Four cancer cases with pathological germline variant RAD51D c.270_271dup.

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.

Survival outcome of upfront surgery for clinical single-station N2 non-small cell lung cancer.

BACKGROUND: Pathological N2 (pN2) non-small cell lung cancer (NSCLC) is diverse; its treatment depends on the clinical N (cN) status. We aimed to determine the efficacy of upfront surgery for cN2pN2 NSCLC. METHODS: The study included 43 cN2pN2 NSCLC patients who underwent upfront surgery at the Shizuoka Cancer Center between 2002 and 2017. Survival outcome, focusing on cN2 status, was retrospectively investigated. Mediastinal lymph nodes were pre-operatively evaluated using computed tomography and positron emission tomography. Surgical eligibility criteria included single-station cN2. N2 with N1 and skip N2 were defined as N2 with and without ipsilateral hilar lymph node metastasis, respectively. A platinum-doublet regimen was used for adjuvant chemotherapy. Survival curves were analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model. RESULTS: Clinical-skip N2 and cN2 with N1 cases included 22 and 21 patients, respectively. Twenty-three patients received adjuvant chemotherapy. The median follow-up duration was 73 months. Clinical-skip N2 had a significantly better 5-year recurrence-free survival (RFS) than cN2 with N1 (58.3 vs 28.6%, P = 0.038) and was an independent favorable RFS predictor. Recurrence within 18 months occurred in 71% of cN2 with N1 cases. Five-year overall survival and RFS rates in patients receiving adjuvant chemotherapy vs those without adjuvant chemotherapy were 82.2 vs 41.9% (P = 0.019) and 56.5 vs 28.0% (P = 0.049), respectively. CONCLUSIONS: Clinical-skip N2 had an excellent prognosis, and upfront surgery was acceptable. Conversely, upfront surgery followed by chemotherapy is not recommended for cN2 with N1 patients because of early recurrence.

The efficacy of a machine learning algorithm for assessing tumour components as a prognostic marker of surgically resected stage IA lung adenocarcinoma.

BACKGROUND: The importance of the stromal components in tumour progression has been discussed widely, but their prognostic role in small size tumours with lepidic components is not fully understood. Applying digital tissue image analysis to whole-slide imaging may enhance the accuracy and reproducibility of pathological assessment. This study aimed to evaluate the prognostic value of tumour components of lung adenocarcinoma by measuring the dimensions of the tumour consisting elements separately, using a machine learning algorithm. METHODS: Between September 2002 and December 2016, 317 patients with surgically resected, pathological stage IA adenocarcinoma with lepidic components were analysed. We assessed the whole tumour area, including the lepidic components, and measured the epithelium, collagen, elastin areas and alveolar air space. We analysed the prognostic impact of each tumour component. RESULTS: The dimensions of the epithelium and collagen areas were independent significant risk factors for recurrence-free survival (hazard ratio, 8.38; 95% confidence interval, 1.14-61.88; P = 0.037, and hazard ratio, 2.58; 95% confidence interval, 1.14-5.83; P = 0.022, respectively). According to the subgroup analysis when combining the epithelium and collagen areas as risk factors, patients with tumours consisting of both large epithelium and collagen areas showed significantly poor prognoses (P = 0.002). CONCLUSIONS: We assessed tumour components using a machine learning algorithm to stratify the post-operative prognosis of surgically resected stage IA adenocarcinomas. This method might guide the selection of patients with a high risk of recurrence.

Pulmonary Vein Stump Thrombosis and Cerebral Infarction after Left Upper Lobectomy.

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.

Osteogenic and brain metastases after non-small cell lung cancer resection.

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.

Radiotherapy for local recurrence of non-small-cell lung cancer after lobectomy and lymph node dissection-can local recurrence be radically cured by radiation?

