Prediction of patient-specific quality assurance for volumetric modulated arc therapy using radiomics-based machine learning with dose distribution.

PURPOSE: We sought to develop machine learning models to predict the results of patient-specific quality assurance (QA) for volumetric modulated arc therapy (VMAT), which were represented by several dose-evaluation metrics-including the gamma passing rates (GPRs)-and criteria based on the radiomic features of 3D dose distribution in a phantom. METHODS: A total of 4,250 radiomic features of 3D dose distribution in a cylindrical dummy phantom for 140 arcs from 106 clinical VMAT plans were extracted. We obtained the following dose-evaluation metrics: GPRs with global and local normalization, the dose difference (DD) in 1% and 2% passing rates (DD1% and DD2%) for 10% and 50% dose threshold, and the distance-to-agreement in 1-mm and 2-mm passing rates (DTA1 mm and DTA2 mm) for 0.5%/mm and 1.0%.mm dose gradient threshold determined by measurement using a diode array in patient-specific QA. The machine learning regression models for predicting the values of the dose-evaluation metrics using the radiomic features were developed based on the elastic net (EN) and extra trees (ET) models. The feature selection and tuning of hyperparameters were performed with nested cross-validation in which four-fold cross-validation is used within the inner loop, and the performance of each model was evaluated in terms of the root mean square error (RMSE), the mean absolute error (MAE), and Spearman's rank correlation coefficient. RESULTS: The RMSE and MAE for the developed machine learning models ranged from <1% to nearly <10% depending on the dose-evaluation metric, the criteria, and dose and dose gradient thresholds used for both machine learning models. It was advantageous to focus on high dose region for predicating global GPR, DDs, and DTAs. For certain metrics and criteria, it was possible to create models applicable for patients' heterogeneity by training only with dose distributions in phantom. CONCLUSIONS: The developed machine learning models showed high performance for predicting dose-evaluation metrics especially for high dose region depending on the metric and criteria. Our results demonstrate that the radiomic features of dose distribution can be considered good indicators of the plan complexity and useful in predicting measured dose evaluation metrics.

Successful left ventricular lead placement by way of an azygos vein for a patient performing cardiac resynchronization therapy implantation with an occluded left subclavian vein: A case report.

Central venous obstruction following pacemaker implantation is not uncommon and can prove challenging in the case of a system upgrade to a cardiac resynchronization therapy pacemaker (CRT-P). We describe the case of a patient who underwent a successful upgrading procedure of a pacemaker to a CRT-P in the presence of an occluded left subclavian vein and superior vena cava, using collateral veins that drained into right atrium.

Deep learning-based detection and classification of multi-leaf collimator modeling errors in volumetric modulated radiation therapy.

PURPOSE: The purpose of this study was to create and evaluate deep learning-based models to detect and classify errors of multi-leaf collimator (MLC) modeling parameters in volumetric modulated radiation therapy (VMAT), namely the transmission factor (TF) and the dosimetric leaf gap (DLG). METHODS: A total of 33 clinical VMAT plans for prostate and head-and-neck cancer were used, assuming a cylindrical and homogeneous phantom, and error plans were created by altering the original value of the TF and the DLG by ± 10, 20, and 30% in the treatment planning system (TPS). The Gaussian filters of σ = 0.5 $\sigma = 0.5$ and 1.0 were applied to the planar dose maps of the error-free plan to mimic the measurement dose map, and thus dose difference maps between the error-free and error plans were obtained. We evaluated 3 deep learning-based models, created to perform the following detections/classifications: (1) error-free versus TF error, (2) error-free versus DLG error, and (3) TF versus DLG error. Models to classify the sign of the errors were also created and evaluated. A gamma analysis was performed for comparison. RESULTS: The detection and classification of TF and DLG error were feasible for σ = 0.5 $\sigma = 0.5$ ; however, a considerable reduction of accuracy was observed for σ = 1.0 $\sigma = 1.0$ depending on the magnitude of error and treatment site. The sign of errors was detectable by the specifically trained models for σ = 0.5 $\sigma = 0.5$ and 1.0. The gamma analysis could not detect errors. CONCLUSIONS: We demonstrated that the deep learning-based models could feasibly detect and classify TF and DLG errors in VMAT dose distributions, depending on the magnitude of the error, treatment site, and the degree of mimicked measurement doses.

