Generation of 3D lacrimal gland organoids from human pluripotent stem cells.

Lacrimal glands are the main exocrine glands of the eyes. Situated within the orbit, behind the upper eyelid and towards the temporal side of each eye, they secrete lacrimal fluid as a major component of the tear film. Here we identify cells with characteristics of lacrimal gland primordia that emerge in two-dimensional eye-like organoids cultured from human pluripotent stem cells1. When isolated by cell sorting and grown under defined conditions, the cells form a three-dimensional lacrimal-gland-like tissue organoid with ducts and acini, enabled by budding and branching. Clonal colony analyses indicate that the organoids originate from multipotent ocular surface epithelial stem cells. The organoids exhibit notable similarities to native lacrimal glands on the basis of their morphology, immunolabelling characteristics and gene expression patterns, and undergo functional maturation when transplanted adjacent to the eyes of recipient rats, developing lumina and producing tear-film proteins.

Neural and Physiological Correlates of Prosocial Behavior: Temporoparietal Junction Activity in 3-year-old Children.

Although the development of prosocial behavior has been widely studied from the behavioral aspect, the neural mechanisms underlying prosocial behavior in the early stages of development remain unclear. Therefore, this study investigated the neural mechanisms underlying the emergence of prosocial behavior in 3-year-old children. Brain activity in the medial pFC and right TPJ (rTPJ) and facial expression activity, which are related to the ability to infer others' mental states (mentalizing), during the observation of prosocial and antisocial scenes were measured using functional near-infrared spectroscopy and electromyography, respectively. Subsequently, the children's helping and comforting behaviors toward an experimenter were assessed to examine prosocial behavioral tendencies. A correlation analysis revealed that the children who showed stronger activity levels in the rTPJ while observing prosocial scenes had more immediate helping behaviors toward others than those who did not show stronger response levels. Moreover, the amount of facial expression activity correlated with prosocial behavior, including both helping and comforting behaviors. These results suggest that the development of mentalizing ability and the social evaluation of others' actions, mediated by the rTPJ, contribute to the emergence of prosocial behavior.

Three-year outcomes of contemporary endovascular treatment in over 25-cm femoropopliteal artery disease from a retrospective multicenter registry: A retrospective observational study.

BACKGROUND: Endovascular therapy (EVT) is often performed for diffuse femoropopliteal lesions. This study investigated 3-year patency and clinical outcomes in patients with EVT-treated femoropopliteal lesions >25 cm. METHODS: This retrospective multicenter registry analyzed patients who presented with lower extremity artery disease having femoropopliteal lesions >25 cm who underwent EVT between 2017 and 2021. The primary outcome was restenosis 3 years after EVT. RESULTS: Overall, 504 patients with 614 lesions undergoing EVT for diffuse femoropopliteal lesions were enrolled. The prevalence of restenosis was 184.3 per 1000 lesion-years. Kaplan-Meier estimate of freedom from restenosis was 58.6% at 3 years. In the multivariate Poisson regression model, female sex (adjusted incidence risk ratio: 1.54; p = 0.003), cilostazol use (0.44; p < 0.001), revascularization history (1.87; p = 0.001), P3 involvement (2.09; p < 0.001), and reference vessel diameter <5 mm (1.88; p < 0.001) were associated independently with restenosis risk. The accumulation of these factors was associated with a lower rate of freedom from restenosis; the Kaplan-Meier estimates of the rates were 49.3% and 22.4% in the subgroups with two and more risk factors, respectively, while they were 81.1% in patients without any risk factors and 70.3% in those with one risk factor. CONCLUSIONS: Female sex, nonuse of cilostazol, revascularization history, P3 involvement, and small vessels were associated with high restenosis risk after EVT for diffuse femoropopliteal lesions. Although patients with multiple risk factors have a low patency rate, EVT offers an acceptable patency rate for those with fewer risk factors.

One-year Outcomes of Drug-Eluting Stent Versus Drug-Coated Balloon for Femoropopliteal Artery Lesions: BEASTARS Study Results.

