Comparison of CAR T-cell vs. bispecific antibody as third- or later-line large B-cell lymphoma therapy: A Meta-analysis.

This meta-analysis evaluates the efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We searched MEDLINE, Embase, and Cochrane databases until July 2023 for trials assessing CAR T-cell therapies and CD20×CD3 bispecific antibodies as third- or subsequent-line in R/R DLBCL. Random effects models estimated the complete response (CR) rate and secondary outcomes, with meta-regressions adjusting for relevant covariates. Sixteen studies comprising 1,347 patients were included in the pooled analysis. The pooled CR rate for bispecific antibodies was 0.36 (95% CI, 0.29 to 0.43), compared to 0.51 (0.46 to 0.56) for CAR T-cell therapy (p<0.01). This superiority persisted when comparing the CAR-T naïve patients within the bispecific antibody group, CR rate of 0.37 (0.32 to 0.43). Multivariable meta-regression also revealed better efficacy of CAR-T with adjustment for the proportion of double-hit lymphoma. The pooled one-year progression-free survival rate mirrored these findings (0.32 [0.26 to 0.38] vs 0.44 [0.41 to 0.48], p<0.01). For adverse events of ≥ grade 3, the bispecific antibody had incidences of 0.02 (0.01 to 0.04) for cytokine release syndrome, 0.01 (0.00 to 0.01) for neurotoxicity, and 0.10 (0.03 to 0.16) for infections. The CAR-T cell had rates of 0.08 (0.03 to 0.12), 0.11 (0.06 to 0.17), and 0.17 (0.11 to 0.22), respectively, with significant differences observed in the first two categories. In summary, CAR-T cell therapy outperformed bispecific antibody in achieving higher CR rates, though with an increase in severe adverse events.

Efficacy and safety of biosimilar trastuzumab (CT-P6) in routine clinical practice in the Republic of Korea: a real-world post-marketing surveillance study.

BACKGROUND: The trastuzumab biosimilar CT-P6 is approved for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), metastatic breast cancer (MBC), and metastatic gastric cancer (MGC). The objective of this post-marketing surveillance (PMS) study was to evaluate the real-world safety and effectiveness of CT-P6 in patients with HER2-positive cancers. RESEARCH DESIGN AND METHODS: This open-label, observational, prospective, PMS study collected data via investigator surveys from 35 centers in the Republic of Korea (5 October 2018-4 October 2022). Eligible patients with HER2-positive EBC, MBC, or MGC started CT-P6 treatment during routine clinical practice, followed by 1-year observation. Evaluations included adverse events (AEs), adverse drug reactions (ADRs), and effectiveness. RESULTS: Safety was analyzed in 642 patients (494 EBC, 94 MBC, 54 MGC). Overall, 325 (50.6%) patients experienced 1316 AEs, and 550 ADRs occurred in 199 (31.0%) patients. Unexpected ADRs occurred in 62 (9.7%) patients. Unexpected ADRs and ADRs of special interest did not raise any new safety signals. Among trastuzumab-naïve patients, 34/106 (32.1%) with EBC achieved pathological complete response; 30/74 (40.5%) MBC and 24/49 (49.0%) MGC patients achieved complete or partial response. CONCLUSIONS: In a real-world setting, CT-P6 demonstrated safety and efficacy findings consistent with previous CT-P6 studies.

Non-Metastatic Clear Cell Renal Cell Carcinoma Immune Cell Infiltration Heterogeneity and Prognostic Ability in Patients Following Surgery.

Predicting which patients will progress to metastatic disease after surgery for non-metastatic clear cell renal cell carcinoma (ccRCC) is difficult; however, recent data suggest that tumor immune cell infiltration could be used as a biomarker. We evaluated the quantity and type of immune cells infiltrating ccRCC tumors for associations with metastatic progression following attempted curative surgery. We quantified immune cell densities in the tumor microenvironment and validated our findings in two independent patient cohorts with multi-region sampling to investigate the impact of heterogeneity on prognostic accuracy. For non-metastatic ccRCC, increased CD8+ T cell infiltration was associated with a reduced likelihood of progression to metastatic disease. Interestingly, patients who progressed to metastatic disease also had increased percentages of exhausted CD8+ T cells. Finally, we evaluated the spatial heterogeneity of the immune infiltration and demonstrated that patients without metastatic progression had CD8+ T cells in closer proximity to ccRCC cells. These data strengthen the evidence for CD8+ T cell infiltration as a prognostic biomarker in non-metastatic ccRCC and demonstrate that multi-region sampling may be necessary to fully characterize immune infiltration within heterogeneous tumors. Tumor CD8+ T cell infiltration should be investigated as a biomarker in adjuvant systemic therapy clinical trials for high-risk non-metastatic RCC.

