiency, or a second hit of RAD51D in the cancer DNA. For genetic counseling, we provided information on surveillance and cascade testing based on Western guidelines. The PGVs of moderate‐risk HR‐related genes are difficult to detect based on phenotype, especially in male‐predominant pedigrees. The current spread of cancer genomic analysis will increase opportunities for incidental variant identification. The establishment of Japanese guidelines is expected to aid in the management of PGV carriers of moderate‐risk genes. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the incidence of late recurrence beyond 5 years after pulmonary resection and aimed to identify candidates for long-term surveillance. Methods: We retrospectively reviewed the medical records of 978 non-small-cell lung cancer patients who underwent pulmonary resection between 2002 and 2015 and survived without recurrence for 5 years. Clinicopathological factors associated with recurrence-free survival beyond 5 years after surgery were investigated using univariate and multivariate analyses. The development of late metachronous malignancies was also investigated. Results: The median follow-up period from 5 years post-surgery was 27 months in the whole cohort. Late recurrence occurred in 37 (3.8%) patients. Late metachronous malignancies were diagnosed in 116 patients (11.9%), including 57 (5.8%) with lung cancer. One-, three-, and five-year recurrence-free survival rates beyond 5 years after surgery were 97.6%, 94.7%, and 94.7%, respectively. The recurrence-free survival of patients with pN1-2 was significantly poorer than that of patients with pN0 disease. Multivariate analysis revealed that adenocarcinoma and pN1-2 status were significantly associated with poor recurrence-free survival beyond 5 years post-surgery (P = 0.009 and 0.007, respectively). Conclusions: Non-adenocarcinoma histology and pN0 status were significant favorable factors for recurrence-free survival beyond 5 years post-surgery. The efficacies of long-term surveillance for the detection of late recurrence were considered limited for these populations. Twelve percent of the patients experienced late metachronous malignancies after pulmonary resection. [ABSTRACT FROM AUTHOR]

Objective: Positive pleural lavage cytology (PLC +) is a poor prognostic factor for non-small cell lung cancer (NSCLC). However, data on the impact of intraoperative rapid diagnosis of PLC (rPLC) are lacking. Therefore, we evaluated the efficacy of rPLC before resection during surgery. Methods: A total of 1,838 patients who underwent rPLC for NSCLC between September 2002 and December 2014 were studied retrospectively. We assessed the clinicopathological factors between rPLC findings and the impact on survival of patients with curative resection. Results: The rPLC + status was observed in 96 (5.3%) among 1,838 patients. The rPLC + group had more unsuspected N2 (30%) than the rPLC− group (p < 0.001). The 5-year overall survival (OS) of patients who underwent lobectomy or more extensive resection with rPLC + , negative rPLC (rPLC−), and microscopic pleural dissemination (PD) and/or malignant pleural effusion (PE) were 67.3, 81.3, and 11.0%, respectively. In the rPLC + group, the prognosis of patients with pN2 was equal to that of pN0–1 (5-year OS: 77.9% vs. 63.4%, p = 0.263). Undetectable dissemination in the first evaluation immediately after starting surgery was found in 9% of rPLC + patients by additional evaluation of the thoracic cavity. Conclusions: Patients with rPLC + have more favorable survival than those with microscopic PD/PE after surgery. Curative resection should be performed in patients with rPLC + , even if N2 is detected during surgery. However, the rPLC + group often has N2 upstaging; therefore, systematic nodal dissection should be performed in rPLC + patients for exact staging. rPLC may contribute to preventing oversight PD by re-evaluation during surgery. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES This study aimed to identify the risk factors for pulmonary functional deterioration after wedge resection for early-stage lung cancer with ground-glass opacity, which remain unclear, particularly in low-risk patients. METHODS We analysed 237 patients who underwent wedge resection for peripheral early-stage lung cancer in JCOG0804/WJOG4507L, a phase III, single-arm confirmatory trial. The changes in forced expiratory volume in 1 s were calculated pre- and postoperatively, and a cutoff value of −10%, the previously reported reduction rate after lobectomy, was used to divide the patients into 2 groups: the severely reduced group (≤−10%) and normal group (>−10%). These groups were compared to identify predictors for severe reduction. RESULTS Thirty-seven (16%) patients experienced severe reduction. Lesions with a total tumour size ≥1 cm were significantly more frequent in the severely reduced group than in the normal group (89.2% vs 71.5%; P  =   0.024). A total tumour size of ≥1 cm [odds ratio (OR), 3.287; 95% confidence interval (CI), 1.114–9.699: P  =   0.031] and pleural indentation (OR, 2.474; 95% CI, 1.039–5.890: P  =   0.041) were significant predictive factors in the univariable analysis. In the multivariable analysis, pleural indentation (OR, 2.667; 95% CI, 1.082–6.574; P  =   0.033) was an independent predictive factor, whereas smoking status and total tumour size were marginally significant. CONCLUSIONS Of the low-risk patients who underwent pulmonary wedge resection for early-stage lung cancer, 16% experienced severe reduction in pulmonary function. Pleural indentation may be a risk factor for severely reduced pulmonary function in pulmonary wedge resection. [ABSTRACT FROM AUTHOR]