BACKGROUND: Previous reports have shown comparable outcomes between drug-eluting stents (DESs) and drug-coated balloons (DCBs) for treating femoropopliteal artery (FPA) lesions; however, DCB outcomes include approximately 10% to 50% bailout stents. Therefore, comparing DESs and DCBs is not simple. The aim of this study was to compare the clinical outcomes of DESs and DCBs in patients with symptomatic FPA disease. MATERIALS AND METHODS: Using the registries of 7 institutions, we retrospectively reviewed the records of 1356 patients who underwent endovascular therapy for FPA with DESs (n=333; Eluvia, 74.0%; Zilver PTX stent, 26.0%) or DCBs without bailout stents (n=1023; IN.PACT, 67.6%; Lutonix, 32.4%). The primary outcome was the 1-year primary patency comparison between DESs and DCBs, using propensity score matching. The severity of the dissection pattern after predilatation (none or grades A-C) was included as an explanatory variable for matching. Patients with grade D dissections were excluded from the main analysis and assessed independently. RESULTS: After matching, the 1-year primary patency between DESs and DCBs was similar (88.8% vs 85.2%, p=0.31). By contrast, perioperative complications were frequent with DES, compared with DCB (5.1% vs 2.2%, p=0.005), and the intravascular ultrasound-evaluated minimum luminal area was significantly larger with DES than with DCB (19 mm2 vs 14 mm2, p<0.001). In the supplemental analysis of lesions with grade D dissection, the 1-year primary patency was significantly higher with DES than with DCB (86.1% vs 55.1%, p=0.014). CONCLUSION: In FPA lesions without severe dissection (ie, no dissection or grade A-C dissection), DESs and DCBs showed comparable 1-year primary patency in matched populations. However, DCBs did not perform well with severe dissection (ie, grade D or more). CLINICAL IMPACT: The results of this study clearly define the appropriate boundaries for the "leaving nothing behind" strategy. Clinicians can now more clearly differentiate between the use of DES and DCB, based on the results of lesion preparation. Further prospective investigations with well-designed trials and larger populations are necessary to confirm these findings.

Prognostic Impact of Reduced Left Ventricular Ejection Fraction After Endovascular Therapy for Lower Extremities.

BACKGROUND: The mechanism underlying a poor prognosis in patients with lower-extremity artery disease (LEAD) with heart failure is unknown. We examined the prognostic impact of the left ventricular ejection fraction (LVEF) in patients with LEAD who underwent endovascular therapy (EVT).Methods and Results: From August 2014 to August 2016, 2,180 patients with LEAD (mean age, 73.2 years; male, 71.9%) underwent EVT and were stratified into low-LVEF (LVEF <40%; n=234, 10.7%) and not-low LVEF groups. In the low- vs. not-low LVEF groups, there was a higher prevalence of heart failure (i.e., history of heart failure hospitalization or New York Heart Association functional class III or IV symptoms) (44.0% vs. 8.3%, respectively), diabetes mellitus, chronic kidney disease, below-the-knee lesion, critical limb ischemia, and incidence of major cardiovascular and cerebrovascular events (MACCEs) and major adverse limb events (MALEs) (P<0.001, all). Low LVEF independently predicted MACCEs (hazard ratio: 2.23, 95% confidence interval: 1.63-3.03; P<0.001) and MALEs (hazard ratio: 1.85, 95% confidence interval: 1.15-2.96; P=0.011), regardless of heart failure (P value for interaction: MACCEs: 0.27; MALEs: 0.52). CONCLUSIONS: Low LVEF, but not symptomatic heart failure, increased the incidence of MACCEs and MALEs. Intensive cardiac dysfunction management may improve LEAD prognosis after EVT.

Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors.

Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders characterized by the aberrant accumulation of α-synuclein (α-syn). Although no treatment is effective for synucleinopathies, the suppression of α-syn aggregation may contribute to the development of numerous novel therapeutic targets. Recent research revealed that nicotinic acetylcholine (nACh) receptor activation has neuroprotective effects and promotes the degradation of amyloid protein by activating autophagy. In an in vitro human-derived cell line model, we demonstrated that galantamine, the nAChR allosteric potentiating ligand, significantly reduced the cell number of SH-SY5Y cells with intracellular Lewy body-like aggregates by enhancing the sensitivity of α7-nAChR. In addition, galantamine promoted autophagic flux, and prevented the formation of Lewy body-resembled aggregates. In an in vivo synucleinopathy mouse model, the propagation of α-syn aggregation in the cerebral cortex was inhibited by galantamine administration for 90 days. These results suggest that α7-nAChR is expected to be a novel therapeutic target, and galantamine is a potential agent for synucleinopathies.