BACKGROUND: There is no standard therapeutic approach for local recurrence of non-small cell lung cancer (NSCLC) after complete resection. We investigated the outcomes of radiotherapy (RT) for patients with local recurrence. METHODS: We reviewed 46 patients who underwent curative-intent RT for local recurrence after lobectomy or pneumonectomy accompanied with mediastinal lymph node dissection between 2002 and 2014. We analyzed overall survival (OS), progression-free survival (PFS), local control, tumour response and the re-recurrence pattern. RESULTS: Among the 46 patients, 16 received concurrent chemotherapy. The median follow-up period was 48 months. The response rate was 91%. The 5-year OS and local control rates were 47.9 and 65.3%, respectively, and the 5-year PFS rate was 22.8%. Female sex and complete response to radiation were favourable prognostic factors. Of the 33 patients with recurrence after radiation, 32 (97%) had distant metastasis. CONCLUSIONS: Although RT for local recurrence has high efficacy, distant relapse after radiation remains a major issue. Therefore, combination systemic therapy for local recurrence at any site should be further investigated. Since it is difficult to achieve a radical cure for local recurrence using RT, further study, for the administration of post-operative adjuvant therapy, is recommended.

Characterization of tumour mutation burden in patients with non-small cell lung cancer and interstitial lung disease.

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.

[Current Status of Limited Resection for Lung Cancer as Minimally Invasive Surgery].

This review article describes limited resection for lung cancer based on previous reports and a retrospective examination of the operative results at our hospital.The importance of limited resection as a surgical treatment is becoming much greater than before. In minimally invasive surgery for lung cancer, ① limited resection for pulmonary functional preservation, ② limited resection of lymph node dissection, and ③ minimally invasive thoracic approach may be considered. Radical segmentectomy was limited to the cases registered in the clinical trials [the Japan Clinical Oncology Group (JCOG) study 0802/1211]to verify the validity of limited surgery. The patients who would not tolerate lobectomy underwent passive sublobar resection. Selective lymph node dissection(SLND) is commonly performed in daily clinical practice in Japan, although there is no scientific verification proven by prospective study clinical trials. Since 2013, the indication for selective lymph node dissection in our hospital has been a clinico-surgical N0 cases with a tumor diameter of 5 cm or less, excluding the right middle lobe, left lingular segment, and S6 primary tumor. Rapid intraoperative diagnosis of lymph node metastases is indispensable. Limited resection involves less surgical invasion in terms of operative duration and blood loss volume than a standard procedure, with fewer postoperative complications. In the future, the results of randomized controlled trials (RCTs) originated in Japan is expected to determine whether segmentectomy and SLND are valid and practical enough to become standard procedures of surgical treatment for early-staged patients. In limited resection for lung cancer, it is important to evaluate lymph node, not only preoperatively but also intraoperatively making appropriate diagnoses.

[Sentinel Lymph Node Diagnosis for Lung Cancer].

Many researchers have reported that the sentinel node (SN) theory has been established for lung cancer. However, sentinel node navigation surgery (SNNS) has not yet become a routine medical procedure in lung cancer surgery. SN identification is important for efficient retrieval of micrometastases. Methods for identifying SNs include the dye method and the radioisotope (RI) method, but methods such as the indocyanine green (ICG) method, computed tomographic lymphography (CTLG), and the magnetic method are also being studied. More careful surgical adaptation is required for reduction surgery for early lung cancer, and rapid intraoperative diagnosis is frequently used. SN lymph nodes may be used as an indicator for selecting lymph nodes to be diagnosed intraoperatively. SN identification is considered an important method for ensuring that reduction surgery is curative. Furthermore, if overlooking lymph node metastases can be avoided by using intraoperative rapid diagnosis of micrometastases, we believe that the safety of reduction surgery will be enhanced. In addition, SN identification provides a theoretical basis to support the omission of lymph node dissection. Future developments of SN research and technology are expected.

[Ingenuity of Lymph Node Dissection Reduction for Minimally Invasive Lung Cancer Surgery].