Background Pulmonary vein stump thrombosis may occur after left upper lobectomy (LUL) and is a potential risk factor for cerebral infarction. However, there are few reports on the role of pulmonary vein stump thrombosis in the development of cerebral infarction. We aimed to clarify the correlation between pulmonary vein stump thrombosis and cerebral infarction following LUL. Methods We evaluated 296 patients who underwent contrast-enhanced computed tomography (CT) after LUL for lung cancer at the Shizuoka Cancer Center Hospital in Shizuoka, Japan, between September 2002 and December 2015. The cerebral infarction in patients with pulmonary vein stump thrombosis was examined, and the risk factors for cerebral infarction were identified via a univariate analysis of the clinicopathological and surgical variables. Results Overall, 179 men and 117 women (median age: 68 years; range: 36–88 years) were included. The median observation period was 68 months. Pulmonary vein stump thrombosis occurred in 21 (7%) patients and cerebral infarction occurred in 15 (5%) patients. None of the 21 patients with pulmonary vein stump thrombosis developed cerebral infarction. Most cerebral infarctions (12/15) were diagnosed in the late phase (> 3 months). The pathological stage of cancer was found to be the only significant risk factor for cerebral infarction by the univariate analysis. Conclusion Pulmonary vein stump thrombosis following LUL was not necessarily associated with cerebral infarction, including the late phase. A prospective observational study with contrast-enhanced chest CT would be required to investigate the risk factors for cerebral infarction in each phase of the postoperative period. [ABSTRACT FROM AUTHOR]

PURPOSE: Several studies reported the possibility of predicting genetic abnormalities in non–small-cell lung cancer by deep learning (DL). However, there are no data of predicting ALK gene rearrangement (ALKr) using DL. We evaluated the ALKr predictability using the DL platform. MATERIALS AND METHODS: We selected 66 ALKr -positive cases and 142 ALKr -negative cases, which were diagnosed by ALKr immunohistochemical staining in our institution from January 2009 to March 2019. We generated virtual slide of 300 slides (150 ALKr -positive slides and 150 ALKr -negative slides) using NanoZoomer. HALO-AI was used to analyze the whole-slide imaging data, and the DenseNet network was used to build the learning model. Of the 300 slides, we randomly assigned 172 slides to the training cohort and 128 slides to the test cohort to ensure no duplication of cases. In four resolutions (16.0/4.0/1.0/0.25 μm/pix), ALKr prediction models were built in the training cohort and ALKr prediction performance was evaluated in the test cohort. We evaluated the diagnostic probability of ALKr by receiver operating characteristic analysis in each ALKr probability threshold (50%, 60%, 70%, 80%, 90%, and 95%). We expected the area under the curve to be 0.64-0.85 in the model of a previous study. Furthermore, in the test cohort data, an expert pathologist also evaluated the presence of ALKr by hematoxylin and eosin staining on whole-slide imaging. RESULTS: The maximum area under the curve was 0.73 (50% threshold: 95% CI, 0.65 to 0.82) in the resolution of 1.0 μm/pix. In this resolution, with an ALKr probability of 50% threshold, the sensitivity and specificity were 73% and 73%, respectively. The expert pathologist's sensitivity and specificity in the same test cohort were 13% and 94%. CONCLUSION: The ALKr prediction by DL was feasible. Further study should be addressed to improve accuracy of ALKr prediction. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Although pulmonary emphysema is a component of chronic obstructive pulmonary disease, the prognostic significance of the quantitative severity of emphysema in patients with primary lung cancer is unclear. This study aimed to identify the association between the quantitative severity of emphysema detected by the low-attenuation area on computed tomography and the prognostic outcome of early non-small-cell lung cancer. METHODS A consecutive series of 1062 patients who underwent lobectomy for clinical stage I and II non-small-cell lung cancer were enrolled in this study. The clinicopathological features and long-term outcomes of patients with primary lung cancer in emphysema were investigated. The extent of emphysema in the lobe where the tumour was present was measured by preoperative computed tomography as a percentage of the low-attenuation area (LAA%). RESULTS LAA% ≥ 1.0% was detected in 145 (13.7%) patients. LAA% was associated with pleural invasion (P  < 0.0001), vascular invasion (P  < 0.0001) and a larger tumour size (P  = 0.001). The overall survival and recurrence-free survival in patients with LAA% ≥ 1.0% and with LAA% < 1.0% at 5 years were 78.6% and 92.1% (P  < 0.0001) and 68.7% and 85.2% (P  < 0.0001), respectively. According to the Cox proportional hazards model, LAA% was an independent prognostic factor for overall survival and recurrence-free survival (P  = 0.0004 and P  = 0.003, respectively). CONCLUSIONS The quantitative severity of pulmonary emphysema was found to be associated with poor prognosis and clinicopathological aggression in early non-small-cell lung cancer. [ABSTRACT FROM AUTHOR]

Objective: Lobe-specific nodal dissection (LND) is increasingly used for non-small cell lung cancer (NSCLC) in Japan; however, its treatment validity remains unclarified. Since 2013, LND has been used as a standard procedure for clinical stage-I (c-stage-I) NSCLC at our institution. We aimed to evaluate its validity using intraoperative frozen section analysis (FSA) for c-stage-I NSCLC. Methods: The participants comprised patients with NSCLC who underwent LND between 2013 and 2016 (n = 307) or systematic nodal dissection (SND) between 2002 and 2013 (n = 367) for c-stage-I disease. FSA was routinely performed in LND to examine at least three stations. Outcomes were compared between the LND and SND groups. Patients in whom LND was converted to SND due to metastasis on FSA of the sampled lymph node were still categorized into the LND group, i.e., intention-to-treat analysis. The prognostic impact was compared using propensity score matching. Results: The rate of conversion from LND to SND was 10.4%. Of the patients converted to SND, 12.5% had metastases outside the LND area. False-negative N2 results were detected in only 0.7% of the LND group patients after FSA. After matching, each group had 220 patients. There were no significant between-group differences in the lymph-node recurrence rate (7% vs. 6%), 5-year recurrence-free survival (80.1% vs. 79.0%), and overall survival (90.4% vs. 90.3%). Conclusions: LND with intraoperative FSA is a valid modality that could serve as a standard surgical procedure for c-stage-I NSCLC. Intraoperative FSA may lower the residual lymph-node metastasis risk in LND. [ABSTRACT FROM AUTHOR]