Identification of Entinostat as a Novel Modifier of STAT3 Pre-mRNA Alternative Splicing.

Signal transducer and activator of transcription 3 (STAT3) is a pleiotropic factor involved in multiple vital biological processes and a key mediator of gene transcription in response to cytokines, growth factors and aberrant activation of oncogenic signaling. STAT3 has two splicing isoforms, STAT3α and STAT3ß, derived from alternative splicing of exon 23 within pre-mRNA. STAT3ß differs from STAT3α by replacement of 55 amino-acid residues in the C-terminal transactivation domain with 7 specific amino acids. Thus, a shorter STAT3ß was originally regarded as a dominant negative isoform of STAT3α. Recently accumulating evidence from independent studies have shown STAT3 splicing isoforms confer distinct and overlapping functions in many fundamental cellular regulatory steps such as cell differentiation, inflammatory responses, and cancer progression. However, relatively little is known about the mechanisms of STAT3 pre-mRNA splicing, and it remains undiscovered which chemical compounds or bioactive substances can induce the STAT3ß expression. In this study, we generated a potent reporter for detection of alternative splicing of STAT3 pre-mRNA optimized for the screening of function-known chemical library, and successfully identified entinostat, a histone deacetylase inhibitor, as a novel inducer of STAT3ß through modulating mRNA splicing. Our findings demonstrate that alternative splicing of STAT3 can be regulated by a compound, providing an important clue for understanding the regulation mechanisms of the expression balance of STAT3 isoforms in a chemical biology approach. Entinostat is likely to be a promising seed compound for elucidating how the higher ratio of STAT3ß expression impacts on biological responses associated with Janus kinase (JAK)/STAT3 signaling pathway.

Lymphangioleiomyomatosis as a potent lung cancer risk factor: Insights from a Japanese large cohort study.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease. METHODS: We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available. RESULTS: Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS. CONCLUSION: Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM.

A rapid simultaneous antigen detection of Haemophilus influenzae and Streptococcus pneumoniae for predicting the prognosis of acute otitis media.

BACKGROUND: Rapid identification of causative bacteria in treatment of acute otitis media (AOM) is of paramount importance for appropriate antibiotic use. MATERIALS AND METHODS: This prospective observational study was conducted in 15 hospitals and clinics in Japan between 2018 and 2020. A new rapid antigen test kit (AOS-116), which simultaneously detects antigens for Streptococcus pneumoniae (Sp) and Haemophilus influenzae (Hi), was applied for middle ear fluids (MEFs) and nasopharyngeal secretions (NPSs) in patients with moderate to severe AOM. We investigated relationship between the results of rapid test, severity at initial visit, and clinical course. RESULTS: Regarding performance accuracy based on culture results, AOS-116 showed 1) high (>80%) sensitivity, specificity, and negative predictive value (NPV) in MEFs for both antigens, 2) high sensitivity, specificity, and positive predictive value (PPV) in NPSs for Hi antigen, and 3) high specificity, and PPV in NPSs for Sp antigen. Regarding predictive value of nasopharyngeal culture and antigen detection for causative middle ear pathogens, similar results were observed between AOS-116 and culture, which was characterized with high sensitivity and NPV for both pathogens. MEFs/NPSs positive for Hi antigen were significantly associated with eardrum findings, and severity. MEFs/NPSs positive for pneumococcal antigen were significantly associated with severity of otalgia, fever, and otorrhea. Among patients with prior antimicrobial treatment, improvement tended to be slower in cases positive for Hi than in cases negative. CONCLUSION: The rapid antigen detection test is useful as a decision-making tool for prescribing antimicrobial agents and may play an important role in promoting appropriate antimicrobial use.

Safety and feasibility of in-hospital autonomous transportation using a driverless mobility for patients with musculoskeletal disorders: preliminary clinical study to achieve mobility as a service in medical care.