Systematic lymph node dissection in radical operation for lung cancer is recognized as an operative procedure which is accurate staging. In clinical early-stage non-small cell lung cancer (NSCLC), if the nodes are negative, complete mediastinal lymph node dissection might be omitted. Selective mediastinal dissection for clinico-surgical stage I NSCLC proved to be as effective as complete dissection. When lymph node metastasis was observed, segmentectomy was converted to lobectomy. Sentinel node( SN) identification is useful to determine the final indication of minimally invasive surgery by targeting the lymph nodes needed for intraoperative frozen section diagnosis. Many evidences suggest that prognosis of NSCLC with lymph node micrometastases (LNMM) is poor compared with those without LNMM. Evaluation of micrometastases of all dissected lymph nodes may be substituted by evaluating micrometastases of SNs. SN identification is important to the efficiency of micrometastases detection of intraoperative diagnosis. To perform a minimally invasive surgery, evaluation of lymph nodes micrometastases in SN is required.

C-reactive protein inhibits expression of N-cadherin and ZEB-1 in murine colon adenocarcinoma.

Epithelial-to-mesenchymal transition (EMT) is thought to play a key role in cancer cell invasion and metastasis. We previously demonstrated that cancer cell migration is inhibited by C-reactive protein (CRP), which is widely used as a biomarker of inflammation, though its functions are not fully understood. In the present study, we evaluated the effect of CRP on cancer cell migration and expression of mesenchymal and epithelial markers of EMT and of related transcription factors. MCA-38 murine colon adenocarcinoma cells were subcutaneously inoculated into the backs of C57BL/6 mice, which also received 1 µg of recombinant mouse CRP or vehicle (phosphate-buffered saline) subcutaneously every 3 days for 4 weeks. Thereafter, the mice were sacrificed for evaluation using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. There was no statistical difference in tumor size between the control and CRP groups, but CRP dose-dependently inhibited MCA-38 cell migration. PCR analysis confirmed that CRP suppresses expression of N-cadherin (p < 0.01), a mesenchymal marker of EMT, and ZEB-1, an EMT-related transcription factor (p < 0.01). These findings suggest that CRP inhibits EMT in a MCA-38 tumor-bearing mouse model. CRP may thus be a potentially useful tool for preventing cancer progression through suppression of EMT.

[Acute Mediastinitis].

Acute mediastinitis is an infectious disease of differentiated etiology, characterized by a rapid and severe course. Causes, diagnosis, and treatment of acute mediastinitis was described. Our experience of descending necrotizing mediastinitis were demonstrated with chest X-ray, computed tomography (CT), and operative findings. Recognition, prompt diagnosis, and early treatment of the disease were emphasized.

Association between recovery from desaturation after stair climbing and postoperative complications in lung resection.

OBJECTIVE: The stair-climbing test (SCT) is used as a surrogate for cardiopulmonary exercise testing, which measures maximal oxygen uptake, and considered a useful method for assessing exercise capacity in thoracic surgery. This study aims to investigate whether the recovery time of percutaneous oxygen saturation (SpO2) after stair climbing is a predictor of postoperative complications after lobectomy. METHODS: We retrospectively identified 54 patients who performed SCT and underwent lobectomy between January 2015 and February 2023 at Shizuoka Cancer Center. The SpO2 recovery time was defined as the time required to recover from the minimum to resting value after stair climbing. The association between SpO2 recovery time and early postoperative pulmonary complications within 30 days after surgery was analyzed. RESULTS: Eleven patients (20.4%) had postoperative pulmonary complications (≥ Clavien-Dindo Classification Grade 2). The cutoff value of SpO2 recovery time obtained from the receiver operating characteristic curve analysis was 90 s [sensitivity, 81.8%; specificity, 72.1%; AUC, 0.77 (95% confidence interval, 0.64-0.90)]. The occurrence of postoperative pulmonary complications was 42.9% in the delayed recovery time (DRT; SpO2 recovery time ≥ 90 s) group and 6.1% in the non-DRT (SpO2 recovery time < 90 s) group (p = 0.002). DRT was a predictor of postoperative pulmonary complications (odds ratio, 11.60; 95% CI 2.19-61.80). CONCLUSIONS: DRT of SpO2 after stair climbing is a predictor of postoperative pulmonary complications following lobectomy in borderline patients who require exercise capacity assessment. SpO2 monitoring after stair climbing may be useful as one of the preoperative assessments in patients undergoing lobectomy.

Intraoperative rapid diagnosis of pleural lavage cytology in non-small cell lung cancer.