PURPOSE: Several studies reported the possibility of predicting genetic abnormalities in non–small-cell lung cancer by deep learning (DL). However, there are no data of predicting ALK gene rearrangement (ALKr) using DL. We evaluated the ALKr predictability using the DL platform. MATERIALS AND METHODS: We selected 66 ALKr -positive cases and 142 ALKr -negative cases, which were diagnosed by ALKr immunohistochemical staining in our institution from January 2009 to March 2019. We generated virtual slide of 300 slides (150 ALKr -positive slides and 150 ALKr -negative slides) using NanoZoomer. HALO-AI was used to analyze the whole-slide imaging data, and the DenseNet network was used to build the learning model. Of the 300 slides, we randomly assigned 172 slides to the training cohort and 128 slides to the test cohort to ensure no duplication of cases. In four resolutions (16.0/4.0/1.0/0.25 μm/pix), ALKr prediction models were built in the training cohort and ALKr prediction performance was evaluated in the test cohort. We evaluated the diagnostic probability of ALKr by receiver operating characteristic analysis in each ALKr probability threshold (50%, 60%, 70%, 80%, 90%, and 95%). We expected the area under the curve to be 0.64-0.85 in the model of a previous study. Furthermore, in the test cohort data, an expert pathologist also evaluated the presence of ALKr by hematoxylin and eosin staining on whole-slide imaging. RESULTS: The maximum area under the curve was 0.73 (50% threshold: 95% CI, 0.65 to 0.82) in the resolution of 1.0 μm/pix. In this resolution, with an ALKr probability of 50% threshold, the sensitivity and specificity were 73% and 73%, respectively. The expert pathologist's sensitivity and specificity in the same test cohort were 13% and 94%. CONCLUSION: The ALKr prediction by DL was feasible. Further study should be addressed to improve accuracy of ALKr prediction. [ABSTRACT FROM AUTHOR]

Background: Medial patellar luxation (MPL) is a common orthopedic condition in dogs. After surgical correction, the recurrent rates appear to be higher and outcomes worse in grade IV than in lower grade MPL. Aim: To describe the outcomes of surgical correction of canine grade IV MPL. Methods: This retrospective study analyzed the medical records of 16 dogs (11 females, 5 males; mean age = 5.05 years) with 22 stifle joints (8 left and 14 right) that underwent MPL surgery at Rakuno Gakuen University between May 2015 and October 2020. The procedures included capsulorrhaphy, trochlear block recession, tibial tuberosity transposition, medial retinacular release, and lateral fabellotibial suturing. The types of postsurgical complications, including a recurrence of MPL, were recorded. Results: Twelve of the 16 (75 %) dogs had concurrent contralateral MPL, and 2 dogs (12.5%) had concurrent cranial cruciate ligament rupture. The mean follow-up was 12.1 months. No lameness was observed. The outcomes of surgery for grade IV MPL were not associated with bilateral surgery, age, sex, body weight, or the preoperative quadriceps angle. Although none of the dogs showed any major or catastrophic complications following surgery, postoperative minor and major complications were observed in 8 of the 22 stifle joints (36.4%). Conclusion: Grade IV MPL is a complex orthopedic disease in dogs, which requires surgical patellar realignment to improve limb function. The surgical techniques used in this study were associated with a good prognosis without a surgical revision. [ABSTRACT FROM AUTHOR]

Objectives: The lung is a major target organ of metastasis in several cancers. To distinguish primary lung cancer from pulmonary metastases is a clinical challenge. Small pulmonary nodules (PNs) are frequently diagnosed by frozen section diagnosis (FSD) intraoperatively after resection. Intraoperative FSD is very important to determine the extent of subsequent surgical procedures. This study aimed to know the validity of surgical decision based on FSD for preoperatively unconfirmed PN with previous malignancy. Methods: We retrospectively evaluated 96 patients with suspected malignant PN who underwent intraoperative FSD between 2018 and 2020. Intraoperative FSD, final diagnosis, and surgical procedure data were examined. Results: Surgical procedure adequacy, based on FSD for preoperatively unconfirmed PN with previous malignancy, was 91% (88/96). The overall diagnostic accuracy of FSD was 83.3% (80/96). Discrepancy was noted in two cases (2.1%), and conclusive diagnosis could not be reached intraoperatively in 14 cases (14.6%). A second surgery was required in three patients and no additional excision for primary lung cancer was performed in three patients. Conversely, there were three cases of over-surgery, namely, lobectomy for pulmonary metastasis. Conclusions: Surgical decision-making based on FSD for preoperatively unconfirmed PN in patients with previous malignancy was generally adequate. However, there were inadequate or excessive surgical procedures due to limitations in the accuracy of intraoperative FSD. Improving the accuracy of intraoperative FSD is a necessary step for obtaining adequate surgical decision-making and precision medicine. [ABSTRACT FROM AUTHOR]

Background: Pulmonary resection with mediastinal lymph node dissection for treating primary lung cancer could sometimes causes chylothorax as a postoperative complication. This study examined the validity of treatments for chylothorax in our hospital.Methods: We evaluated 2019 patients who underwent lobectomy, bilobectomy, or pneumonectomy with mediastinal lymph node dissection for primary lung cancer at Shizuoka Cancer Center Hospital, Shizuoka, Japan, between September 2002 and March 2018. The diagnostic criteria for postoperative chylothorax were that the drainage from the pleural drain was evidently white and turbid, or the pleural effusion contained a triglyceride level of > 110 mg/dL. The clinical courses and treatments were retrospectively reviewed.Results: Postoperative chylothorax occurred in 37 patients (1.8%), 20 men and 17 women, with a median age of 70 years (33-80). A low-fat diet was instituted to all patients; 35 cases improved with conservative treatment, and 2 cases required reoperation. Nine cases had a drainage volume ≥ 500 mL one day following the low-fat diet commencement, which was resolved with conservative treatment and decreased drainage was observed on the third day of treatment in seven of those cases. Two cases with excessive drainage of ≥ 1000 mL in one day and systemic symptoms associated with chyle loss needed surgery.Conclusions: Even when the daily drainage volume exceeds 500 mL following a low-fat diet, there were many cases that could be cured conservatively. The indication for surgery needs to be carefully considered. [ABSTRACT FROM AUTHOR]

