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.

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.

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.

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.

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.

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.

A novel quasi-one-dimensional topological insulator in bismuth iodide ß-Bi4I4.

Recent progress in the field of topological states of matter has largely been initiated by the discovery of bismuth and antimony chalcogenide bulk topological insulators (TIs; refs ,,,), followed by closely related ternary compounds and predictions of several weak TIs (refs ,,). However, both the conceptual richness of Z2 classification of TIs as well as their structural and compositional diversity are far from being fully exploited. Here, a new Z2 topological insulator is theoretically predicted and experimentally confirmed in the ß-phase of quasi-one-dimensional bismuth iodide Bi4I4. The electronic structure of ß-Bi4I4, characterized by Z2 invariants (1;110), is in proximity of both the weak TI phase (0;001) and the trivial insulator phase (0;000). Our angle-resolved photoemission spectroscopy measurements performed on the (001) surface reveal a highly anisotropic band-crossing feature located at the  point of the surface Brillouin zone and showing no dispersion with the photon energy, thus being fully consistent with the theoretical prediction.

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.

The clinical and radiographic results of intertrochanteric curved varus osteotomy for idiopathic osteonecrosis of the femoral head.

PURPOSE: In this study, postoperative results of intertrochanteric curved varus osteotomy (CVO) for idiopathic osteonecrosis of the femoral head (ION) were studied retrospectively and optimal indication of CVO was considered. METHODS: Between 1995 and 2011, CVO was performed in 51 patients (53 hips) for the treatment of ION in our department. The patients who had the potential to obtain acetabular coverage of more than one-third of the intact articular surface on pre-operative AP hip radiographs in maximum abduction were considered suitable for this operation. For radiological assessment, a ratio of necrotic volume, a ratio of postoperative intact surface on the weight-bearing area, progression of collapse, shortening length of the lower limb, and lateralization of great trochanter were evaluated. RESULTS: The mean ratio of necrotic volume was 16.9 %. The mean ratio of postoperative intact surface on the weight-bearing area of the femoral head was 51.7 %. The progression of collapse was observed in two hips (ratio of necrotic volume 10.4, 39.8 %; ratio of postoperative intact area 36.5, 38.1 %). The mean shortening length of the lower limb was 9 mm, and the mean lateralization of great trochanter was 3 mm. One hip (ratio of necrotic volume 11.6 %, ratio of intact area 35.8 %) was converted to THA because of the progression of osteoarthritis at 55 months after CVO. CONCLUSION: The results of CVO for ION were successful, if this procedure was indicated for cases with intact load-bearing area more than 40 %.

Ten year results of transtrochanteric valgus osteotomy with or without the shelf procedure.

PURPOSE: The purpose of this study was to examine retrospectively the effectiveness of Sugioka's transtrochanteric valgus osteotomy (TVO) combined with the shelf procedure for patients who had advanced osteoarthritis (OA) of the hip with severe acetabular dysplasia. METHODS: Sixty-two hips in 61 patients were reviewed retrospectively between April 1993 and March 2009. Of these hips, 25 hips with the pre-operative acetabular head index (AHI) ≥ 60 % (single group) underwent a TVO, whereas the other 37 with AHI < 60 % (combined group) underwent a TVO combined with the shelf procedure. RESULTS: Using conversion to total hip arthroplasty as the endpoint, the Kaplan-Meier survival rates at ten years were calculated to be 85.5 % for the single group and 100 % for the combined group; there was a significant difference between the two groups (p < 0.05, log-rank test). Similarly, calculated using progressive OA as the endpoint, survival rates at ten years were 69.5 % and 89.3 % respectively; there was also a significant difference between the two groups (p < 0.05, log-rank test). In the single group, the latest radiographic evaluations of the patients with the pre-operative AHI ≥ 70 % were significantly better than those of the patients with the pre-operative AHI < 70 % (P < 0.05). CONCLUSION: More satisfactory ten year results of TVO were obtained in cases that had a pre-operative AHI of ≥70 %, or where the shelf procedure was added. It is desirable that acetabuloplasty be added for patients with pre-operative AHI < 70 %.

Bony impingement depends on the bone morphology of the hip after total hip arthroplasty.

PURPOSE: The purpose of this study was to evaluate whether the bone morphology of the hip affects the range of motion (ROM) in total hip arthroplasty (THA). METHODS: Using the CT data of 63 patients who underwent THA, we calculated the ROM of flexion (Flex), internal rotation (Int-R) and external rotation (Ext-R) using 3D dynamic analysis software. We measured the distance between the anterior surface of the stem and anterior aspect of the greater trochanter (GTa length) at the cutting point and between the tip of the antero-inferior iliac spine (AIIS) and coronal plane of both femoral heads (AIIS length), as a parameter of the femur and pelvis, respectively. The relationship between the ROM, bone anatomy and impingement site was evaluated. RESULTS: We found a significant decrease in the ROM of Flex and the Int-R to be inversely proportional to the GTa and AIIS length. In Flex and Int-R, the anterior intertrochanteric region often impinges on the AIIS in patients with larger bone anatomy. CONCLUSIONS: We demonstrated that the bone morphology of the hip substantially affects the ROM of Flex and Int-R, especially in patients with large bone anatomy. For these patients we should consider bony impingement in THA.

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.

Difficulties facing physician mothers in Japan.

Despite recent increases in the number of female physicians graduating in Japan, their premature resignations after childbirth are contributing to the acute shortage of physicians. Previous Japanese studies have explored supportive measures in the workplace, but have rarely focused on the specific problems or concerns of physician-mothers. Therefore, this study explored the challenges facing Japanese physician-mothers in efforts to identify solutions for their retention. Open-ended questionnaires were mailed to 646 alumnae of Juntendo University School of Medicine. We asked subjects to describe their opinions about 'The challenges related to female physicians' resignations'. Comments gathered from alumnae who graduated between 6 and 30 years ago and have children were analyzed qualitatively. Overall, 249 physicians returned the questionnaire (response rate 38.5%), and 73 alumnae with children who graduated in the stated time period provided comments. The challenges facing physician-mothers mainly consisted of factors associated with Japanese society, family responsibilities, and work environment. Japanese society epitomized by traditional gender roles heightened stress related to family responsibilities and promoted gender discrimination at work environment. Additionally, changing Japanese society positively influenced working atmosphere and husband's support. Moreover, the introduction of educational curriculums that alleviated traditional gender role was proposed for pre- and post- medical students. Traditional gender roles encourage discrimination by male physicians or work-family conflicts. The problems facing female physicians involve more than just family responsibilities: diminishing the notion of gender role is key to helping retain them in the workforce.

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.

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.

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.

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.