BACKGROUND: Recent advancements in and the proliferation of autonomous mobility technology, such as intelligent wheelchairs, have made it possible to provide mobility services for patients with reduced mobility due to musculoskeletal disorders. In the present study, we conducted a preliminary clinical study to assess the safety and feasibility of in-hospital autonomous transportation using a driverless mobility (wheelchair) for patients with musculoskeletal disorders. METHODS: From January to February 2022, 51 patients with musculoskeletal disorders exhibiting gait disturbance who presented to our institution were included in the present study. Driverless mobility rides were conducted over a straight-line distance of 100 m from the orthopaedic outpatient reception to the payment counter after the outpatient consultation. We assessed the quality of life using an EQ-5D-5 L index and pain using a VAS score before riding the mobility to investigate the patient's condition. After the ride, a questionnaire survey was conducted to assess patient satisfaction on a 5-point scale. In addition, adverse events during the mobility ride were investigated. RESULTS: Overall satisfaction levels showed that 44 out of 51 (86%) patients rated the level as 3 or higher. There were no significant differences in the level of satisfaction based on the cause of disorders or EQ-5D-5 L Index. Among 19 patients who rated the level of satisfaction as 2-3, the ratio of postoperative patients and those with pain tended to be higher (p < 0.05). While 26 of 51 (51%) patients reported moments of feeling unsafe during the mobility ride, no actual adverse events, such as collisions, were observed. CONCLUSIONS: An in-hospital autonomous transportation service using a driverless mobility for patients with musculoskeletal disorders demonstrated high satisfaction levels and was safe with no severe adverse events observed. The expansion of autonomous mobility deployment is expected to achieve mobility as a service in medical care.

Postoperative management using a digital drainage system for massive air leakage after pulmonary resection.

PURPOSE: To elucidate clinical outcomes using a digital drainage system (DDS) for massive air leakage (MAL) after pulmonary resection. METHODS: A total of 135 consecutive patients with pulmonary resection air leakage of > 100 ml/min on the DDS were evaluated retrospectively. In this study, MAL was defined as ≥ 1000 ml/min on the DDS. We analyzed the clinical characteristics and surgical outcomes of patients with MAL compared with non-MAL (101-999 ml/min). Using the DDS data, the duration of the air leak was plotted with the Kaplan‒Meier method and compared using the log-rank test. RESULTS: MAL was detected in 19 (14%) patients. The proportions of heavy smokers (P = 0.04) and patients with emphysematous lung (P = 0.03) and interstitial lung disease (P < 0.01) were higher in the MAL group than in the non-MAL group. The MAL group had a higher persistence rate of air leakage at 120 h after surgery than the non-MAL group (P < 0.01) and required significantly more frequent pleurodesis (P < 0.01). Drainage failure occurred in 2 (11%) and 5 (4%) patients from the MAL and non-MAL groups, respectively. Neither reoperation nor 30-day surgical mortality was observed in patients with MAL. CONCLUSIONS: MAL was able to be treated conservatively without surgery using the DDS.

Salvage extended surgery after immune-checkpoint inhibitor treatment for advanced non-small cell lung cancer.

PURPOSE: We evaluated the surgical outcomes of salvage extended surgery after definitive medical treatment with an immune-checkpoint inhibitor (ICI) for locally advanced or unresectable non-small-cell lung cancer (NSCLC). METHODS: The subjects of this single-center retrospective analysis were 14 patients who underwent salvage surgery after ICI treatment between May, 2017 and April, 2023 at our institute. We reviewed the comprehensive surgical outcomes, including operative procedures, intraoperative findings, and postoperative morbidities. Overall survival (OS) was calculated using a Kaplan-Meier estimation. RESULTS: The initial clinical stage before medical treatment (c-stage) was stage III in eight patients, stage IV in five patients, and one patient had postoperative lung cancer recurrence. The indications for surgery were as follows: local control for relapse or residual tumor in ten patients and discontinuation of systemic therapy because of treatment-related complications in four patients. The surgical modes were segmentectomy (n = 1), lobectomy (n = 4), bilobectomy (n = 3), pneumonectomy (n = 6), and bronchoplasty (n = 7). Grade 3 or higher postoperative morbidities were observed in six patients, including only one case of 90-day mortality. CONCLUSIONS: Our series demonstrated that the surgical outcome of salvage extended surgery after ICI therapy may be positive with careful selection of the procedure and indication.

