Clinical predominance of whole-exome sequencing to evaluate microsatellite instability status.

The microsatellite instability (MSI)/mismatch repair (MMR) status is one of the critical genomic biomarkers for predicting patient response to immune checkpoint inhibitors (ICIs). In this study, we aimed to investigate the concordance among the MSIsensor score obtained from whole-exome sequencing (WES), which could be a futuristic clinical cancer sequencing method, using only tumor tissues, MSI-PCR results, and immunohistochemistry (IHC) results to analyze various solid cancer types. We first endeavored to set the cut-off value of MSIsensor to determine functional deficient mismatch repair (f-dMMR) status. The MSI status of 1054 patients analyzed using WES was evaluated using MSIsensor. In addition, 87 of these patients were further analyzed using MSI-PCR and MMR IHC to calculate the sensitivity and specificity of the MSIsensor cut-off score. Our results showed that score 12.5 was an adequate cut-off score equivalent to PCR-confirmed MSS/MSI-low and MSI-high statuses, with sensitivity, specificity, and area under the curve values of 95.2%, 100%, and 0.998, respectively. Moreover, we identified false-positive cases of tumors with high mutational burden with an MSIsensor score <12.5, and optional IHC examination could rescue these cases. In conclusion, the MSIsensor score obtained using WES with tumor tissue showed a high clinical validity, with a cut-off value of 12.5 for f-dMMR detection, in combination with optional IHC analysis for MMR. Our novel algorithm will provide insights into the development of ICIs for cancer treatment, particularly when WES becomes a more common cancer genomic test in the near future.

Spin-polarized spatially indirect excitons in a topological insulator.

The exciton, a bound state of an electron and a hole, is a fundamental quasiparticle induced by coherent light-matter interactions in semiconductors. When the electrons and holes are in distinct spatial locations, spatially indirect excitons are formed with a much longer lifetime and a higher condensation temperature. One of the ultimate frontiers in this field is to create long-lived excitonic topological quasiparticles by driving exciton states with topological properties, to simultaneously leverage both topological effects and correlation1,2. Here we reveal the existence of a transient excitonic topological surface state (TSS) in a topological insulator, Bi2Te3. By using time-, spin- and angle-resolved photoemission spectroscopy, we directly follow the formation of a long-lived exciton state as revealed by an intensity buildup below the bulk-TSS mixing point and an anomalous band renormalization of the continuously connected TSS in the momentum space. Such a state inherits the spin-polarization of the TSS and is spatially indirect along the z axis, as it couples photoinduced surface electrons and bulk holes in the same momentum range, which ultimately leads to an excitonic state of the TSS. These results establish Bi2Te3 as a possible candidate for the excitonic condensation of TSSs3 and, in general, opens up a new paradigm for exploring the momentum space emergence of other spatially indirect excitons, such as moiré and quantum well excitons4-6, and for the study of non-equilibrium many-body topological physics.

Evaluation of antero-posterior instability of the hip using modified Lequesne's false profile view.

BACKGROUND: Accurate evaluation of hip instability is critical for the diagnosis and successful treatment of developmental dysplasia of the hip (DDH). However, dynamic evaluation of hip instability is not well established. This study aimed to use the lateral view from a radiograph to evaluate dynamic antero-posterior hip instability in patients with DDH. METHODS: Seventy-four patients (92 hips) with DDH (DDH group) and 46 patients (59 hips) without hip pain and DDH (Control group) were examined. A false profile view (FPV) according to Lequesne was taken at standard and 90° flexion with the hip of interest defined as functional FPV; the translation of the center of the femoral head (CFH) obtained from the functional FPV was measured. As a validation test, we measured the anterior translation of the CFH using ultrasonography (US). RESULTS: There was a significant difference between the two groups in the translation of the CFH (p < 0.01). The degree of CFH translation depended on the severity of DDH (lateral center edge angle, r = -0.56, p < 0.01; vertical center anterior margin angle, r = -0.57, p<0.01) and lateralization of the femoral head (head lateralization index, r = 0.54, p < 0.01). There was a significant correlation between functional FPV and US measurements (r = 0.71, p < 0.01). CONCLUSION: The present study confirmed that antero-posterior hip instability in DDH patients can be detected using functional FPV. Our novel measurement, as a new method for assessing hip instability, may be useful for evaluating hip dynamic instability in diagnosing the etiology, and determining and evaluating the treatment for DDH at lower cost and improved accessibility.