Maxillofacial morphological characteristics in growing orthodontic patients with non-syndromic oligodontia.

OBJECTIVE: Patients with oligodontia frequently show different types of malocclusions. However, how oligodontia affects the maxillofacial growth remains uncertain. This study aimed to investigate the maxillofacial morphological characteristics in growing patients with oligodontia. SETTING AND SAMPLE POPULATION: The study subjects included 33 Japanese children with non-syndromic oligodontia (14 boys and 19 girls; mean age: 10.2 years) who visited the orthodontic clinic of Fukuoka Dental College Medical and Dental Hospital from 1999 to 2019. MATERIALS AND METHODS: Cephalometric analyses were performed, and the variables measured in each subject were converted into Z scores in relation to the mean and standard deviation of the Japanese norms matched for growth stage. The one-sample t-test or Wilcoxon signed-rank test was performed to compare the mean scores in the patients with oligodontia with those of the Japanese norms. RESULTS: Compared with the Japanese norms, patients with oligodontia showed a smaller convexity and larger A-B plane and SNB angles. The Frankfort-mandibular plane and gonial angles were smaller, whereas the height of the ramus was larger. The vertical height of the alveolar bone in the maxillary and mandibular incisors and molar areas was smaller in patients with oligodontia. CONCLUSIONS: Patients with oligodontia showed Class III skeletal tendency with mandibular prognathism and flattened mandibular plane with a smaller gonial angle. These maxillofacial morphological features can be induced by a deficiency in the vertical growth of the alveolar bone in the maxillary and mandibular molar areas due to the lack of tooth germs.

Embedded Human Periodontal Ligament Stem Cells Spheroids Enhance Cementogenic Differentiation via Plasminogen Activator Inhibitor 1.

Spheroids reproduce the tissue structure that is found in vivo more accurately than classic two-dimensional (2D) monolayer cultures. We cultured human periodontal ligament stem cells (HPLSCs) as spheroids that were embedded in collagen gel to examine whether their cementogenic differentiation could be enhanced by treatment with recombinant human plasminogen activator inhibitor-1 (rhPAI-1). The upregulated expression of cementum protein 1 (CEMP1) and cementum attachment protein (CAP), established cementoblast markers, was observed in the 2D monolayer HPLSCs that were treated with rhPAI-1 for 3 weeks compared with that in the control and osteogenic-induction medium groups. In the embedded HPLSC spheroids, rhPAI-1 treatment induced interplay between the spheroids and collagenous extracellular matrix (ECM), indicating that disaggregated HPLSCs migrated and spread into the surrounding ECM 72 h after three-dimensional (3D) culture. Western blot and immunocytochemistry analyses showed that the CEMP1 expression levels were significantly upregulated in the rhPAI-1-treated embedded HPLSC spheroids compared with all the 2D monolayer HPLSCs groups and the 3D spheroid groups. Therefore, 3D collagen-embedded spheroid culture in combination with rhPAI-1 treatment may be useful for facilitating cementogenic differentiation of HPLSCs.

Femoral morphology affects postoperative alignment of the lower extremities in hybrid closed-wedge high tibial osteotomy.