Treatment Patterns and Prognosis of Palliative Chemotherapy Combined With Targeting Agents in Patients With Unresectable Metastatic Colorectal Cancer: CHOICE, A Multicenter Longitudinal Observational Study.

BACKGROUND/AIM: This study investigated the treatment patterns and prognosis of patients with metastatic or unresectable colorectal cancer (mCRC) treated with chemotherapy with targeting agents. PATIENTS AND METHODS: This longitudinal multicenter study included 963 patients with mCRC who were treated in Korea between 2016 and 2020. Treatment patterns and efficacy were compared according to the mutation status and clinical factors. RESULTS: As first-line therapy, most of the patients (83.5%) received FOLFOX plus bevacizumab (35.4%), followed by FOLFIRI plus bevacizumab (18.8%), FOLFIRI plus cetuximab (17.0%), and FOLFOX plus cetuximab (12.3%). Bevacizumab was the most frequent agent (78.8%) combined with chemotherapy in RAS-mutated CRC, while cetuximab (57.2%) in RAS wild-type CRC. Cetuximab was frequently combined with a doublet regimen in patients with left-sided CRC than in those with right-sided CRC (34.4% vs. 16%). As second-line therapy, most patients (63.4%) also received doublet regimens with bevacizumab, and FOLFIRI plus aflibercept was administered in 15.1%. The objective response rate with FOLFIRI plus cetuximab was significantly higher in patients with left-sided CRC than in those with right-sided CRC (59.2% vs. 30.8%, p=0.008) and marginally higher in patients with RAS wild-type CRC than in those with RAS-mutated CRC (55.6% vs. 0.0%, p=0.092). Progression-free survival (PFS) with FOLFOX plus bevacizumab was significantly shorter than that with FOLFIRI plus bevacizumab (p=0.030) in RAS-mutated CRC, whereas there were no significant differences between regimens in RAS wild-type CRC. CONCLUSION: In patients with unresectable metastatic colorectal cancer, doublet chemotherapy with targeting agents is the most common therapy and efficacy depends on the mutation status as well as clinical factors.

Lipocalin-2 Levels, Insulin Resistance, and Urinary Albumin Excretion in Type 2 Diabetes Subgroups.

BACKGROUND: Lipocalin-2 (LCN2) level in type 2 diabetes mellitus (T2DM) subgroups has not been investigated. The aim of this study was to investigate LCN2 levels, insulin resistance, urinary albumin excretion, and inflammation status in T2DM subgroups. METHODS: A total of 251 patients with newly diagnosed T2DM were evaluated. LCN2, glycated hemoglobin (HbA1c), FPG, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) levels were measured. Patients with diabetes were categorized into three subgroups: patients diagnosed with fasting plasma glucose (FPG) alone (FPG-DM), those with isolated hemoglobin A1c (HbA1c) diabetes (A1c-DM), and those who met the criteria for both FPG and HbA1c (FPG/A1c-DM). The albumin-to-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), homeostasis model assessment of insulin resistance (HOMA-IR), and adjusted LCN2 values, such as the LCN2/inflammation index (LCN2/Inf) and LCN2/creatinine (LCN2/ Cr), were calculated. RESULTS: The ACR, HOMA-IR, and glycosuria prevalence were significantly higher in FPG-DM than in A1c-DM. In contrast, no significant difference was observed in LCN2, eGFR, and proinflammatory cytokine levels between the two groups. Patients with FPG/A1c-DM had significantly higher LCN2, TNF-α, IL-6, and hsCRP levels than those with A1c-DM or FPG-DM. The percent difference between LCN2 and LCN2/Inf was 3.2-fold greater than that between LCN2 and LCN2/Cr in FPG/A1c-DM. The presence of FPG-DM led to a 1.8-fold increase in the prevalence of proteinuria (odds ratio, 1.876; 95% CI, 1.014 - 3.295; p < 0.001). The ability of FPG to identify proteinuria outperformed that of HbA1c (area under the curve: 0.629, 95% CI, 0.553 - 0.706 versus 0.522, 95% CI, 0.436 - 0.605, p < 0.001). CONCLUSIONS: LCN2 elevation may be more largely due to inflammation than kidney function, particularly in FPG/A1c-DM. Patients with FPG-DM may be at a greater risk of diabetic nephropathy and insulin resistance than those with A1c-DM.