Observation of a Flat and Extended Surface State in a Topological Semimetal.

A flat band structure in momentum space is considered key for the realization of novel phenomena. A topological flat band, also known as a drumhead state, is an ideal platform to drive new exotic topological quantum phases. Using angle-resolved photoemission spectroscopy experiments, we reveal the emergence of a highly localized surface state in a topological semimetal BaAl4 and provide its full energy and momentum space topology. We find that the observed surface state is localized in momentum, inside a square-shaped bulk Dirac nodal loop, and in energy, leading to a flat band and a peak in the density of state. These results imply this class of materials as an experimental realization of drumhead surface states and provide an important reference for future studies of the fundamental physics of correlated quantum effects in topological materials.

Targeted amplicon sequencing for primary tumors and matched lymph node metastases in patients with extrahepatic cholangiocarcinoma.

BACKGROUND: Lymph node metastasis (LNM) is one of the most adverse prognostic factors in extrahepatic cholangiocarcinoma (EHCC) cases. As next-generation sequencing technology has become more widely available, the genomic profile of biliary tract carcinoma has been clarified. However, whether LNMs have additional genomic alterations in patients with EHCC has not been investigated. Here, we aimed to compare the genomic alterations between primary tumors and matched LNMs in patients with EHCC. METHODS: Sixteen patients with node-positive EHCCs were included. Genomic DNA was extracted from tissue samples of primary tumors and matched LNMs. Targeted amplicon sequencing of 160 cancer-related genes was performed. RESULTS: Among the 32 tumor samples from 16 patients, 91 genomic mutations were identified. Genomic mutations were noted in 31 genes, including TP53, MAP3K1, SMAD4, APC, and ARID1A. TP53 mutations were most frequently observed (12/32; 37.5%). Genomic mutation profiles were highly concordant between primary tumors and matched LNMs (13/16; 81.3%), and an additional genomic mutation of CDK12 was observed in only one patient. CONCLUSION: Genomic mutations were highly concordant between primary tumors and matched LNMs, suggesting that genotyping of archived primary tumor samples may help predict genomic mutations of metastatic tumors in patients with EHCC.

Genomic profiling of intestinal/mixed-type superficial non-ampullary duodenal epithelial tumors.

BACKGROUND AND AIM: The mechanism underlying carcinogenesis and the genomic features of superficial non-ampullary duodenal epithelial tumors (SNADETs) have not been elucidated in detail. In this study, we examined the genomic features of incipient SNADETs, such as small lesions resected via endoscopic treatment, using next-generation sequencing (NGS). METHODS: Twenty consecutive patients who underwent endoscopic treatment for SNADETs of less than 20 mm between January and December 2017 were enrolled. Targeted genomic sequencing was performed through NGS using a panel of 160 cancer-related genes. Furthermore, the alteration/mutation frequencies in SNADETs were examined. RESULTS: The maximum size of the SNADETs examined in this study was 12 mm in diameter. Five SNADETs were classified as low-grade dysplasia (LGD) tumors, while 14 SNADETs were classified as high-grade dysplasia tumors. Only one carcinoma in situ was detected. NGS data for 16 samples were obtained. APC alterations were detected in 81% of samples (13/16). KRAS, BRAF, and TP53 alterations were detected in 25% (4/16), 18.8% (3/16), and 6.3% (1/16) of cases, respectively. CONCLUSION: We detected APC alterations in most small SNADETs resected via endoscopic treatment, from LGD to carcinoma samples. Even in SNADETs classified as small LGD exhibited KRAS and BRAF alterations.

Lateral wall fixation with bone pegs for advanced osteochondritis dissecans of the humeral capitellum.