INTRODUCTION: This study aimed to determine correction error predictors of lower extremitiy alignment after hybrid closed-wedge high tibial osteotomy (HCWHTO). MATERIALS AND METHODS: From 2011 to 2015, 102 knees in 75 patients with medial compartment knee osteoarthritis of the knee and varus knee deformities who underwent HCWHTO were evaluated in this retrospective study with a minimum 2-year follow-up. Preoperative radiological parameters including weight-bearing line ratio (WBL ratio), mechanical leg axis angle, mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), joint line convergence angle (JLCA), and JLCA under varus or valgus stress were measured. The knees were divided into the following three groups based on the WBL ratio on average 54 months after procedure: acceptable (WBL crossing the tibial plateau between 50 and 70%), under-correction (< 50%), and overcorrection (> 70%). A multiple regression analysis was performed to evaluate predictors that could influence postoperative WBL ratio and cut-off values of predictive preoperative factors was analysed. RESULTS: Significant differences in pre- and postoperative WBL ratios and mechanical leg axis angles were found. Preoperative mLDFA in the under-correction group (89.4° ± 2.1°) was significantly higher than that in the overcorrection group (87.4° ± 2.2°) (p = 0.015), while other preoperative parameters revealed no significant differences. The postoperative MPTA in the under-correction group (92.1° ± 3.7°) was significantly lower than that in the other two groups (p = 0.005 and p = 0.0001, respectively), while there was no significant change between the acceptable (94.6° ± 3.4°) and the overcorrection (96.7° ± 3.2°) groups. Multiple regression analysis revealed that mLDFA (ß = - 0.316; p = 0.010) had a significant impact on postoperative WBLR. The cut-off value for under-correction of mLDFA was 89.5°and sensitivity and specificity were 53.6 and 71.6%, respectively (p = 0.014). CONCLUSIONS: Preoperative mLDFA is significantly associated with postoperative alignment in HCWHTO. While postoperative MPTA is important, disregarding the preoperative mLDFA may bears a high risk of malcorrection. Varus alignment of the knee with larger mLDFA may be an indication for not only HCWHTO, but also for distal femoral osteotomy.

Preoperative CT Findings for Predicting Acute Exacerbation of Interstitial Pneumonia After Lung Cancer Surgery: A Multicenter Case-Control Study.

BACKGROUND. Acute exacerbation (AE) is a life-threatening complication of inter-stitial pneumonia (IP). Thoracic surgery may trigger AE. OBJECTIVE. The purpose of this study is to explore the role of preoperative CT findings in predicting postoperative AE in patients with IP and lung cancer. METHODS. This retrospective case-control study included patients from 22 institutions who had IP and underwent thoracic surgery for lung cancer. AE was diagnosed on the basis of symptoms and imaging findings noted within 30 days after surgery and the absence of alternate causes. For each patient with AE, two control patients without AE were identified. After exclusions, the study included 92 patients (78 men and 14 women; 31 with AE [the AE group] and 61 without AE [the no-AE group]; mean age, 72 years). Two radiologists independently reviewed preoperative thin-slice CT examinations for pulmonary findings and resolved differences by consensus. The AE and no-AE groups were compared using the Fisher exact and Mann-Whitney U tests. Multivariable logistic regression was performed. Interreader agreement was assessed by kappa coefficients. RESULTS. A total of 94% of patients in the AE group underwent segmentectomy or other surgery that was more extensive than wedge resection versus 75% in the no-AE group (p = .046). The usual IP pattern was present in 58% of the AE group versus 74% of the no-AE group (p = .16). According to subjective visual scoring, the mean (± SD) ground-glass opacity (GGO) extent was 6.3 ± 5.4 in the AE group versus 3.9 ± 3.8 in the no-AE group (p = .03), and the mean consolidation extent was 0.5 ± 1.2 in the AE group versus 0.1 ± 0.3 in the no-AE group (p = .009). Mean pulmonary trunk diameter was 28 ± 4 mm in the AE group versus 26 ± 3 mm in the no-AE group (p = .02). In a model of CT features only, independent predictors of AE (p < .05) were GGO extent (odds ratio [OR], 2.8), consolidation extent (OR, 9.4), and pulmonary trunk diameter (OR, 4.2); this model achieved an AUC of 0.75, a PPV of 71%, and an NPV of 77% for AE. When CT and clinical variables were combined, undergoing segmentectomy or more extensive surgery also independently predicted AE (OR, 8.2; p = .02). CONCLUSION. The presence of GGO, consolidation, and pulmonary trunk enlargement on preoperative CT predicts AE in patients with IP who are undergoing lung cancer surgery. CLINICAL IMPACT. Patients with IP and lung cancer should be carefully managed when predictive CT features are present. Wedge resection, if possible, may help reduce the risk of AE in these patients. TRIAL REGISTRATION. University Hospital Medical Information Clinical Trial Registry UMIN000029661.

Low Tube Voltage Computed Tomography Venography for Patients With Deep Vein Thrombosis of the Lower Extremities　- A Comparison With Venous Ultrasonography.

