Effect of IL-2 polymorphism rs2069762 on single-unit cord blood transplant outcomes.

BACKGROUND: Interleukin-2 (IL-2) is one of the most important cytokines that regulate the activation and proliferation of T cells and natural killer cells. The production of IL-2 may be affected by polymorphisms in the promoter region of the IL-2 gene (rs2069762). In allogeneic hematopoietic cell transplantation (HCT) from adult donors, rs2069762 has been associated with the incidence of acute and chronic graft-versus-host disease (GVHD). However, the impacts of IL-2 polymorphism on cord blood transplantation (CBT) outcomes remain unclear. OBJECTIVE: The objective of this study was to assess the impact of IL-2 polymorphism rs2069762 on transplant outcomes, such as hematopoietic recovery, GVHD, overall survival, relapse, and non-relapse mortality (NRM) after CBT. STUDY DESIGN: We conducted a retrospective analysis of data from adult patients who underwent single-unit CBT at our institution from November 2005 to March 2023 for whom DNA samples from recipients and donors were available. IL-2 genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs2069762. RESULTS: A total of 143 recipient and donor pairs were included in this study. The proportion of recipient IL-2 polymorphism rs2069762 was 48 % (n = 69) for AA, 42 % (n = 60) for CA, and 10 % (n = 14) for CC. The proportion of donor IL-2 polymorphism rs2069762 was 43 % (n = 61) for AA, 48 % (n = 69) for CA, and 9 % (n = 13) for CC. In the multivariate analysis, the use of an rs2069762 CA + CC donor was associated with lower neutrophil recovery compared to an rs2069762 AA donor (hazard ratio [HR], 0.66; 95 % confidence interval [CI], 0.50-0.88; P = 0.004). Furthermore, recipients of rs2069762 CA + CC were associated with higher NRM compared to recipients of rs2069762 AA (HR, 2.32; 95 % CI, 1.01-5.34; P = 0.047). Serum IL-2 levels at 8 weeks were significantly higher in rs2069762 CA + CC recipients compared to those with rs2069762 AA recipients (P = 0.014). CONCLUSION: Our data showed that donor IL-2 polymorphism affects neutrophil recovery and recipient IL-2 polymorphism affects NRM in adults undergoing single-unit CBT. The polymorphism of IL-2 rs2069762 in recipients and donors might be associated with the clinical outcomes of single-unit CBT.

Feasibility and safety of the discontinuation of systemic immunosuppressive treatment after single-unit cord blood transplantation in adults.

We retrospectively evaluated the incidence, factors, and clinical outcomes of the discontinuation of immunosuppressive treatment (IST) after single-unit unrelated cord blood transplantation (CBT) in adults receiving cyclosporine-based graft-versus-host disease (GVHD) prophylaxis at our institute. Among the 309 patients who achieved engraftment, 247 were able to discontinue IST with a median follow-up of 121 months for survivors. The cumulative incidence of the discontinuation of IST was 46.2% at 180 days, 72.8% at 2 years, and 79.3% at 5 years post-CBT. In the multivariate analysis, discontinuation of IST after CBT was significantly associated with the requirement for steroid therapy (hazard ratio [HR]: 0.46; P < 0.001) and the recent calendar year of CBT (HR: 1.79; P < 0.001). In the conditional landmark analysis at 180 days, discontinuation of IST was not associated with the development of extensive chronic GVHD (HR: 1.00; P = 0.989), non-relapse mortality (HR: 0.49; P = 0.122), relapse (HR: 1.46; P = 0.388), or overall survival (HR: 1.91; P = 0.065). Our data showed that successful discontinuation of IST is common after single-unit CBT in adults. Discontinuation of IST did not affect subsequent outcomes, suggesting that discontinuation of IST is both feasible and safe in adults undergoing single-unit CBT.

Osimertinib plus local treatment for brain metastases versus osimertinib alone in patients with EGFR-Mutant Non-Small Cell Lung Cancer.

OBJECTIVES: Osimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib. MATERIALS AND METHODS: This multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors. RESULTS: Of the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan-Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR-NR vs. 31.2, 21.7-33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16-0.87) and 0.36 (95 %CI, 0.15-0.87), respectively. CONCLUSIONS: The OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib.

Phosphoproteomic Analysis Identified Mutual Phosphorylation of FAK and Src as a Mechanism of Osimertinib Resistance in EGFR-Mutant Lung Cancer.