BACKGROUND AND HYPOTHESIS: It is generally considered that fragment fixation with bone pegs (FFBP) for osteochondritis dissecans (OCD) of the humeral capitellum can be indicated for stages I and II according to the International Cartilage Repair Society (ICRS) classification of OCD and it is difficult to obtain complete bone union for advanced lesions. However, the clinical and radiologic results of FFBP with cancellous bone graft for ICRS-OCD stage III with lateral wall involvement have not been described in detail. Good bone union can be achieved with the lateral wall fragment of the capitellum by FFBP in combination with refreshing the sclerotic surface at the base of the lesion and cancellous bone grafting even in ICRS-OCD stage III lesions. METHODS: In total, 10 adolescent baseball players with a diagnosis of OCD, a median age of 13.5 years at the time of surgery, and 26.7 months of postoperative follow-up were included. Preoperative imaging showed that all patients had lesions in the late detached stage and of the lateral-widespread type based on the site of the focal lesion. The intraoperative ICRS-OCD classification was stage III. We aimed to preserve and fix the lateral wall fragment with cancellous bone grafting if the condition of the articular cartilage was good and the size and thickness of the segment could withstand fixation. RESULTS: Bone union of the lateral wall fragment was achieved in all cases. The elbow extension range of motion was -3.9° ± 9.7° before surgery and was eventually -0.4° ± 6.7° at the final assessment. Flexion range of motion ranged from 138.1° ± 10.5° to 142.4° ± 6.2°. The Timmerman and Andrews score significantly improved from 165.5 ± 10.9 points before surgery to 197.0 ± 6.3 points after surgery, demonstrating excellent results in all patients. All patients were able to return to competitive baseball. CONCLUSION: The radiographic and clinical outcomes of FFBP for lateral wall fragments with cancellous bone graft were satisfactory, showing that the indications for this procedure could be extended to ICRS-OCD stage III.

CDX2 Expression and Prognostic Factors of Resectable Pulmonary Large Cell Neuroendocrine Carcinoma.

BACKGROUND AND AIM: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare neoplasm, and its clinical features and management are still limited. We evaluated the clinicopathological factors, including CDX2 immunohistochemical expression, to predict survival in patients with LCNEC. PATIENTS AND METHODS: In all, 50 patients with LCNEC who underwent surgery at 4 institutes between 2001 and 2017 were included. Clinicopathological characteristics were evaluated for prognostic factors and statistically analyzed by Kaplan-Meier curve with a log-rank test or Cox regression models. We used immunohistochemical (IHC) analysis to determine the expressions of CDX2 and compared them with clinicopathological factors and survival. RESULTS: Sixteen of the 50 cases (32%) were CDX2 positive. No correlation was found between the CDX2 expression by IHC and clinicopathological factors. Multivariate analysis identified adjuvant chemotherapy (hazard ratio [HR] =2.86, 95% confidence interval [CI] = 1.04-8.16, P = .04) and vascular invasion (HR = 4.35, 95% CI = 1.21-15.63, P = .03) as being associated with a significantly worse rate of recurrence-free survival. CONCLUSION: CDX2 was expressed in 1/3 of LCNEC but not associated with prognostic factor. Adjuvant chemotherapy and vascular invasion were associated with a negative prognostic factor of LCNEC.

Clinical impact of a cancer genomic profiling test using an in-house comprehensive targeted sequencing system.

Precision medicine is a promising strategy for cancer treatment. In this study, we developed an in-house clinical sequencing system to perform a comprehensive cancer genomic profiling test as a clinical examination and analyzed the utility of this system. Genomic DNA was extracted from tumor tissues and peripheral blood cells collected from 161 patients with different stages and types of cancer. A comprehensive targeted amplicon exome sequencing for 160 cancer-related genes was performed using next-generation sequencing (NGS). The sequencing data were analyzed using an original bioinformatics pipeline, and multiple cancer-specific gene alterations were identified. The success rate of our test was 99% (160/161), while re-biopsy was required for 24% (39/161) of the cases. Potentially actionable and actionable gene alterations were detected in 91% (145/160) and 46% (73/160) of the patients, respectively. The actionable gene alterations were frequently detected in PIK3CA (9%), ERBB2 (8%), and EGFR (4%). High tumor mutation burden (TMB) (≥10 mut/Mb) was observed in 12% (19/160) of the patients. The secondary findings in germline variants considered to be associated with hereditary tumors were detected in 9% (15/160) of the patients. Seventeen patients (11%, 17/160) were treated with genotype-matched therapeutic agents, and the response rate was 47% (8/17). The median turnaround time for physicians was 20 days, and the median survival time after the initial visit was 8.7 months. The results of the present study prove the feasibility of implementing in-house clinical sequencing as a promising laboratory examination technique for precision cancer medicine.