BACKGROUND: Low tube voltage computed tomography venography (CTV) can be expected to increase imaging contrast and decrease radiation exposure by using iterative reconstruction (IR). This study evaluated the diagnostic ability of low tube voltage CTV with IR for deep vein thrombosis (DVT), compared to ultrasonography (US).Methods and Results:Two experienced radiologists retrospectively reevaluated the CTV data of 55 of 318 consecutive patients suspected of having DVT or pulmonary embolism between December 2015 and April 2017. The 55 patients had undergone both low tube voltage CTV and US (within 1 day before or after CTV). The lower extremity veins were divided into 10 segments. The DVT forms were categorized into 3 types: complete, concentric, and eccentric. We analyzed the 534 overall segments (16 segments excluded in US) measured using both CTV and US. The sensitivity-specificity was overall 73.3-90.0%, for femoropopliteal, it was 90.0-93.2%, and for the calf, it was 71.1-87.2%. The diagnostic accuracy between the 'eccentric only' and 'others' groups focusing on DVT forms was compared, and significant differences were revealed, especially in the muscular vein. CONCLUSIONS: The DVT diagnostic ability above the knee was comparable between low tube voltage CTV with IR and conventional CTV, and the radiation dose was reduced. It was suggested that eccentric DVT measured by CTV tend to be a false-positive, especially in the calf muscular vein.

Radiobiological evaluation considering setup error on single-isocenter irradiation in stereotactic radiosurgery.

PURPOSE: We calculated the dosimetric indices and estimated the tumor control probability (TCP) considering six degree-of-freedom (6DoF) patient setup errors in stereotactic radiosurgery (SRS) using a single-isocenter technique. METHODS: We used simulated spherical gross tumor volumes (GTVs) with diameters of 1.0 cm (GTV 1), 2.0 cm (GTV 2), and 3.0 cm (GTV 3), and the distance (d) between the target center and isocenter was set to 0, 5, and 10 cm. We created the dose distribution by convolving the blur component to uniform dose distribution. The prescription dose was 20 Gy and the dose distribution was adjusted so that D95 (%) of each GTV was covered by 100% of the prescribed dose. The GTV was simultaneously rotated within 0°-1.0° (δR) around the x-, y-, and z-axes and then translated within 0-1.0 mm (δT) in the x-, y-, and z-axis directions. D95, conformity index (CI), and conformation number (CN) were evaluated by varying the distance from the isocenter. The TCP was estimated by translating the calculated dose distribution into a biological response. In addition, we derived the x-y-z coordinates with the smallest TCP reduction rate that minimize the sum of squares of the residuals as the optimal isocenter coordinates using the relationship between 6DoF setup error, distance from isocenter, and GTV size. RESULTS: D95, CI, and CN were decreased with increasing isocenter distance, decreasing GTV size, and increasing setup error. TCP of GTVs without 6DoF setup error was estimated to be 77.0%. TCP were 25.8% (GTV 1), 35.0% (GTV 2), and 53.0% (GTV 3) with (d, δT, δR) = (10 cm, 1.0 mm, 1.0°). The TCP was 52.3% (GTV 1), 54.9% (GTV 2), and 66.1% (GTV 3) with (d, δT, δR) = (10 cm, 1.0 mm, 1.0°) at the optimal isocenter position. CONCLUSION: The TCP in SRS for multiple brain metastases with a single-isocenter technique may decrease with increasing isocenter distance and decreasing GTV size when the 6DoF setup errors are exceeded (1.0 mm, 1.0°). Additionally, it might be possible to better maintain TCP for GTVs with 6DoF setup errors by using the optimal isocenter position.

An orthodontic perspective on Larsen syndrome.