Prior coronary stent does not exclude major pulmonary resection regardless of antiplatelet therapy.

PURPOSE: We assessed the safety of general thoracic surgery in patients with prior coronary stents undergoing lung resection, based on differences in perioperative antiplatelet therapy management. METHODS: We retrospectively examined 150 patients with coronary artery stents who underwent pulmonary resection between July 2009 and July 2018. The impact of the antiplatelet agent on thoracic surgery safety was assessed by comparing perioperative outcomes, including major adverse cardiac and cerebrovascular events, among the discontinued antiplatelet therapy (group D), heparin bridging (group H), and continuous antiplatelet therapy (group C) groups. RESULTS: Groups D, H, and C included twenty-four, eighty-four, and forty-two patients, respectively. Second-generation drug-eluting stents were used in > 50% of the patients. No significant differences were found in the estimated blood loss, transfusion rate, or operative duration. Major adverse cardiac and cerebrovascular events occurred in four (2.7%) patients, which was comparable among the groups. In group H, postoperative heart failure and transient ischemic attack with stroke occurred in one patient each. Major bleeding occurred in two (4.7%) patients in group C. CONCLUSIONS: Pulmonary resection surgical outcomes in patients with coronary artery stents were feasible regardless of antiplatelet therapy continuation. However, discontinuing dual-antiplatelet or single-antiplatelet therapy in such patients may be reasonable because this generation of drug-eluting stents has a higher safety profile than bare-metal and first-generation drug-eluting stents.

Preoperative risk-factors for secondary spontaneous pneumothorax surgery in Japan: a nationwide database study.

PURPOSE: We aimed to identify preoperative risk factors for secondary spontaneous pneumothorax surgery. METHODS: The National Clinical Database of Japan, with six annual datasets from 2014 to 2019, was used. All patients who underwent surgery for secondary spontaneous pneumothorax were included, excluding those < 15 years old and those with incomplete data. The effects of preoperative risk factors were analyzed for operative mortality (mortality during hospitalization or within 30 days, regardless of hospitalization status), 30-day mortality, and postoperative respiratory morbidities. RESULTS: Of the 18,309 patients enrolled in the study, operative mortality, 30-day mortality, and postoperative respiratory morbidities were observed in 654 (3.6%), 343 (1.9%), and 2258 (12.3%) patients, respectively. Increasing age, male sex, body mass index < 18.5 or > 30, performance status > 2, emergent surgery, interstitial pneumonia, and diabetes in preoperative co-morbidity, tumors, and other diseases in underlying lung disease were significant risk factors for operative mortality. Those for 30-day mortality included autoimmune disease instead of male sex and diabetes, while those for postoperative respiratory morbidities included lymphangiomyomatosis instead of a body mass index > 30. CONCLUSION: We identified many preoperative risk factors for operative mortality, 30-day mortality, and postoperative respiratory morbidities in secondary spontaneous pneumothorax surgery. These findings will assist in selecting appropriate surgical candidates.

Long-term outcomes of 5-year survivors without recurrence after the complete resection of non-small cell lung cancer after lobectomy: a landmark analysis in consideration of competing risks.

PURPOSE: Among non-small cell lung cancers (NSCLC), 5 years is a benchmark in cancer control and treatment, but a certain percentage of cases recur after 5 years. The long-term post-recurrence outcomes remain controversial. To examine the accurate prognostic factors associated with survival and cancer recurrence among 5-year survivors, a landmark analysis that considered competing risks was performed. METHODS: Complete resection of NSCLC was performed in 2482 patients between January 2003 and December 2015. A total of 1431 patients were 5-year survivors without recurrence. A landmark time analysis was applied to the overall survival (OS) and recurrence-free survival (RFS) from 5 years after surgery, and the findings were calculated using the Kaplan-Meier method. The cumulative incidence of cause-specific death and recurrence was estimated using the cumulative incidence function, while carefully considering the competing risks. RESULTS: Postoperative recurrence was detected in 732 patients, of whom 68 (9.3%) had recurrence after 5 years. The median follow-up period was 8.2 years. In the competing risk analysis, the independent poor prognostic factors associated with cause-specific death were age ≥ 75 years, lymph node metastasis and pleural invasion. CONCLUSIONS: Patients requiring a follow-up for > 5 years were aged ≥ 75 years and had either lymph node metastasis or pleural invasion.