Controlling a Van Hove singularity and Fermi surface topology at a complex oxide heterostructure interface.

The emergence of saddle-point Van Hove singularities (VHSs) in the density of states, accompanied by a change in Fermi surface topology, Lifshitz transition, constitutes an ideal ground for the emergence of different electronic phenomena, such as superconductivity, pseudo-gap, magnetism, and density waves. However, in most materials the Fermi level, [Formula: see text], is too far from the VHS where the change of electronic topology takes place, making it difficult to reach with standard chemical doping or gating techniques. Here, we demonstrate that this scenario can be realized at the interface between a Mott insulator and a band insulator as a result of quantum confinement and correlation enhancement, and easily tuned by fine control of layer thickness and orbital occupancy. These results provide a tunable pathway for Fermi surface topology and VHS engineering of electronic phases.

Genomic testing for pancreatic cancer in clinical practice as real-world evidence.

BACKGROUND: Precision medicine guided by comprehensive genome sequencing represents a potential treatment strategy for pancreatic cancer. However, clinical sequencing for pancreatic cancer entails several practical difficulties. We have launched an in-house clinical sequencing system and started genomic testing for patients with cancer in clinical practice. We have analyzed the clinical utility of this system in pancreatic cancer. METHODS: We retrospectively reviewed 20 patients with pancreatic cancer who visited our division. Genomic DNA was extracted from both tumor tissue and peripheral blood mononuclear cells obtained from the patients. We performed a comprehensive genomic testing using targeted amplicon sequencing for 160 cancer-related genes. The primary endpoints were the detection rates of potential actionable and druggable gene alterations. The secondary endpoints were the detection rate of secondary germline findings, the rate of re-biopsy required for genome sequencing, survival time after the initial visit (post-sequencing survival time), and turnaround time. RESULTS: Although re-biopsy was required for 25% (5/20) of all patients, genomic testing was performed in all patients. Actionable and druggable gene alterations were detected in 100% (20/20) and 35% (7/20) of patients, respectively, whereas secondary germline findings were detected in 5% (1/20) of patients. The median turnaround times for physicians and patients were 20 and 26 days, respectively. The median post-sequencing survival time was 10.3 months. Only 10% (2/20) of all patients were treated with therapeutic agents based on the outcomes of genomic testing. CONCLUSIONS: The clinical application of comprehensive genomic testing for pancreatic cancer was feasible and promising in clinical practice.

Assessment of pleural air leakage using digital chest drainage system after surgical pulmonary resection: Comparison of visible alveolar air leakage with the digital value measured by a digital chest drainage system.

BACKGROUND: The sensitivity of postoperative pleural air leakage (PAL) after pulmonary resection is evaluated by a simple subjective grading method in clinical practice. A new electronic digital chest drainage evaluation system (DCS) recently became clinically available. This study was designed to evaluate the clinical application of the DCS in monitoring the airflow volume and managing postoperative PAL. METHODS: We prospectively enrolled 25 patients who underwent pulmonary resection. Postoperative PAL was evaluated using both conventional PAL grading based on the physician's visual judgment (analog chest drainage evaluation system [ACS]: Level 0 = no leakage to 4 = continuous leakage) and the DCS. The DCS digital measurement was recorded as the flow volume (ml/min), which was taken once daily from postoperative day 1 to the day of chest drainage tube removal. RESULTS: In total, 45 measurements were performed on 25 patients during the evaluation period. Postoperative PAL was observed in five patients (20.0%) and judged as ACS Level >1. The mean DCS values corresponding to ACS Levels 0, 1, 2, and 3 were 2.42 (0.0-11.3), 48.6 (35.4-67.9), 95.6 (79.7-111.5), and 405.3 (150.3-715.6), respectively. The Spearman correlation test showed a significant positive correlation between the ACS PAL level and DCS flow volume (R = 0.8477, p < 0.001). CONCLUSIONS: A relationship between the visual PAL level by the ACS and the digital value by the DCS was identified in this study. The numeric volume obtained by the DCS has been successful in information-sharing with all staff. The digital PAL value evaluated by the DCS is appropriate, and the use of the DCS is promising in the treatment of postoperative PAL after pulmonary resection.