BACKGROUND: Larsen syndrome (LS) is a rare disorder of osteochondrodysplasia. In addition to large-joint dislocations, craniofacial anomalies are typical characteristics. In this report, we performed orthodontic analyses, including skeletal and occlusal evaluations, to examine whether the craniofacial skeletal morphology leads to the craniofacial anomalies in LS. CASE PRESENTATION: A 5 year old Japanese girl who was clinically diagnosed with LS was referred to the orthodontic clinic in the Fukuoka Dental College Medical and Dental Hospital because of a malocclusion. Clinical findings at birth were knee-joint dislocations, equinovarus foot deformities, and cleft soft palate. The patient showed craniofacial anomalies with hypertelorism, prominent forehead, depressed nasal bridge, and flattened midface. To evaluate the craniofacial skeletal morphology, cephalometric analysis was performed. In the frontal cephalometric analysis, the larger widths between bilateral points of the orbitale were related to hypertelorism. The lateral cephalometric analysis revealed the midface hypoplasia and the retrognathic mandible. These findings were responsible for the flattened appearance of the patient's face, even if the anteroposterior position of the nasion was normal. Her forehead looked prominent in relation to the face probably because of the retrognathic maxilla and mandible. Both the study model and the frontal cephalometric analysis indicated constriction of the upper and lower dental arches. The posterior crossbite facilitated by the premature contacts had developed in association with the constriction of the upper dental arch. CONCLUSIONS: This patient had some craniofacial anomalies with characteristic appearances in LS. It was evident that the underlying skeletal morphology led to the craniofacial dysmorphism.

A New Secretory Peptide of Natriuretic Peptide Family, Osteocrin, Suppresses the Progression of Congestive Heart Failure After Myocardial Infarction.

RATIONALE: An increase of severe ischemic heart diseases results in an increase of the patients with congestive heart failure (CHF). Therefore, new therapies are expected in addition to recanalization of coronary arteries. Previous clinical trials using natriuretic peptides (NPs) prove the improvement of CHF by NPs. OBJECTIVE: We aimed at investigating whether OSTN (osteocrin) peptide potentially functioning as an NPR (NP clearance receptor) 3-blocking peptide can be used as a new therapeutic peptide for treating CHF after myocardial infarction (MI) using animal models. METHODS AND RESULTS: We examined the effect of OSTN on circulation using 2 mouse models; the continuous intravenous infusion of OSTN after MI and the OSTN-transgenic (Tg) mice with MI. In vitro studies revealed that OSTN competitively bound to NPR3 with atrial NP. In both OSTN-continuous intravenous infusion model and OSTN-Tg model, acute inflammation within the first week after MI was reduced. Moreover, both models showed the improvement of prognosis at 28 days after MI by OSTN. Consistent with the in vitro study binding of OSTN to NPR3, the OSTN-Tg exhibited an increased plasma atrial NP and C-type NP, which might result in the improvement of CHF after MI as indicated by the reduced weight of hearts and lungs and by the reduced fibrosis. CONCLUSIONS: OSTN might suppress the worsening of CHF after MI by inhibiting clearance of NP family peptides.

Quantitative 3D Shape Analysis of CT Images of Thymoma: A Comparison With Histological Types.

OBJECTIVE. The purpose of this study is to differentiate between low- and high-risk types of thymoma using quantitative 3D shape analysis of CT images. MATERIALS AND METHODS. This retrospective study included 44 patients with a pathologic diagnosis of thymoma. Two radiologists semiautomatically contoured CT images of the tumors and evaluated 3D shape parameters-namely, quantitative indicators of surface smoothness, including sphericity, ellipsoidality, and discrete compactness. The visual CT findings that were analyzed included longest diameter, shape (round-oval, lobulated, or irregular), calcification, cystic or necrotic changes, and enhancement pattern (homogeneous or heterogeneous). The difference and discriminating performance between low-risk (types A, AB, and B1) and high-risk (types B2 and B3) thymomas were statistically assessed. Interobserver agreement was determined using the concordance correlation coefficient. RESULTS. Twenty-three low-risk and 21 high-risk thymomas were identified on the basis of pathologic findings. The median values of sphericity and ellipsoidality were significantly higher for low-risk thymomas than for high-risk thymomas (for sphericity, 0.566 vs 0.517; for ellipsoidality, 0.941 vs 0.875; p < 0.05 for both). The AUC values of sphericity and ellipsoidality were 0.704 and 0.712, respectively. The best cutoff values were 0.528 and 0.919 for sphericity and ellipsoidality, respectively. Risk assessment combining these cutoff values and the mode of tumor detection (incidental detection or detection based on the presence of symptoms) improved the AUC value to 0.856 (sensitivity, 81.0% [17 of 21 patients]; specificity, 82.6% [19 of 23 patients]). All 3D shape parameters showed almost perfect interobserver agreement (concordance correlation coefficient, > 0.90). The visual CT findings were not significantly different between low- and high-risk thymomas (p > 0.05 for all). CONCLUSION. Quantitative 3D shape analysis has excellent reproducibility, and combining this technique with information on the detection mode helps differentiate low- from high-risk thymomas.