Background: A significant number of non-small cell lung cancer (NSCLC) patients develop osteogenic metastases (OMs) and/or brain metastases (BMs) after surgery, however, routine chest computed tomography (CT) sometimes fails to diagnose these recurrences. We investigated the incidence of BMs and OMs after pulmonary resection and aimed to identify candidates who can benefit from brain magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in addition to CT. Methods: We retrospectively reviewed medical records of 1099 NSCLC patients who underwent pulmonary resection between 2002 and 2013. Clinicopathological factors associated with OM and/or BM were investigated using univariate and multivariate analyses. Results: Postoperative recurrence occurred in 344 patients (32.6%). OMs were diagnosed in 56 patients (5.6%) with 93% within 3 years. BMs were identified in 72 patients (6.6%) with 91.1% within 3 years. Multivariate analysis revealed that poorly differentiated tumor and the presence of pathological nodal metastases were significantly associated with postoperative BM (p = 0.037, < 0.001), preoperative serum carcinoembryonic antigen (CEA) level of 5 ng/mL or higher and the presence of pathological nodal metastases were significantly associated with OM (p = 0.034, < 0.001). The prevalence of OM and/or BM in 5 years was as high as 25.9% in patients with pathological nodal metastases. Conclusions: We identified significant predictive factors of postoperative BM and OM. Under patient selection, the effectiveness of intensive surveillance for the modes of recurrence should be investigated with respect to earlier detection, maintenance of quality of life, and survival outcomes. [ABSTRACT FROM AUTHOR]

Two women in their sixties were diagnosed with inoperable locally advanced epithelioid malignant pleural mesothelioma, c-stage IIIB. Post-chemotherapy, the tumors down-staged to yc-stage IA, and pleurectomy/decortication were performed. The pathological diagnoses were p-stages II and IA. One patient had tumor recurrence 6 months after surgery; she is currently undergoing fourth-line chemotherapy and is alive 30 months postoperatively. The second patient had tumor recurrence 4 months after surgery and died 2 months later. Conversion surgery for advanced malignant mesothelioma does not improve progression-free survival but might have a chance to extend overall survival in selected patients without deteriorating performance status. [ABSTRACT FROM AUTHOR]

Objective: The current nodal staging for lung cancer is defined only by the anatomical site of metastasis. However, the International Association for the Study of Lung Cancer (IASLC) proposed further subdivisions of the N descriptor that considers the locations and numbers of involved lymph node stations. This study aimed to test the new IASLC categories and compare their prognostic abilities to those of our proposed model that considers only the number of involved lymph node stations instead of the sites of metastasis. Methods: Between September 2002 and December 2016, 1581 patients who underwent complete resection for pathologically diagnosed Tis-4N0-2M0 non-small cell lung cancer were retrospectively analyzed. We evaluated the survival rates according to the patients' N classification as recently proposed by the IASLC and by the number of involved lymph node stations, and determined the optimal N classification. Results: The 5-year survival rates for patients with IASLC stages N1a, N1b, N2a1, N2a2, and N2b were 71.5%, 49.9%, 73.7%, 62.1%, and 46.9%, respectively. These results showed relatively good categorizations; however, some prognostic overlaps existed and not all differences were significant. After redefining the number of involved stations as Nα for 1, Nβ for 2–3, and Nγ for ≥ 4 without considering the metastasis sites, the 5-year survival rates for patients in these categories were 72.1%, 58.3%, and 29.6%, respectively; the differences between them were significant. Conclusion: The number of involved lymph node stations is a more accurate prognostic indicator in patients with completely resected non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Background and objective: The efficacy expectation of immune checkpoint inhibitors against NSCLC in patients with ILD seems to be high because these populations are supposed to have high TMB. However, information about the characterization of TMB in patients with NSCLC and ILD is limited. Therefore, this study aimed to evaluate TMB in samples of NSCLC with ILD and clarify factors that influence TMB values. Methods: The medical records of patients with NSCLC who underwent thoracic surgery at our institution between January 2014 and January 2017 were retrospectively reviewed. Whole‐exome sequencing with an Ion Proton system and gene expression profiling of fresh surgical specimens were performed. Results: Among 367 patients with NSCLC, 62 (16.9%) were diagnosed with ILD. All samples were collected from primary tumours with a median TMB of approximately 2.1 (range: 0.1–64.4) mutation/Mb. Among 81 squamous cell carcinomas, we compared 27 tumours with concomitant ILD and 54 tumours without ILD. Univariate analyses revealed that tumours with concomitant ILD showed lower TMB values than those without ILD. Multivariate analysis revealed that concomitant ILD was significantly associated with low TMB values. Conversely, no difference was noted in the TMB value of adenocarcinoma between patients with and without ILD. Conclusion: Squamous cell carcinoma and adenocarcinoma with ILD do not have high TMB values. Therefore, considering the risk of severe pneumonitis, immune checkpoint inhibitors should not be used routinely against patients with NSCLC and ILD based on the expectation of high TMB values. Patients with NSCLC and ILD did not have high TMB and could develop severe pneumonitis if immune checkpoint inhibitors are used. Therefore, immune checkpoint inhibitors should not be used based on expectations of high TMB in patients with NSCLC and ILD. See relatedEditorial [ABSTRACT FROM AUTHOR]