Prognostic Significance of BMI-1 But Not MEL-18 Expression in Pulmonary Squamous Cell Carcinoma.

AIM: We investigated the possibility of BMI-1 and MEL-18 to predict survival in patients with pulmonary squamous cell carcinoma. MATERIALS AND METHODS: One hundred and ninety-nine patients underwent surgery in our Institute between 1995 and 2005. We used immunohistochemical (IHC) analysis to determine the expressions of BMI-1 and MEL-18 and compared them with clinicopathological factors and survival. RESULTS: Forty-one of 199 cases (21%) were BMI-1-positive. No correlation was found between BMI-1 and MEL-18 expression by IHC and clinicopathological factors. Five-year overall survival in the BMI-1-positive group (66.8%), but not MEL-18, was significantly better than that in the negative group (45.5%, p=0.04). In multivariate analysis, positive BMI-1 was a better prognostic factor of overall survival (hazard ratio (HR)=0.561, 95% confidence interval (CI)=0.271-1.16, p=0.12). CONCLUSION: BMI-1 expression, but not MEL-18, is associated with a favorable prognosis and is a possible prognostic factor of pulmonary squamous cell carcinoma.

Stage IV pleomorphic carcinoma of the lung without recurrence for 6 years: a case report.

BACKGROUND: Pleomorphic carcinoma is a rare primary lung carcinoma that occurs at a rate of about 0.3%. Even with complete resection, the tumor usually recurs aggressively, resulting in a poor prognosis. Herein, we report a case of advanced pleomorphic carcinoma of the lung who had a long survival time after resection of the primary and metastatic sites. CASE PRESENTATION: A 48-year-old man was admitted to our hospital due to abdominal pain. Systemic examination revealed a lung mass on the right and a tumor in the jejunum. Surgical resection of both tumors revealed pleomorphic carcinoma of the lung with metastasis to the jejunum. Follow-up after 6 years showed that the patient remained recurrence-free, without the need for additional postoperative treatment. CONCLUSIONS: A vigorous treatment strategy that included surgery had the potential to offer long-term survival, despite an advanced pleomorphic carcinoma with distant metastasis to other organs. Reports on more similar cases are needed to evaluate the value of this treatment option.

The Impact of Pleural Lavage Cytology Both Before and After Lung Resection on Recurrence of Non-Small Cell Lung Cancer.

BACKGROUND: Pleural lavage cytology (PLC) involves cytologic examination during surgery for non-small cell lung cancer (NSCLC). The timing regarding the performance of PLC is potentially important; however, a consensus remains to be established. We sought to retrospectively analyze the impact of PLC both before (pre-PLC) and after (post-PLC) lung resection on recurrence in NSCLC. METHODS: From July 1994 to December 2011, 700 consecutive patients with surgically resected NSCLC were selected. Both pre-PLC and post-PLC status was tested using univariate and multivariate Cox regression analyses of recurrence-free survival (RFS). RESULTS: By analyzing RFS, post-PLC status but not pre-PLC status together with pathologic N factor and pathologic stage, was identified as an independent factor for poor prognosis (p = 0.0040). A statistically significant association was observed between positive post-PLC status and pleural invasion, pathologic T factor, pathologic N factor, pathologic stage, and postoperative recurrence (p = 0.0004, p = 0.0033, p = 0.0001, p < 0.0001, and p < 0.0001, respectively). The RFS was similarly worse for patients with positive post-PLC status regardless of pre-PLC status. Conversely, the RFS was similarly better for patients with negative post-PLC status regardless of pre-PLC status. CONCLUSIONS: Positive post-PLC status was found to be a predictive factor for postoperative recurrence in patients with surgically resected NSCLC. Moreover, post-PLC status might be an additional factor not only for identifying a patient group with a high risk of postoperative recurrence, but also to avoid unnecessary treatment of patients with low risk of postoperative recurrence.

Predictive Impact for Postoperative Recurrence of Preoperative Serum Krebs von den Lungen-6 Concentration in Pathologic Stage IA Non-Small Cell Lung Cancer.