Introduction: Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance. Methods: We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3. Results: Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA-mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib. Conclusions: Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.

Giant nanomechanical energy storage capacity in twisted single-walled carbon nanotube ropes.

A sustainable society requires high-energy storage devices characterized by lightness, compactness, a long life and superior safety, surpassing current battery and supercapacitor technologies. Single-walled carbon nanotubes (SWCNTs), which typically exhibit great toughness, have emerged as promising candidates for innovative energy storage solutions. Here we produced SWCNT ropes wrapped in thermoplastic polyurethane elastomers, and demonstrated experimentally that a twisted rope composed of these SWCNTs possesses the remarkable ability to reversibly store nanomechanical energy. Notably, the gravimetric energy density of these twisted ropes reaches up to 2.1 MJ kg-1, exceeding the energy storage capacity of mechanical steel springs by over four orders of magnitude and surpassing advanced lithium-ion batteries by a factor of three. In contrast to chemical and electrochemical energy carriers, the nanomechanical energy stored in a twisted SWCNT rope is safe even in hostile environments. This energy does not deplete over time and is accessible at temperatures ranging from -60 to +100 °C.

Fourth national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from patients with complicated urinary tract infections.

INTRODUCTION: Antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species. MATERIALS AND METHODS: Data were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan. RESULTS: Fluoroquinolone required a minimum inhibitory concentration (MIC) of 2-64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 µg/mL) decreased from 14.7% to 7.7%. DISCUSSION: Bacterial strains that produced extended-spectrum ß-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years.

Challenges in Global Access to CAR-T cells: an Asian Perspective.

The use of cell therapy for clinical applications has seen a dramatic increase in recent years, primarily in oncology, especially with the use of chimeric antigen receptor (CAR) T-cell therapies. However, there are some barriers to the widespread adoption of CAR-T cell therapies globally, primarily because of the high cost of manufacturing these cells and clinical infrastructure considerations. We reviewed the different strategies adopted across Asia to implement CAR-T cell therapy and found that these included patient assistance programs, close engagement with funders, cost-effectiveness studies, on-site manufacturing of CAR-T cells, and joint ventures between local partners and foreign pharmaceutical companies. Although on-site manufacturing can reduce the cost of genetic engineering and expansion, it does not address many other hidden costs and quality considerations. Future growth in large-scale regional manufacturing, facilitated by cutting-edge science and innovation, could reduce costs through economies of scale and facilitate the eagerly needed global access.

Multi-institutional study of osimertinib dose-optimization in non-small cell lung cancer patients with EGFR activating mutation aged 70 years or older ('MONEY' trial).

Osimertinib is the standard of care for patients with epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer. Dose-toxicity has been previously reported, but no dose-response data within the range of 20-240 mg daily (mg/d). Thus, the current 80 mg/d dosing might be too high for elderly Japanese patients with an average body weight of only 50 kg, resulting in excessive toxicity and cost. We therefore initiated a study to investigate whether osimertinib at 40 mg/d is non-inferior to 80 mg/d in patients with advanced or recurrent epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer aged ≥70 years, using a regression discontinuity design. Osimertinib is administered at 40 mg/d for body weight ≤50 kg, and 80 mg/d for body weight >50 kg. The primary endpoint is progression-free survival. Sample size is 550 patients, based on a non-inferiority margin of the progression-free survival hazard ratio 1.333, 0.10 one-sided type I error and 80% power.

Development of the external carotid artery system including the middle temporal artery after direct-indirect revascularization surgery for moyamoya disease.