Peer-to-Peer Ultra-Wideband Localization for Hands-Free Control of a Human-Guided Smart Stroller.

We propose a hands-free control system for a human-guided smart stroller. The proposed method uses real-time peer-to-peer localization technology of the human and stroller to realize an intuitive hands-free control system based on the relative position between the human and the stroller. The control method is also based on functional and mechanical safety to ensure the safety of the stroller's occupant (child) and the pilot (parent) during locomotion. In this paper, first, we present a preliminary investigation of the humans' preference for the relative position in the context of hands-free guided strollers. Then, we present the control method and a prototype implemented with an electric wheelchair and UWB sensors for localization. We present an experimental evaluation of the proposed method with 14 persons walking with the developed prototype to investigate the usability and soundness of the proposed method compared to a remote joystick and manual operation. The evaluation experiments were conducted in an indoor environment and revealed that the proposed method matches the performance of joystick control but does not perform as well as manual operation. Notably, for female participants, the proposed method significantly surpasses joystick performance and achieves parity with manual operation, which shows its efficacy and potential for a smart stroller. Also, the results revealed that the proposed method significantly decreased the user's physical load compared to the manual operation. We present discussions on the controllability, usability, task load, and safety features of the proposed method, and conclude this work with a summary assessment.

Molecular Mechanisms Regulating Vascular Endothelial Permeability.

Vascular endothelial cells form a monolayer in the vascular lumen and act as a selective barrier to control the permeability between blood and tissues. To maintain homeostasis, the endothelial barrier function must be strictly integrated. During acute inflammation, vascular permeability temporarily increases, allowing intravascular fluid, cells, and other components to permeate tissues. Moreover, it has been suggested that the dysregulation of endothelial cell permeability may cause several diseases, including edema, cancer, and atherosclerosis. Here, we reviewed the molecular mechanisms by which endothelial cells regulate the barrier function and physiological permeability.

Comparison of the Pre-Established and Finally Selected Treatment Strategies for Endovascular Treatment in Femoropopliteal Artery Lesions.

This study aimed to compare lower limb events associated with preplanned and finally selected treatment strategies-the validity and usefulness of the physician-chosen strategy were verified.We examined the data of 1003 patients in the registry of multicenter endovascular treatment for superficial femoral and popliteal artery disease study and prospectively enrolled patients who underwent endovascular treatment (EVT) of the femoropopliteal (FP) artery between February 2017 and June 2018 from 67 Japanese institutes. The outcome measures were major adverse limb events (MALE) and target vessel revascularization.The EVT strategies were classified into balloon angioplasty-alone (37.3%), primary stenting (26.7%), and provisional stenting (36.0%) groups. In the initial strategy analysis for the balloon angioplasty-alone, primary stenting, and provisional stenting groups, two-year rates of freedom from MALE (95% confidence interval) were 0.680 (0.620-0.732), 0.754 (0.688-0.808), and 0.798 (0.746-0.840), respectively. Additionally, the rate of MALE was significantly higher among patients in the balloon angioplasty-alone group than among those in the primary or provisional stenting groups in the initial strategy analysis (P = 0.007). Changes in treatment strategy were more frequent in the primary stenting group than in the other groups. Furthermore, the rate of MALE did not significantly differ among the three groups in the final strategy analysis (P = 0.56).Limb outcomes for the final applied strategy did not differ among the three strategies. Additionally, the physician's selection bias was mostly appropriate in the EVT of the FP artery.

Clinicopathological features and prognostic impact of dirty necrosis in metastatic lung cancers from the colon and rectum.