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.

Prediction of Pleural Lavage Cytology According to Thin-Section Computed Tomography in Non-Small-Cell Lung Cancer.

BACKGROUND: Although the positive rate of preresection pleural lavage cytology (PLC) is low, it is an important indicator of poor prognosis for non-small-cell lung cancer patients with frequent pleural dissemination (PD) recurrence. Thin-section computed tomography (TSCT) can reveal relationships between a primary tumor and the pleura at 1 to 2 mm intervals, and this is associated with visceral pleural invasion (VPI). However, its association with PLC remains unclear. Therefore, we aimed to improve PLC efficiency and predict PD recurrence by understanding the relationship between PLC and preoperative TSCT findings. PATIENTS AND METHODS: Between January 2014 and December 2018, we reviewed 978 patients with non-small-cell lung cancer who underwent PLC tests during complete resection surgery. Preoperative TSCT findings were evaluated, and factors with the highest specificity (proportion of patients with radiologically to pathologically diagnosed positive PLC) were investigated. We also evaluated their relationships with VPI and PD recurrence. RESULTS: PLC positive was identified in 55 (5.6%) of the 978 patients. The two TSCT findings predicting PLC results, "the absence of pleural findings," ie, tumor not attached to pleura or without pleural tag, and "consolidation-to-tumor ratio ≤0.5", had a specificity of 100% (95% confidence interval: 90.4%-100%); additionally, all cases with these findings were VPI negative and had no PD recurrence. And 24% of the cohort had either of these findings. CONCLUSION: The absence of pleural findings and/or consolidation-to-tumor ratio ≤0.5 of primary tumor on preoperative TSCT can predict PLC negativity with very high probability; therefore, PLC can be omitted for such patients.

Brain Metastasis of Non-small Cell Lung Cancer After Disease-Free Survival of 5 years: Case Series and Comprehensive Literature Review.

BACKGROUND: In the treatment of nonsmall cell lung cancer (NSCLC), a disease-free survival of 5 years is a criterion for cure. This study aimed to evaluate the characteristics and outcomes of patients with brain metastases of NSCLC after a disease-free survival of 5 years (late recurrent brain metastasis [LRBM]). METHODS: We reviewed 1281 consecutive patients with brain metastasis of lung cancer at a single institute between November 2014 and December 2022. Relevant articles were retrieved from PubMed. Only peer-reviewed journals published in English were included. RESULTS: Six patients (0.47%) showed LRBM. Three were male. The median age at lung cancer diagnosis was 45 years. The histological diagnosis of all patients was adenocarcinoma. Driver gene mutations were observed in five patients. The median latency period from lung cancer treatment to the development of brain metastasis was 13 years. All patients had no metastasis to any other organs and underwent craniotomies. The median follow-up duration after craniotomy was 3.5 years. No local intracranial recurrences were observed. Three patients had distant intracranial recurrences at 7, 2, and 0.6 years after craniotomy. Five patients survived for 8, 4, 3, 2, and 0.3 years after craniotomy. One patient experienced re-recurrence in the lung 4 years after craniotomy and died 3.7 years later. In our systematic review, only six studies described LRBM of NSCLC. CONCLUSIONS: LRBM is rare in patients with NSCLC. In our institution, many of these patients harbored driver gene mutations, and achieved long-term survival with aggressive local therapy. Multicenter analysis is mandatory.

Detection of pleural lymph flow using indocyanine green fluorescence imaging in non-small cell lung cancer surgery: a preliminary study.