BACKGROUND: The aim of this study was to clarify when and from which blood vessels indirect revascularization develops after combined revascularization surgery for moyamoya disease and how the donor vessels that undergo direct revascularization change in the medium to long term. In particular, we focused on the middle temporal artery (MTA), which has not received much attention in indirect revascularization surgery for moyamoya disease until now. METHODS: We targeted 20 sides that were suitable for evaluating the diameter of the external carotid artery system involved in combined revascularization surgery among moyamoya disease patients who underwent a composite revascularization procedure utilizing a 'U'-shaped skin incision encircling the parietal branch of the superficial temporal artery (STA) at our institution from 2018 to 2023. We identified the STA parietal branch, MMA, DTA, and MTA in the TOF source MR images acquired preoperatively and three and six months after surgery; measured the long and short diameters of each blood vessel; approximated the blood vessel shape as an ellipse, and calculated its cross-sectional area. RESULTS: The cross-sectional areas of the MMA, DTA, and MTA involved in indirect revascularization significantly increased compared to presurgery three months after surgery, and this trend continued six months after surgery, but no significant change was observed between three and six months after surgery. There were no cases in which the MTA was clearly confirmed before surgery in the TOF reconstructed images, but the MTA was clearly confirmed in 55% (11/20 cases) of hemispheres three months after surgery and in 85% (17/20 cases) of hemispheres six months after surgery. The crosssectional area of the STA parietal branch, which was the donor for direct revascularization, had increased by more than 150% compared to before surgery in 55% (11/20 cases) of hemispheres three months after surgery. CONCLUSIONS: Indirect revascularization can be expected three months after combined revascularization surgery for moyamoya disease. The MTA, which has not received much attention in terms of indirect revascularization for moyamoya disease patients thus far, was found to be a useful blood flow source for indirect revascularization in combined revascularization surgery for patients with moyamoya disease. Whether or not the cross-sectional area of the superficial temporal artery used as a donor for direct revascularization increased in the medium to long term varied on a case-by-case basis.

Corrigendum: Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 complex as a serum biomarker for COVID-19.

[This corrects the article DOI: 10.3389/fimmu.2023.1299792.].

Gut microbiota and metabolites in patients with COVID-19 are altered by the type of SARS-CoV-2 variant.

Introduction: Patients with COVID-19 have dysbiosis of the intestinal microbiota with altered metabolites in the stool. However, it remains unclear whether the differences among SARS-CoV-2 variants lead to differences in intestinal microbiota and metabolites. Thus, we compared the microbiome and metabolome changes for each SARS-CoV-2 variant in patients with COVID-19. Materials and methods: We conducted a multicenter observational study of patients with COVID-19 and performed fecal microbiome, metabolome, and calprotectin analyses and compared the results among the different SARS-CoV-2 variants. Results: Twenty-one patients with COVID-19 were enrolled and stratified according to the SARS-CoV-2 strain: six with the Alpha, 10 with the Delta, and five with the Omicron variant. Fecal microbiome analysis showed that α-diversity was reduced in the order of the Omicron, Delta, and Alpha variants (p = 0.07). Linear discriminant analysis revealed differences in the abundance of short-chain fatty acid-producing gut microbiota for each SARS-CoV-2 variant. Fecal metabolome analysis showed that the Omicron and Delta variants had markedly reduced propionic and lactic acid levels compared to the Alpha strain (p < 0.05). Conclusion: The intestinal microbiota of patients with COVID-19 varies depending on the SARS-CoV-2 variant. Dysbiosis of the intestinal microbiota due to differences in SARS-CoV-2 variants causes a decrease in intestinal short-chain fatty acids.

Advances in cancer DNA methylation analysis with methPLIER: use of non-negative matrix factorization and knowledge-based constraints to enhance biological interpretability.

DNA methylation is an epigenetic modification that results in dynamic changes during ontogenesis and cell differentiation. DNA methylation patterns regulate gene expression and have been widely researched. While tools for DNA methylation analysis have been developed, most of them have focused on intergroup comparative analysis within a dataset; therefore, it is difficult to conduct cross-dataset studies, such as rare disease studies or cross-institutional studies. This study describes a novel method for DNA methylation analysis, namely, methPLIER, which enables interdataset comparative analyses. methPLIER combines Pathway Level Information Extractor (PLIER), which is a non-negative matrix factorization (NMF) method, with regularization by a knowledge matrix and transfer learning. methPLIER can be used to perform intersample and interdataset comparative analysis based on latent feature matrices, which are obtained via matrix factorization of large-scale data, and factor-loading matrices, which are obtained through matrix factorization of the data to be analyzed. We used methPLIER to analyze a lung cancer dataset and confirmed that the data decomposition reflected sample characteristics for recurrence-free survival. Moreover, methPLIER can analyze data obtained via different preprocessing methods, thereby reducing distributional bias among datasets due to preprocessing. Furthermore, methPLIER can be employed for comparative analyses of methylation data obtained from different platforms, thereby reducing bias in data distribution due to platform differences. methPLIER is expected to facilitate cross-sectional DNA methylation data analysis and enhance DNA methylation data resources.

Application of ethanol alleviates heat damage to leaf growth and yield in tomato.