Dirty necrosis (DN) is a form of tumor necrosis (TN) with prominent neutrophil infiltration and cell detritus in the necrotic foci. This study aimed to characterize the clinicopathological features of DN in metastatic lung cancers of the colon and rectum (MLCRs). A total of 227 patients who underwent pulmonary metastasectomy and complete resection for MLCR were included in this study. TN was evaluated using digitally scanned resection specimens. These slides were immunostained for biomarkers of NETosis (citrullinated histone H3 [citH3] and myeloperoxidase [MPO]), and the area positive for citH3 and MPO was further quantified. TN was observed in 216 cases (95.2%), and 54 (25.0%) of these cases had DN. The presence of TN was not associated with a worse prognosis; however, patients with DN had a significantly shorter overall survival than those without DN (p < 0.01). Furthermore, the presence of DN was a poor prognostic factor in both the univariate and multivariate analyses. Immunohistochemical analysis revealed that the percentage of citH3-positive and MPO-positive areas in the DN-positive cases was significantly higher than that in the DN-negative cases (p < 0.01 and p < 0.01, respectively). In surgically resected MLCR, DN is the characteristic TN subtype associated with poor prognosis and neutrophil extracellular traps (NETs).

Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial.

BACKGROUND: Lobectomy is the standard of care for early-stage non-small-cell lung cancer (NSCLC). The survival and clinical benefits of segmentectomy have not been investigated in a randomised trial setting. We aimed to investigate if segmentectomy was non-inferior to lobectomy in patients with small-sized peripheral NSCLC. METHODS: We conducted this randomised, controlled, non-inferiority trial at 70 institutions in Japan. Patients with clinical stage IA NSCLC (tumour diameter ≤2 cm; consolidation-to-tumour ratio >0·5) were randomly assigned 1:1 to receive either lobectomy or segmentectomy. Randomisation was done via the minimisation method, with balancing for the institution, histological type, sex, age, and thin-section CT findings. Treatment allocation was not concealed from investigators and patients. The primary endpoint was overall survival for all randomly assigned patients. The secondary endpoints were postoperative respiratory function (6 months and 12 months), relapse-free survival, proportion of local relapse, adverse events, proportion of segmentectomy completion, duration of hospital stay, duration of chest tube placement, duration of surgery, amount of blood loss, and the number of automatic surgical staples used. Overall survival was analysed on an intention-to-treat basis with a non-inferiority margin of 1·54 for the upper limit of the 95% CI of the hazard ratio (HR) and estimated using a stratified Cox regression model. This study is registered with UMIN Clinical Trials Registry, UMIN000002317. FINDINGS: Between Aug, 10, 2009, and Oct 21, 2014, 1106 patients (intention-to-treat population) were enrolled to receive lobectomy (n=554) or segmentectomy (n=552). Patient baseline clinicopathological factors were well balanced between the groups. In the segmentectomy group, 22 patients were switched to lobectomies and one patient received wide wedge resection. At a median follow-up of 7·3 years (range 0·0-10·9), the 5-year overall survival was 94·3% (92·1-96·0) for segmentectomy and 91·1% for lobectomy (95% CI 88·4-93·2); superiority and non-inferiority in overall survival were confirmed using a stratified Cox regression model (HR 0·663; 95% CI 0·474-0·927; one-sided p<0·0001 for non-inferiority; p=0·0082 for superiority). Improved overall survival was observed consistently across all predefined subgroups in the segmentectomy group. At 1 year follow-up, the significant difference in the reduction of median forced expiratory volume in 1 sec between the two groups was 3·5% (p<0·0001), which did not reach the predefined threshold for clinical significance of 10%. The 5-year relapse-free survival was 88·0% (95% CI 85·0-90·4) for segmentectomy and 87·9% (84·8-90·3) for lobectomy (HR 0·998; 95% CI 0·753-1·323; p=0·9889). The proportions of patients with local relapse were 10·5% for segmentectomy and 5·4% for lobectomy (p=0·0018). 52 (63%) of 83 patients and 27 (47%) of 58 patients died of other diseases after lobectomy and segmentectomy, respectively. No 30-day or 90-day mortality was observed. One or more postoperative complications of grade 2 or worse occurred at similar frequencies in both groups (142 [26%] patients who received lobectomy, 148 [27%] who received segmentectomy). INTERPRETATION: To our knowledge, this study was the first phase 3 trial to show the benefits of segmentectomy versus lobectomy in overall survival of patients with small-peripheral NSCLC. The findings suggest that segmentectomy should be the standard surgical procedure for this population of patients. FUNDING: National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.