PURPOSE: Lymphatic spread of lung carcinoma to the mediastinum is a key determinant of prognosis. The lymph flow often carries metastases from the pulmonary segment directly into the mediastinal lymph nodes, without passing through the hilar nodes. This phenomenon is termed as "skip metastasis." This study investigated the subpleural lymphatic flow to the mediastinum using indocyanine green (ICG) with a near-infrared fluorescence imaging system. METHODS: Seventeen patients with lung cancer were enrolled in this study. A 0.3 ml sample of solution containing the fluorescent dye ICG (5 mg/ml) was injected into subpleural sites near the primary tumor. Fluorescence imaging was used to monitor the flow of ICG-containing lymph from the injection site for 5 min. The relationship between the anatomical segment of the primary tumor and the lymphatic flow was assessed. RESULTS: The lymphatic vessels draining from the injection site were revealed by the bright ICG fluorescence in 14 of the patients (82.4 %). A direct lymphatic flow to the mediastinum was confirmed in 3 of those 14 (21.4 %). CONCLUSIONS: These findings confirm the direct flow of lymph to the mediastinum without passage through the hilum pulmonis intraoperatively. These preliminary results may provide a valuable clue for further investigations of the mechanisms underlying skip metastasis.

Long term outcomes beyond 5 years after pulmonary resection for non-small-cell lung cancer.

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.

Diagnostic sensitivity of solid volume measurement for pathological invasion in non-solid lung adenocarcinoma.

Background: In the current tumor-node-metastasis (TNM) classification, the clinical T descriptor is defined by solid size (SS) on a computed tomography (CT) slice and the pathological one is done by invasive size (IS) in microscopic evaluations. We sometimes experience discrepancies in diagnosis of both descriptors. A volume analyzing application enables semi-automatic measurement of three-dimensional (3D) parameters in cases where there are discrepancies in diagnosing tumors' solid size and IS. In this study, we aimed to evaluate the association between 3D parameters and pathological invasion in non-solid small-sized lung adenocarcinomas. Methods: We enrolled 246 consecutive patients who underwent pulmonary resection at Shizuoka Cancer Center. Patients with lung adenocarcinomas that were radiologically non-solid, node-negative and sized ≤3 cm were eligible. We used a volume analyzing application to retrospectively measure 3D parameters of max and mean Hounsfield units (HUs) and solid volume (SV). The cut-off value of these parameters for diagnosing invasive adenocarcinoma (IAD) was set by describing receiver operating characteristic (ROC) curves. The correlation of IAD with these parameters was compared to its correlation with the SS. This study was not registered. Results: Of 246 patients with adenocarcinoma, 183 (74.4%) had IADs. In multivariate analyses, the total size (TS) and SS were significantly associated with IAD (P=0.006, 0.001, respectively), whereas 3D parameters including SV were not (P=0.80). In radiological adenocarcinoma (2.1-3.0 cm), SV >300 mm3 diagnosed IAD with a higher sensitivity than that of the SS (0.93 and 0.83, respectively). Conclusions: TS >20 mm and SS >5 mm were well-correlated with IAD. SV measurement may complement the current computed tomographic diagnosis of IAD based on the SS (2.1-3.0 cm).

Acquired xanthine dehydrogenase expression shortens survival in patients with resected adenocarcinoma of lung.

Xanthine dehydrogenase (XDH), also known as xanthine oxidoreductase (XOR), has long been recognized as the key enzyme in the catabolism of purines, oxidizing hypoxanthine into xanthine and then xanthine into uric acid. In addition, levels of XDH expression are reportedly related to the prognosis of patients with malignant tumors, though the relationship between the clinicopathological features of lung cancer and XDH is not fully understood. We therefore used semiquantitative real-time reverse transcription polymerase chain reaction to assess expression of XDH mRNA in tumor samples from 88 patients with adenocarcinoma of the lung. We then correlated XDH mRNA levels with known clinicopathological factors. We found that the 5-year overall survival rate among patients strongly expressing XDH was significantly poorer than among those expressing lower levels of XDH (P < 0.001; log-rank test). Normal lung tissue does not express XDH. Multivariate Cox proportional hazard analyses revealed that being male (hazard ratio, 3.14; 95 % confidence interval (CI), 1.45-7.07; P = 0.004), nodal metastasis positivity (hazard ratio, 5.74; 95 % CI, 1.94-19.3; P = 0.001), and high XDH expression (hazard ratio, 2.33; 95 % CI, 1.11-5.02; P = 0.026) were all independent factors affecting 5-year disease-free survival. In conclusion, high tumoral XDH expression is an independent predictor of a poor prognosis in patients with adenocarcinoma of the lung.