Background: It is unclear whether clinical factors and immune microenvironment (IME) factors are associated with tumor mutation burden (TMB) in patients with nonsmall cell lung cancer (NSCLC). Materials and methods: We assessed TMB in surgical tumor specimens by performing whole exome sequencing. IME profiles, including PD‐L1 tumor proportion score (TPS), stromal CD8 tumor‐infiltrating lymphocyte (TIL) density, and stromal Foxp3 TIL density, were quantified by digital pathology using a machine learning algorithm. To detect factors associated with TMB, clinical data, and IME factors were assessed by means of a multiple regression model. Results: We analyzed tumors from 200 of the 246 surgically resected NSCLC patients between September 2014 and September 2015. Patient background: median age (range) 70 years (39‐87); male 37.5%; smoker 27.5%; pathological stage (p‐stage) I/II/III, 63.5/22.5/14.0%; histological type Ad/Sq, 77.0/23.0%; primary tumor location upper/lower, 58.5/41.5%; median PET SUV 7.5 (0.86‐29.8); median serum CEA (sCEA) level 3.4 ng/mL (0.5‐144.3); median serum CYFRA 21‐1 (sCYFRA) level 1.2 ng/mL (1.0‐38.0); median TMB 2.19/ Mb (0.12‐64.38); median PD‐L1 TPS 15.1% (0.09‐77.4); median stromal CD8 TIL density 582.1/mm2 (120.0‐4967.6);, and median stromal Foxp3 TIL density 183.7/mm2 (6.3‐544.0). The multiple regression analysis identified three factors associated with higher TMB: smoking status: smoker, increase PET SUV, and sCEA level: >5 ng/mL (P <.001, P <.001, and P =.006, respectively). Conclusions: The IME factors assessed were not associated with TMB, but our findings showed that, in addition to smoking, PET SUV and sCEA levels may be independent predictors of TMB. TMB and IME factors are independent factors in resected NSCLC. [ABSTRACT FROM AUTHOR]

Recent advances in radiographic imaging and thoracic surgery have facilitated surgery for small lung tumors by eliminating the need for pathological diagnosis. To date, we have experienced two cases of small lung tumors that were surgically resected without pathological diagnosis as malignant. Computed tomography (CT) revealed sub-solid nodules in the peripheral lung. After tumor resection, both tumors were pathologically diagnosed as peribronchiolar metaplasia. To the best of our knowledge, solitary peribronchiolar metaplasia showing a sub-solid nodule on CT imaging has not previously been reported. [ABSTRACT FROM AUTHOR]

Objectives: In lung cancer resection, chronic obstructive pulmonary disease is a risk factor for post-operative complications. Few studies on post-operative complications of lung cancer resection have considered radiographic emphysematous change as an index. Here, we have examined the relationship between the regional ratio of the emphysematous area in pre-operative computed tomography images and cardiopulmonary complications in patients with chronic obstructive pulmonary disease who underwent lung cancer resection. Methods: We retrospectively evaluated 159 patients with chronic obstructive pulmonary disease who underwent lobectomy for lung cancer at Shizuoka Cancer Center Hospital, Shizuoka, Japan, between 2002 and 2011. Pre-operative factors, including the proportion of the emphysematous area measured by computed tomography as a percentage of the low attenuation area (LAA%), as well as intraoperative factors were analyzed. Cardiopulmonary complications, including pyothorax, pneumonia and atelectasis, acute pulmonary injury, indwelling chest tube, long duration of oxygen supply, and arrhythmia, were evaluated. Results: Cardiopulmonary complications were observed among 61 patients (38%). Univariate analysis revealed that patient age, percentage of forced expiratory volume in 1 s, LAA%, and volume of blood loss were significantly associated with cardiopulmonary complications. Multivariate analysis indicated patient age and LAA% as being significant independent predictors of cardiopulmonary complications. Conclusions: The regional ratio of the emphysematous area is useful for predicting cardiopulmonary complications in patients with chronic obstructive pulmonary disease who undergo lobectomy for lung cancer. In such patients who are also ≥ 70 years of age and exhibit LAA% ≥ 1.0%, careful intra- and post-operative management is warranted. [ABSTRACT FROM AUTHOR]

Objectives: The indication of limited resection for radiographically pure-solid, small-sized lung adenocarcinoma is controversial. This study aimed to reveal the long-term outcome of standard surgical treatment and determine the predictive factors for pathological lymph node metastasis in optimal candidates undergoing limited surgical resection for pure-solid, small-sized lung adenocarcinoma. Methods: The medical records of 107 consecutive patients were retrospectively reviewed at our hospital between December 2002 and December 2013. Inclusion criteria were histopathological diagnosis of lung adenocarcinoma, radiographically pure-solid tumor, ≤ 2 cm tumor size measured using thin-section computed tomography, clinical N0M0, patients who underwent lobectomy with systematic or lobe-specific lymph node dissection, and R0 resection. Overall and disease-free survival curves were calculated using the Kaplan–Meier method. Clinicopathological factors predicting pathological node-positive metastasis were identified by univariate and multivariate analysis. Results: The 5-year overall and disease-free survival rates were 91.4% and 87.3%, respectively. Multivariate analysis demonstrated maximum standardized uptake value > 5 as the independent predictor of pathological node-positive metastasis (odds ratio 3.81; 95% confidence interval 1.25–12.3; p = 0.02). In all patients, the pathological node-positive rate was 16.7%; in patients who had a maximum standardized uptake value of ≤ 5, the rate was 7.9%. Conclusion: The long-term outcome of standard surgical treatment was favorable. Maximum standardized uptake value was a significant predictor of pathological node-positive metastasis; however, diagnostic accuracy was not favorable. Therefore, the selection of optimal candidates is difficult, and limited surgical resection may not be applicable in pure-solid, small-sized lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Despite the poor prognosis of recurrent esophageal squamous cell cancer (ESCC), long-term survival could be achieved in a subset of patients who successfully underwent surgical resection for recurrence. In this study, we investigated the outcomes of surgical resection for lymph node (LN) or pulmonary (PUL) recurrence in ESCC patients. Methods: We retrospectively analyzed the outcomes of ESCC patients who underwent surgical resection between January 2008 and March 2015 for either LN or PUL recurrence after complete response (CR) by chemoradiotherapy or R0 esophagectomy. Every patient fulfilled the original institutional criteria: no recurrence at primary site; recurrence involving in only one organ; expectation of complete resection; and for PUL recurrence, no rapid growth with at least 2 months of observation. Results: Among the 13 patients analyzed, surgical resection was performed in nine and four patients with LN and PUL recurrence, respectively. R0 resection was achieved in all patients with no fatal surgical complications. Mean duration from the day of the first CR/R0 to the recurrence was 809 (110–2575) days. Median recurrence-free survival following surgical resection for recurrence and overall survival following the first diagnosis of recurrence was 387 and 1297 days, respectively. Conclusion: Surgical resection for LN or PUL recurrence of ESCC according to our institutional criteria can be performed safely for selected patients. [ABSTRACT FROM AUTHOR]