Radiobiological effects of the interruption time with Monte Carlo Simulation on multiple fields in photon beams.

PURPOSE: The interruption time is the irradiation interruption that occurs at sites and operations such as the gantry, collimator, couch rotation, and patient setup within the field in radiotherapy. However, the radiobiological effect of prolonging the treatment time by the interruption time for tumor cells is little evaluated. We investigated the effect of the interruption time on the radiobiological effectiveness with photon beams based on a modified microdosimetric kinetic (mMK) model. METHODS: The dose-mean lineal energy yD (keV/µm) of 6-MV photon beams was calculated by the particle and heavy ion transport system (PHITS). We set the absorbed dose to 2 or 8 Gy, and the interruption time (τ) was set to 1, 3, 5, 10, 30, and 60 min. The biological parameters such as α0, ß0, and DNA repair constant rate (a + c) values were acquired from a human non-small-cell lung cancer cell line (NCI-H460) for the mMK model. We used two-field and four-field irradiation with a constant dose rate (3 Gy/min); the photon beams were paused for interruption time τ. We calculated the relative biological effectiveness (RBE) to evaluate the interruption time's effect compared with no interrupted as a reference. RESULTS: The yD of 6-MV photon beams was 2.32 (keV/µm), and there was little effect by changing the water depth (standard deviation was 0.01). The RBE with four-field irradiation for 8 Gy was decreased to 0.997, 0.975, 0.900, and 0.836 τ = 1, 10, 30, 60 min, respectively. In addition, the RBE was affected by the repair constant rate (a + c) value, the greater the decrease in RBE with the longer the interruption time when the (a + c) value was large. CONCLUSION: The ~10-min interruption of 6-MV photon beams did not significantly impact the radiobiological effectiveness, since the RBE decrease was <3%. Nevertheless, the RBE's effect on tumor cells was decreased about 30% by increasing the 60 min interruption time at 8 Gy with four-field irradiation. It is thus necessary to make the interruption time as short as possible.

Cold stress-induced ferroptosis involves the ASK1-p38 pathway.

A wide variety of cell death mechanisms, such as ferroptosis, have been proposed in mammalian cells, and the classification of cell death attracts global attention because each type of cell death has the potential to play causative roles in specific diseases. However, the precise molecular mechanisms leading to cell death are poorly understood, particularly in ferroptosis. Here, we show that continuous severe cold stress induces ferroptosis and the ASK1-p38 MAPK pathway in multiple cell lines. The activation of the ASK1-p38 pathway is mediated by critical determinants of ferroptosis: MEK activity, iron ions, and lipid peroxide. The chemical compound erastin, a potent ferroptosis inducer, also activates the ASK1-p38 axis downstream of lipid peroxide accumulation and leads to ASK1-dependent cell death in a cell type-specific manner. These lines of evidence provide mechanistic insight into ferroptosis, a type of regulated necrosis.

The impact of emphysema on surgical outcomes of early-stage lung cancer: a retrospective study.

BACKGROUND: The presence of emphysema on computed tomography (CT) is associated with an increased frequency of lung cancer, but the postoperative outcomes of patients with pulmonary emphysema are not well known. The objective of this study was to investigate the association between the extent of emphysema and long-term outcomes, as well as mortality and postoperative complications, in early-stage lung cancer patients after pulmonary resection. METHODS: The clinical records of 566 consecutive lung cancer patients who underwent pulmonary resection in our department were retrospectively reviewed. Among these, the data sets of 364 pathological stage I patients were available. The associations between the extent of lung emphysema and long-term outcomes and postoperative complications were investigated. Emphysema was assessed on the basis of semiquantitative CT. Surgery-related complications of Grade ≥ II according to the Clavien-Dindo classification were included in this study. RESULTS: Emphysema was present in 63 patients. The overall survival and relapse-free survival of the non-emphysema and emphysema groups at 5 years were 89.0 and 61.3% (P < 0.001), respectively, and 81.0 and 51.7%, respectively (P < 0.001). On multivariate analysis, significant prognostic factors were emphysema, higher smoking index, and higher histologic grade (p < 0.05). Significant risk factors for poor recurrence-free survival were emphysema, higher smoking index, higher histologic grade, and presence of pleural invasion (P < 0.05). Regarding Grade ≥ II postoperative complications, pneumonia and supraventricular tachycardia were more frequent in the emphysema group than in the non-emphysema group (P = 0.003 and P = 0.021, respectively). CONCLUSION: The presence of emphysema affects the long-term outcomes and the development of postoperative complications in early-stage lung cancer patients.