Chemical priming has emerged as a promising area in agricultural research. Our previous studies have demonstrated that pretreatment with a low concentration of ethanol enhances abiotic stress tolerance in Arabidopsis and cassava. Here, we show that ethanol treatment induces heat stress tolerance in tomato (Solanum lycopersicon L.) plants. Seedlings of the tomato cultivar 'Micro-Tom' were pretreated with ethanol solution and then subjected to heat stress. The survival rates of the ethanol-pretreated plants were significantly higher than those of the water-treated control plants. Similarly, the fruit numbers of the ethanol-pretreated plants were greater than those of the water-treated ones. Transcriptome analysis identified sets of genes that were differentially expressed in shoots and roots of seedlings and in mature green fruits of ethanol-pretreated plants compared with those in water-treated plants. Gene ontology analysis using these genes showed that stress-related gene ontology terms were found in the set of ethanol-induced genes. Metabolome analysis revealed that the contents of a wide range of metabolites differed between water- and ethanol-treated samples. They included sugars such as trehalose, sucrose, glucose, and fructose. From our results, we speculate that ethanol-induced heat stress tolerance in tomato is mainly the result of increased expression of stress-related genes encoding late embryogenesis abundant (LEA) proteins, reactive oxygen species (ROS) elimination enzymes, and activated gluconeogenesis. Our results will be useful for establishing ethanol-based chemical priming technology to reduce heat stress damage in crops, especially in Solanaceae.

Successful Treatment With Venetoclax Plus Azacytidine Combined With Radiation Therapy and Donor Lymphocyte Infusion in a Patient With Extramedullary Relapse of Acute Myeloid Leukemia After Stem Cell Transplantation.

Extramedullary (EM) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) is rare and causes systemic relapse. Consequently, the prognosis is very poor because limited treatment is feasible in post-transplant patients. The efficacy and safety of venetoclax (VEN), a newly developed oral inhibitor of B-cell leukemia/lymphoma-2, plus azacytidine (AZA) in patients newly diagnosed with AML who are ineligible for intensive chemotherapy have been reported. We report a case in which VEN + AZA salvage treatment following radiation therapy and donor lymphocyte infusion afforded promising results in a patient with AML who showed post-allo-HSCT EM relapse.

Region-specific DNA hydroxymethylation along the malignant progression of IDH-mutant gliomas.

The majority of low-grade isocitrate dehydrogenase-mutant (IDHmt) gliomas undergo malignant progression (MP), but their underlying mechanism remains unclear. IDHmt gliomas exhibit global DNA methylation, and our previous report suggested that MP could be partly attributed to passive demethylation caused by accelerated cell cycles. However, during MP, there is also active demethylation mediated by ten-eleven translocation, such as DNA hydroxymethylation. Hydroxymethylation is reported to potentially contribute to gene expression regulation, but its role in MP remains under investigation. Therefore, we conducted a comprehensive analysis of hydroxymethylation during MP of IDHmt astrocytoma. Five primary/malignantly progressed IDHmt astrocytoma pairs were analyzed with oxidative bisulfite and the Infinium EPIC methylation array, detecting 5-hydroxymethyl cytosine at over 850,000 locations for region-specific hydroxymethylation assessment. Notably, we observed significant sharing of hydroxymethylated genomic regions during MP across the samples. Hydroxymethylated CpGs were enriched in open sea and intergenic regions (p < 0.001), and genes undergoing hydroxymethylation were significantly associated with cancer-related signaling pathways. RNA sequencing data integration identified 91 genes with significant positive/negative hydroxymethylation-expression correlations. Functional analysis suggested that positively correlated genes are involved in cell-cycle promotion, while negatively correlated ones are associated with antineoplastic functions. Analyses of The Cancer Genome Atlas clinical data on glioma were in line with these findings. Motif-enrichment analysis suggested the potential involvement of the transcription factor KLF4 in hydroxymethylation-based gene regulation. Our findings shed light on the significance of region-specific DNA hydroxymethylation in glioma MP and suggest its potential role in cancer-related gene expression and IDHmt glioma malignancy.

Machine Learning Prediction Model for Neutrophil Recovery after Unrelated Cord Blood Transplantation.

Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. A predictive model for neutrophil recovery after single-unit CBT was developed by using a machine learning method, which can handle large and complex datasets, allowing for the analysis of massive amounts of information to uncover patterns and make accurate predictions. Japanese registry data, the largest real-world dataset of CBT, was selected as the data source. Ninety-eight variables with observed values for >80% of the subjects known at the time of CBT were selected. Model building was performed with a competing risk regression model with lasso penalty. Prediction accuracy of the models was evaluated by calculating the area under the receiver operating characteristic curve (AUC) using a test dataset. The primary outcome was neutrophil recovery at day (D) 28, with recovery at D14 and D42 analyzed as secondary outcomes. The final cord blood engraftment prediction (CBEP) models included 2991 single-unit CBT recipients with acute leukemia. The median AUC of a D28-CBEP lasso regression model run 100 times was .74, and those for D14 and D42 were .88 and .68, respectively. The predictivity of the D28-CBEP model was higher than that of 4 different legacy models constructed separately. A highly predictive model for neutrophil recovery by 28 days after CBT was constructed using machine learning techniques; however, identification of significant risk factors was insufficient for outcome prediction for an individual patient, which is necessary for improving therapeutic outcomes. Notably, the prediction accuracy for post-transplantation D14, D28, and D42 decreased, and the model became more complex with more associated factors with increased time after transplantation.

Updated comparable efficacy of cord blood transplantation for chronic myelomonocytic leukaemia: a nationwide study.

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.

Development of an umbilical cord blood transplantation-specific nonrelapse mortality risk assessment score.

ABSTRACT: Higher rate of nonrelapse mortality (NRM) remains yet to be resolved in umbilical cord blood transplantation (UCBT). Considering that UCBT has some unique features compared with allogeneic hematopoietic cell transplantation from other graft sources, a UCBT-specific NRM risk assessment system is required. Thus, in this study, we sought to develop a UCBT-specific NRM Risk Assessment (CoBRA) score. Using a nationwide registry database, we retrospectively analyzed 4437 recipients who had received their first single-unit UCBT. Using the backward elimination method, we constructed the CoBRA score in a training cohort (n = 2687), which consisted of recipients age ≥55 years (score 2), hematopoietic cell transplantation-specific comorbidity index ≥3 (score 2), male recipient, graft-versus-host disease prophylaxis other than tacrolimus in combination with methotrexate, performance status (PS) 2 to 4, HLA allele mismatch ≥ 2, refined Disease Risk Index high risk, myeloablative conditioning, and CD34+ cell doses < 0.82 × 105/kg (score 1 in each). The recipients were categorized into 3 groups: low (0-4 points), intermediate (5-7 points), and high (8-11 points) groups according to the CoBRA score. In the validation cohort (n = 1750), the cumulative incidence of NRM at 2 years was 14.9%, 25.5%, and 47.1% (P < .001), and 2-year overall survival (OS) was 74.2%, 52.7%, and 26.3% (P < .001) in the low, intermediate, and high groups, respectively. In summary, the CoBRA score could predict the NRM risk as well as OS after UCBT. Further external validation will be needed to confirm the significance of the CoBRA score.

Association between pathological infiltrative tumor growth pattern and prognosis in patients with resected lung squamous cell carcinoma.

INTRODUCTION: Lung squamous cell carcinoma (LUSC) usually shows expansive growth with large tumor nests; few reports on invasive growth patterns (INF) in LUSC have been associated with poor prognosis in gastrointestinal and urothelial cancers. In this study, we examine the association between INF and the prognosis of LUSC. MATERIALS AND METHODS: We analyzed INF as a potential prognostic factor in 254 consecutive patients with LUSC who underwent complete surgical resection at our hospital between 2008 and 2017. INF was classified into 3 categories based on the structure of the tumor other than the large round solid nest of tumor cells. RESULTS: INF was categorized as INFa in 59 patients (23 %) with only well-demarcated large solid tumor cell nests, INFb in 89 patients (35 %) with medium to small, alongside large solid nests, and INFc in 98 patients (39 %) with cord-like/small nests or isolated cells plus large or medium solid nests. No significant lymph node metastasis differences were observed between INFc and INFa/b tumors. However, in patients with p-stage I, INFc had a poorer prognosis with regard to recurrence-free survival (RFS), with a 5-year RFS rate of 53.3 %, compared to 74.9 % for INFa/b (p = 0.010). CONCLUSION: Our study highlights a novel pathological concept of INF in LUSC, and contributed to the proposal that it is a factor indicating an unfavorable prognosis in patients with early-stage LUSC. A prospective multicenter study is warranted for INFc patients, as careful follow-up and adjuvant chemotherapy might lead to the early detection and prevention of recurrence.