Isolated cleft of the anterior mitral leaflet (ICAML) in dogs without a septal defect is a rare pathological condition. Until now, only one paper has contributed to the detailed understanding of canine ICAML. Reports have confirmed that 3-dimensional echocardiography (3-DE) is a simple and fast imaging technique that is useful for the diagnosis of ICAML and morphological evaluation of the mitral valve in humans. However, to our knowledge, no studies have provided details about the effectiveness of 3-DE in ICAML diagnosis in dogs. Thus, we aimed to determine the usefulness of a diagnostic technique using 3-DE in a 2-year-old Cavalier King Charles Spaniel with ICAML that exhibited mild mitral valve regurgitation. ICAML was initially assessed by transthoracic two-dimensional echocardiography. A diagnosis of congenital mitral regurgitation due to ICAML and understanding of the morphological structure of the valve was established based on the 3-DE findings. [ABSTRACT FROM AUTHOR]

Purpose: Despite the efficacy of postoperative adjuvant cisplatin (CDDP)-based chemotherapy for patients who have undergone surgical resection of non-small cell lung cancer (NSCLC), few reports have presented survival data for Asian patients treated with adjuvant chemotherapy involving a combination of CDDP and vinorelbine (VNR). This study was performed to evaluate the survival of patients with NSCLC who received postoperative adjuvant chemotherapy comprising CDDP + VNR.Methods: We retrospectively evaluated patients with NSCLC who received adjuvant chemotherapy comprising CDDP + VNR at the Shizuoka Cancer Center between February 2006 and October 2011.Results: One hundred patients who underwent surgical resection of NSCLC were included in this study. The patients' characteristics were as follows: median age 63 years (range 36-74 years), female 34%, never-smokers 20%, and non-squamous NSCLC 73%. Pathological stages IIA, IIB, and IIIA were observed in 31, 22, and 47% of patients, respectively. The 5- and 2-year overall survival rates were 73 and 93%, respectively. The 5- and 2-year relapse-free survival rates were 53 and 62%, respectively. Univariate analysis of prognostic factors showed that patient characteristics (sex, histology, and pathological stage) and CDDP dose intensity were not significantly associated with survival. In 48 patients who developed NSCLC recurrence, the 5-year survival rate after recurrence was 29%, and the median survival time after recurrence was 37 months.Conclusions: Our results suggest that the prognosis after surgical resection of NSCLC and adjuvant chemotherapy comprising CDDP + VNR might be improving compared with previous survival data of adjuvant chemotherapy for NSCLC. [ABSTRACT FROM AUTHOR]

Background: Thoracic epidural analgesia (EDA) is the gold standard for pain control after thoracotomy. However, because of its severe side effects, it is contraindicated in patients taking anticoagulant or antiplatelet drugs. In addition, some patients' anatomy can make epidural catheter insertion challenging. We therefore investigated the safety and efficacy of paravertebral block (PVB) using a thoracoscopic insertion technique, which avoids damage to the parietal pleura, for postoperative pain after thoracotomy.Methods: Patients who underwent thoracotomy with thoracic PVB in our hospital between March 2013 and March 2014 were examined retrospectively. Prior to creating the thoracotomy incision, a catheter for PVB was inserted percutaneously into the paravertebral space under thoracoscopic guidance. A matched-pair control group was selected at a 1:2 ratio from patients who underwent thoracotomy with thoracic EDA in our hospital from April 2011 to February 2013. Pain control and side effects were compared between groups and the results statistically analyzed.Results: Thoracic PVB was performed in 56 patients during this period, and 112 patients were selected as matched controls. Numeric Rating Scale scores on postoperative day 2 did not differ significantly between the PVB group (3.25 ± 1.80) and the EDA group (3.56 ± 2.05) (p = 0.334). In terms of side effects, urinary retention occurred less frequently in thoracic PVB patients (p = 0.03).Conclusion: Under the conditions of the present study, continuous thoracic PVB was at least as effective as epidural analgesia for postoperative pain control after thoracotomy with lung resection. [ABSTRACT FROM AUTHOR]

Purpose: The role of surgery for patients with non-small cell lung cancer (NSCLC) with clinical mediastinal lymph node metastasis (N2) remains controversial. We specified 4 criteria for performing initial surgery in these patients (single-station N2, non-bulky N2, N2 with regional mode of spread, and N2 without N1) and examined the outcomes to validate the treatment options. Methods: Between September 2002 and December 2010, of 1290 patients who underwent complete resection for NSCLC, 808 patients underwent initial standard resection, including 779 patients with cN0-1 and 29 with cN2. We compared the outcomes, and evaluated patients with cN2-pN2. Results: The median follow-up was 45.5 months (3-119 months). Seventy (9.0 %) and 24 (82.8 %) patients had p-N2 in the cN0-1 and cN2 groups, respectively ( p < 0.0001). The 5-year disease-free survival (DFS) rates in the cN0-1 and cN2 groups were 73.3 and 50.6 %, respectively ( p = 0.0053), and the 5-year overall survival (OS) rates were 81.3 and 71.1 %, respectively ( p = 0.051). The 5-year DFS and OS of patients with cN2-pN2 were 52.5 and 72.6 %, respectively. Conclusions: Patients with clinical N2 disease based on our criteria represent a highly specific group with a favorable prognosis. Resection should therefore be the initial treatment for these patients. [ABSTRACT FROM AUTHOR]