Hybrid closed wedge high tibial osteotomy improves patellofemoral joint congruity compared with open wedge high tibial osteotomy.

PURPOSE: To evaluate clinical outcomes and radiographic changes in patellofemoral (PF) joint congruity between open wedge high tibial osteotomy (OWHTO) and hybrid closed wedge HTO (HCWHTO). METHODS: From 2011 to 2013, 36 knees in 31 patients who underwent OWHTO and 21 knees in 17 patients who underwent HCWHTO were evaluated in this retrospective study with a minimum 5-year follow-up. Radiological outcomes including hip-knee-ankle angle (HKA), femoral patellar height index (FPHI), preoperative PF osteoarthritis (OA) grade, medial and lateral joint spaces of the PF joint, and congruence angle were measured. Clinical parameters including the Knee injury and Osteoarthritis Outcome Score (KOOS) and the Oxford Knee Score (OKS) were also evaluated. Preoperative and final follow-up values for each procedure were compared in outcome analyses. RESULTS: Mean preoperative HKA and the degree of PF-OA were significantly more severe for patients treated with HCWHTO compared with those treated with OWHTO (p = 0.001, p = 0.0001). Mean postoperative FPHI was significantly decreased with proximalization of the patella in HCWHTO (p = 0.01) but showed no significant change in OWHTO (n.s.). Regarding PF joint congruity after HCWHTO, lateral joint space and congruence angle were significantly improved (p = 0.0001, p = 0.005), while medial joint space was not significantly changed (n.s.). After OWHTO, congruence angle showed no significant difference (n.s.), but medial and lateral joint spaces were significantly decreased (p = 0.0001, p = 0.018). There were no significant differences in KOOS and OKS between the groups (n.s., n.s.). CONCLUSIONS: Although degrees of varus knee and PF-OA were more severe in HCWHTO than those in OWHTO, HCWHTO led to improved PF joint congruity, and its mid-term clinical outcomes were equivalent to those of OWHTO. Therefore, in patients with varus knee combined with PF-OA preoperatively, HCWHTO is a more effective treatment than OWHTO. LEVEL OF EVIDENCE: Therapeutic level III.

Survival after repeated surgery for lung cancer with idiopathic pulmonary fibrosis: a retrospective study.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) have a high risk of developing lung cancer, but few studies have investigated the long-term outcomes of repeated surgery in such patients. The purpose of this study was to evaluate the surgical outcomes of repeated lung cancer surgery in patients with IPF. METHODS: From January 2001 to December 2015, 108 lung cancer patients with IPF underwent pulmonary resection at two institutions; 13 of these patients underwent repeated surgery for lung cancer, and their data were reviewed. RESULTS: The initial procedures of the 13 patients were lobectomy in 8, segmentectomy in 2, and wedge resection in 3. The subsequent procedures were wedge resection in 10 and segmentectomy in 3. The clinical stage of the second tumor was stage IA in 12 and stage IB in 1. Postoperatively, 3 patients (23.1%) developed acute exacerbation (AE) of IPF and died. The rate of decrease in percent vital capacity was significantly higher in patients with AE than in those without AE (p = 0.011). The 3-year overall survival rate was 34.6%. The causes of death were cancer-related in 7, AE of IPF in 3, and metachronous lung cancer in 1. CONCLUSIONS: Despite limited resection, a high incidence of AE was identified. The early and long-term outcomes of repeated surgery in lung cancer patients with IPF were poor because of the high risk of AE of IPF and lung cancer recurrence. Long-term intensive surveillance will be required to determine whether surgical intervention is justified in patients with multiple primary lung cancers and IPF.

O-fucose monosaccharide of Drosophila Notch has a temperature-sensitive function and cooperates with O-glucose glycan in Notch transport and Notch signaling activation.