BACKGROUND: Although stage IA non-small cell lung cancer has an optimistic survival rate, up to 10% of these patients relapse after surgical procedures and die. We retrospectively analyzed clinicopathologic features of patients with stage IA non-small cell lung cancer to identify recurrence predictors and to investigate effects of preoperative serum Krebs von den Lungen-6 (PS-KL-6) concentrations. METHODS: We selected 204 consecutive patients with stage IA non-small cell lung cancer treated from December 2003 to December 2009 for this study and tested their PS-KL-6 concentrations in univariate and multivariate Cox regression analyses of recurrence-free survival (RFS). RESULTS: High PS-KL-6 concentration (PS-KL6(High)) was significantly associated with sex (p = 0.0006), smoking status (p = 0.0438), histology (p = 0.0049), and postoperative recurrence (p = 0.0058). Both intratumoral blood vessel invasion (p = 0.0345) and PS-KL6(High) (p = 0.0021) were identified as independent predictors of shorter RFS. Relative risk of patients with PS-KL6(High) was 3.478 compared with patients with low PS-KL-6 concentration (PS-KL6(Low); 95% confidence interval: 1.576 to 8.013). Among patients with tumors larger than 2 cm (T1b), the PS-KL6(High) group had significantly shorter RFS than the PS-KL6(Low) group (p = 0.0040). CONCLUSIONS: PS-KL-6 concentration is a simple and novel predictor of recurrence in patients with stage IA non-small cell lung cancer and might help to identify patients who will need more careful follow-up among T1bN0M0 series.

The Prognostic Impact of Tumor Volume in Patients with Clinical Stage IA Non-Small Cell Lung Cancer.

INTRODUCTION: Tumor volume promises to be an important factor for predicting the prognosis of patients with non-small cell lung cancer (NSCLC). METHODS: A total of 255 patients who underwent curative surgical resection for clinical stage IA NSCLC were included. We performed semiautomated measurement of the whole tumor volume and the volume of the solid part (referred to as the solid part volume) from a volumetric analysis of chest three-dimensional computed tomography scans using the SYNAPSE VINCENT imaging software program (Fujifilm Medical, Tokyo, Japan). We evaluated the relationships among tumor size, tumor volume, and survival. RESULTS: The mean whole tumor size, the ratio of the maximum diameter of consolidation to the maximum tumor diameter (CTR), the whole tumor volume, and the solid part volume were 20 mm (range 0-30 mm), 0.84 (range 0-1.0), 3080 mm(3) (range 123-17509 mm(3)), and 2032 mm(3) (0-12466 mm(3)), respectively. The receiver operating characteristic area under the curve for the whole tumor size, CTR, whole tumor volume, and solid part volume used to identify recurrence were 0.60, 0.68, 0.58, and 0.69, respectively. A univariate analysis revealed that the whole tumor size, CTR, whole tumor volume, and solid part volume were associated with disease-free survival (DFS). A multivariate analysis of these factors identified the solid part volume to be the only independent factor for the prediction of DFS. CONCLUSIONS: The whole tumor volume and the solid part volume were associated with DFS. In particular, the solid part volume was a very useful factor for predicting prognosis in clinical stage IA NSCLC.

Clinicopathological Features and Outcome of Lung Cancer Patients with Hematological Malignancy.

PURPOSE: The aim of this study was to report the incidence of lung cancer in patients with hematological malignancy (HM), as well as patient characteristics and outcome. METHODS: We investigated 1503 consecutive patients treated for HM and 1208 patients who underwent surgical resection for lung cancer. RESULTS: Lung cancer with HM was observed in 12 patients (0.8 % of HM cases and 1.0 % of lung cancer cases), including eight men who were smokers and four women who had never smoked. The average Brinkman index was 1010, which suggested heavy smokers. In synchronous cases, all four patients preceded to HM treatment; however, three patients died from HM. In metachronous cases, during a mean 52.7 months after treatment of lung cancer, three patients had HM. At a mean 41.4 months after HM treatment, five patients had lung cancer and underwent surgery without serious postoperative events. CONCLUSIONS: A second cancer tended to be detected within 5 years after treatment of the first cancer. Men with a history of heavy smoking might be at risk for combined lung cancer and HM. Careful follow-up is recommended within 5 years after treatment of the first cancer. Most lung cancer detected synchronously with HM had poor prognosis. In metachronous cases, surgical resection of lung cancer after treatment of HM was feasible and safe.