Inherited factor VII (FVII) deficiency is a rare recessive inherited coagulation disorder with limited available information, especially in patients undergoing major thoracic surgery. In addition, an optimal management strategy for the disease has not been defined. We herein report a case involving a 61-year-old man with asymptomatic FVII deficiency who underwent a right middle and lower lobectomy to treat lung cancer. To the best of our knowledge, the present report is the first to describe the use of recombinant activated FVII continuous infusion for bleeding control after a major thoracic surgery in a patient with inherited FVII deficiency. [ABSTRACT FROM AUTHOR]

We herein present a case of synchronous multiple thymoma that was suspected based on the findings of positron emission tomography with fluorine-18-labeled-fluorodeoxyglucose (F-FDG PET). The patient was a 70-year-old male with two similarly sized and heterogeneously enhanced masses on the right side of the anterior mediastinum on chest computed tomography. F-FDG PET revealed variation in FDG accumulation between the masses, in which the maximum standardized uptake value was 4.4 in Tumor 1 and 8.7 in Tumor 2. Based on these imaging findings, the masses were suspected to be independent, likely synchronous double primary thymoma. Total thymectomy with removal of the two tumors was performed via median sternotomy. A pathological examination identified Tumor 1 as type AB thymoma and Tumor 2 as type A thymoma. This is the first reported case of synchronous multiple thymoma which was suspected based on a variation in the F-FDG PET findings between the tumors. [ABSTRACT FROM AUTHOR]

BACKGROUND Integration of mutational profiling to identify driver genetic alterations in a clinical setting is necessary to facilitate personalized lung cancer medicine. A tumor genotyping panel was developed and the Shizuoka Lung Cancer Mutation Study was initiated as a prospective tumor genotyping study. This study reports the frequency of driver genetic alterations in Japanese lung adenocarcinoma patients, and clinicopathologic correlations with each genotype. METHODS Between July 2011 and January 2013, 411 lung adenocarcinoma patients admitted to the Shizuoka Cancer Center were included in this study with their written informed consent. Surgically resected tissues, tumor biopsies, and/or body cavity fluids were collected and tested for 23 hotspot sites of driver mutations in 9 genes ( EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2), gene amplifications in 5 genes ( EGFR, MET, PIK3CA, FGFR1, and FGFR2), and ALK, ROS1, and RET fusions. RESULTS Genetic alterations were detected in 54.3% (223 of 411) of all patients. The most common genetic alterations detected in this study were EGFR mutations (35.0%) followed by KRAS mutations (8.5%) and ALK fusions (5.0%). Concurrent genetic alterations were detected in 22 patients (5.4%), and EGFR mutations were observed in 16 patients as the most common partner for concurrent genetic alteration. Significantly more concurrent genetic alterations were observed in older patients. CONCLUSIONS This is one of the largest reports of a prospective tumor genotyping study on Japanese patients with adenocarcinoma. These data suggest that mutational profiling data using a multimutational testing platform would be valuable for expanding the range of molecular-targeted therapeutics in lung cancer. Cancer 2014;120:1471-1481. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: Interstitial lung disease (ILD) has been associated with primary lung cancer and an increased risk of postoperative acute exacerbation (AE). The effectiveness of 2-[18]-fluoro-2-deoxy- d-glucose (F-FDG) positron emission tomography (PET) for staging lung cancer is well established. This study investigates the association of FDG uptake on PET in patients with AE of ILD. Methods: The subjects of this retrospective study were 1309 patients with lung cancer, who underwent pulmonary resection at Shizuoka Cancer Center between September, 2002 and January, 2011. ILD was diagnosed with chest computed tomography in 95 patients, 81 of whom underwent F-FDG PET before surgery. Six patients suffered from AE after surgery (AE group), while the remaining 75 (non-AE group) did not. We investigated the clinico-pathological findings and the results of FDG uptake on PET using the value of the I/ M ratio, which is the ratio of the peak of standardized uptake value (SUV) of the ILD area to the mean SUV of the mediastinum. Results: There was no significant difference in clinico-pathological findings, but a significance difference in the I/ M ratio ( P = 0.0102). Conclusion: The FDG uptake in PET may be a predictive factor for AE of ILD in patients who have undergone lung cancer surgery. [ABSTRACT FROM AUTHOR]

A 57-year-old Japanese man presented with massive right pleural effusion, and a huge tumor arising in the pleural cavity was detected by chest computed tomography. A thoracoscopic tumor biopsy revealed that the tumor protruded extensively into the pleural cavity, and its gross appearance was cystic and glossy. Microscopically, the tumor cells were rounded and epithelioid in shape. Prominent and abundant myxoid stroma was also present together with an inflammatory infiltrate, and the tumor was anaplastic lymphoma kinase ( ALK)-immunopositive. Fluorescence in situ hybridization revealed that the Ran- binding protein 2- ALK fusion gene was present. Taken together, these findings supported the diagnosis of epithelioid inflammatory myofibroblastic sarcoma (EIMS), which is a variant of an inflammatory myofibrobrastic tumor. This is the first reported case of an EIMS arising in the pleural cavity. [ABSTRACT FROM AUTHOR]