Notch (N) is a transmembrane receptor that mediates the cell-cell interactions necessary for many cell fate decisions. N has many epidermal growth factor-like repeats that are O-fucosylated by the protein O-fucosyltransferase 1 (O-Fut1), and the O-fut1 gene is essential for N signaling. However, the role of the monosaccharide O-fucose on N is unclear, because O-Fut1 also appears to have O-fucosyltransferase activity-independent functions, including as an N-specific chaperon. Such an enzymatic activity-independent function could account for the essential role of O-fut1 in N signaling. To evaluate the role of the monosaccharide O-fucose modification in N signaling, here we generated a knock-in mutant of O-fut1 (O-fut1(R245A knock-in)), which expresses a mutant protein that lacks O-fucosyltransferase activity but maintains the N-specific chaperon activity. Using O-fut1(R245A knock-in) and other gene mutations that abolish the O-fucosylation of N, we found that the monosaccharide O-fucose modification of N has a temperature-sensitive function that is essential for N signaling. The O-fucose monosaccharide and O-glucose glycan modification, catalyzed by Rumi, function redundantly in the activation of N signaling. We also showed that the redundant function of these two modifications is responsible for the presence of N at the cell surface. Our findings elucidate how different forms of glycosylation on a protein can influence the protein's functions.

Integrin α6ß4 and TRPV1 channel coordinately regulate directional keratinocyte migration.

The directional migration of epithelial cells is crucial for wound healing. Among integrins, a family of cell adhesion receptors, integrin ß4 has been assumed to be a promigratory factor, in addition to its role in stable adhesion. In turn, Ca(2+) signaling is also a key coordinator of migration. Keratinocytes reportedly express transient receptor potential vanilloid channels (TRPV1); however, the function of these channels as a regulator of intracellular Ca(2+) level in cell migration has remained uncharacterized. In the present study, we investigated the role of TRPV1 in directional migration related to integrin ß4 using a scratch wound assay on a confluent monolayer sheet of murine keratinocytes (Pam212 cells). Double immunofluorescence staining revealed the de novo expression of integrin ß4 and TRPV1 in migrating cells at the wound edge in response to scratch wounding, and both expression levels were almost matched. Epidermal growth factor (EGF) not only promoted keratinocyte migration, but also caused the further up-regulation of both integrin ß4 and TRPV1. In addition, the knockdown of the integrin ß4 or TRPV1 gene significantly impeded wound closure. The TRPV1 agonist capsaicin significantly promoted migration, while a selective TRPV1 antagonist inhibited it. The gene knockdown of TRPV1 inhibited the expression of the integrin ß4 gene and that of ß4 protein in migrating cells. These findings suggest that TRPV1 may stimulate directional migration directly by eliciting a Ca(2+) signal or indirectly via integrin ß4 expression.

Rescue of Notch signaling in cells incapable of GDP-L-fucose synthesis by gap junction transfer of GDP-L-fucose in Drosophila.

Notch (N) is a transmembrane receptor that mediates cell-cell interactions to determine many cell-fate decisions. N contains EGF-like repeats, many of which have an O-fucose glycan modification that regulates N-ligand binding. This modification requires GDP-L-fucose as a donor of fucose. The GDP-L-fucose biosynthetic pathways are well understood, including the de novo pathway, which depends on GDP-mannose 4,6 dehydratase (Gmd) and GDP-4-keto-6-deoxy-D-mannose 3,5-epimerase/4-reductase (Gmer). However, the potential for intercellularly supplied GDP-L-fucose and the molecular basis of such transportation have not been explored in depth. To address these points, we studied the genetic effects of mutating Gmd and Gmer on fucose modifications in Drosophila. We found that these mutants functioned cell-nonautonomously, and that GDP-L-fucose was supplied intercellularly through gap junctions composed of Innexin-2. GDP-L-fucose was not supplied through body fluids from different isolated organs, indicating that the intercellular distribution of GDP-L-fucose is restricted within a given organ. Moreover, the gap junction-mediated supply of GDP-L-fucose was sufficient to support the fucosylation of N-glycans and the O-fucosylation of the N EGF-like repeats. Our results indicate that intercellular delivery is a metabolic pathway for nucleotide sugars in live animals under certain circumstances.