Background: Until date, there are no clear recommendations for regular perioperative measurements of serum CEA levels for lung cancer in any guidelines. The purpose in the present study is to evaluate the prognostic significance of perioperative serum carcinoembryonic antigen (CEA) levels in patients with pathological-stage I non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed 263 completely resected pathological-stage I NSCLC patients whose preoperative and postoperative serum CEA levels were measured. Patients were subdivided according to the perioperative change of CEA levels: continuously normal CEA levels (NN group), continuously high CEA levels (HH group), and high preoperative CEA levels that returned to normal levels post-operation (HN group). The clinicopathological factors and overall survival (OS) among these 3 groups were compared. Univariate and multivariate analyses of the correlation between clinicopathological factors and OS were performed. Results: High preoperative CEA levels significantly correlated with men aged >70 years with smoking history, high serum CYFRA 21-1 levels, greater tumor diameter, presence of visceral pleural invasion (VPI), and moderate-to-poor differentiation. Five-year OS rates in the NN and HH groups were 95.5% and 59.3%, respectively. Four-year OS rate in the HN group was 85.5%. Multivariate analyses indicated tumor diameter of more than 30 mm, presence of VPI, and the HH group were independent unfavorable prognostic factors. Conclusions: A high postoperative CEA level was an independent unfavorable prognostic factor in pathological-stage I NSCLC patients. Patients with high postoperative CEA levels may benefit from adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Interstitial lung disease (ILD) is associated with primary lung cancer and an increased risk of postoperative acute exacerbation (AE). Although the preoperative factors associated with AE of ILD are well described, there is little information about the postoperative factors. Thus, the present study focuses on the postoperative management of chest-tube drainage associated with AE of ILD. Methods: We conducted a retrospective chart study of 1,309 patients with lung cancer, who underwent pulmonary resection at Shizuoka Cancer Center between September 2002 and January 2011. ILD was diagnosed by chest computed tomography (CT) findings in 95 patients. After the exclusion of 6 patients with a history of pneumonectomy, the subjects of this study were 8 patients who suffered AE after surgery (AE group) and 81 patients (non-AE group) who did not. We investigated the clinicopathological findings and postoperative management of chest-tube drainage in the two groups. Results: The clinicopathological findings of the two groups did not differ significantly. The chest tubes could not be removed before postoperative day 5 because of pleural effusion in 5 patients (62.5 %) from the AE group and 12 patients (14.8 %) from the non-AE group ( P = 0.0040). Conclusions: The postoperative volume draining from the chest-tube is an important sign of AE of ILD. [ABSTRACT FROM AUTHOR]

Since the World Health Organization histological criteria were published in 1999, several studies have focused on adenosquamous carcinoma of the lung. Therefore, we aimed to clinicopathologically re-evaluate this tumor using immunohistochemical methods. In our hospital, there have been 21 surgically resected adenosquamous carcinomas. The frequency of adenosquamous carcinoma was 1.9% and the clinical data including the patient prognosis data obtained in this study were similar to those reported previously. A fluorodeoxyglucose positron emission tomography study first revealed that the median maximum standardized uptake value of adenosquamous carcinoma was 9.3 and ranged from 2.0 to 24.5. According to the results of immunohistochemical staining for thyroid transcription factor-1 (TTF-1) and p63, adenosquamous carcinomas were divided into four subgroups: group 1, TTF-1+ and p63+ (10 cases); group 2, TTF-1- and p63+ (six cases); group 3, TTF-1+ and p63- (three cases); and group 4, TTF-1- and p63- (two cases). Of the six group 2 tumors, three were composed of unique solid nests with mucin-filled cysts and showed characteristic p63 expression, which might suggest a special type of adenosquamous carcinoma. Immunohistochemical analysis of TTF-1 and p63 expression shows that adenosquamous carcinoma is composed of diverse tumor groups, for which the biological and histogenetic nature further needs to be clarified. [ABSTRACT FROM AUTHOR]

Calcifying tumor of the pleura is a rare benign tumor, similar to the calcifying fibrous pseudotumor originally described in the subcutaneous and deep soft tissues of the extremities, trunk, and neck. Calcifying tumors of the pleura have also been reported infrequently as disseminated lesions. Here we report a case of disseminated calcifying tumor of the pleura, with some new findings obtained in this study, and review the literature of disseminated calcifying tumor of the pleura. [ABSTRACT FROM AUTHOR]

A 60-year-old Japanese man was found to have diffuse pneumonia-like shadow in the left S10 segment on chest computed tomographic scan. Transbronchial lung biopsy yielded a pathological diagnosis of poorly differentiated adenocarcinoma; subsequently, left lower lobectomy was performed. Histopathological analysis showed that the tumor consisted solely of discohesive cells with involvement of the hilar and mediastinal lymph nodes. The immunohistochemical expression of E-cadherin and β-catenin was low, whereas that of p53 was high in the tumor cells. Here, we describe a rare lung adenocarcinoma with discohesive cells, which are considered to indicate high tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase ( EML4-ALK) and kinesin family member 5B ( KIF5B) -ALK are newly identified transforming fusion oncogenes causing non-small-cell lung cancers. These molecular abnormalities have become detectable using not only molecular biological methods, but also highly sensitive immunohistochemistry. During the immunohistochemical study of ALK expression in adenocarcinoma of the lung, we unexpectedly discovered that a small bronchioloalveolar carcinoma (BAC) showed strong ALK immunoreactivity. However, FISH studies failed to reveal EML4-ALK and KIF5B-ALK fusion genes in this BAC. These findings suggest the possibility that a novel or unknown ALK fusion gene plays a crucial role in BAC development. ( Cancer Sci 2012; 103: 390-392) [ABSTRACT FROM AUTHOR]

We performed surgical treatment for abnormal echoes in the left ventricular outflow tract caused by ruptured mitral chordae tendineae. An asymptomatic 68-year-old man had a chordal rupture exhibiting a tumor-like lesion in the left ventricular outflow tract on echocardiography. Considering a high level of mobility of the tumor as well as its texture, the risk of embolization was found to be significant. Therefore, it was decided on the surgical resection of the tumor-like lesion under extracorporeal circulation. We report a highly rare case of rupture in redundant mitral chordae tendineae without mitral regurgitation, revealed by uncommon echoes in the left ventricular outflow tract during systole. [ABSTRACT FROM AUTHOR]