A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice.

We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12D/+ p53-/- (NP-/-) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergized to establish an NPmut-AML transcriptome distinct from that of NP-/- cells. The NPmut-AML transcriptome showed GATA2 downregulation and elevated the expression of inflammatory genes, including those linked to NF-κB signaling. NF-κB was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEK and NF-κB inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-κB-inhibitory protein IκBα, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.

Lipocalin-2, Soluble Transferrin Receptor, and Erythropoietin in Anemia During Mild Renal Dysfunction.

Background: Mild renal dysfunction (MRD) is a common condition often associated with diabetes or inflammation and regarded as a risk factor for cardiovascular disease in patients with hypertension. Few studies have examined the role of lipocalin-2 (LCN2) as a regulator of iron and a contributor to anemia in MRD. The aim of this study was to investigate the relationship between LCN2, soluble transferrin receptor (sTfR), erythropoietin (EPO), reticulocyte production, and the prevalence of anemia in MRD. Methods: A total of 235 subjects with MRD were evaluated. LCN2, sTfR, EPO, and iron levels were measured. Reticulocyte maturity index (RMI) and corrected LCN2 (cLCN2) values were calculated using reticulocyte subpopulations and the inflammation index, respectively. Results: Subjects with LCN2 elevation had significantly higher sTfR and significantly lower RMI levels than those without LCN2 elevation. Compared to subjects without LCN2 elevation, those with LCN2 elevation exhibited significantly lower hemoglobin (12.9 ± 1.6 g/dL vs 14.0 ± 1.7 g/dL, p < 0.001) and more prevalent anemia (27.7% vs 13.3%, p = 0.008). Patients with anemia had significantly higher LCN2 and cLCN2 than those without anemia. LCN2 was positively correlated with sTfR and negatively correlated with RMI but not EPO. Elevated LCN2 led to a 1.3-fold increase in the prevalence of anemia (odds ratio: 1.302; 95% CI: 1.012-2.527; p < 0.001). Conclusion: LCN2 elevation may contribute to the development of anemia in MRD, particularly in conjunction with restricted iron availability and suppressed reticulocyte production.

Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma.

The successful use of expanded tumor-infiltrating lymphocytes (TIL) in adoptive TIL therapies has been reported, but the effects of the TIL expansion, immunophenotype, function, and T cell receptor (TCR) repertoire of the infused products relative to the tumor microenvironment (TME) are not well understood. In this study, we analyzed the tumor samples (n = 58) from treatment-naïve patients with renal cell carcinoma (RCC), "pre-rapidly expanded" TILs (pre-REP TIL, n = 15) and "rapidly expanded" TILs (REP TIL, n = 25) according to a clinical-grade TIL production protocol, with single-cell RNA (scRNA)+TCRαß-seq (TCRαß sequencing), TCRß-sequencing (TCRß-seq), and flow cytometry. REP TILs encompassed a greater abundance of CD4+ than CD8+ T cells, with increased LAG-3 and low PD-1 expressions in both CD4+ and CD8+ T cell compartments compared with the pre-REP TIL and tumor T cells. The REP protocol preferentially expanded small clones of the CD4+ phenotype (CD4, IL7R, KLRB1) in the TME, indicating that the largest exhausted T cell clones in the tumor do not expand during the expansion protocol. In addition, by generating a catalog of RCC-associated TCR motifs from >1,000 scRNA+TCRαß-seq and TCRß-seq RCC, healthy and other cancer sample cohorts, we quantified the RCC-associated TCRs from the expansion protocol. Unlike the low-remaining amount of anti-viral TCRs throughout the expansion, the quantity of the RCC-associated TCRs was high in the tumors and pre-REP TILs but decreased in the REP TILs. Our results provide an in-depth understanding of the origin, phenotype, and TCR specificity of RCC TIL products, paving the way for a more rationalized production of TILs. Significance: TILs are a heterogenous group of immune cells that recognize and attack the tumor, thus are utilized in various clinical trials. In our study, we explored the TILs in patients with kidney cancer by expanding the TILs using a clinical-grade protocol, as well as observed their characteristics and ability to recognize the tumor using in-depth experimental and computational tools.

Likelihood interval for nonlinear regression.

Wald confidence interval has been used as the conventional method of interval estimation for the parameters in nonlinear models. Because Wald confidence interval is symmetric around the point estimate, it does not reflect the asymmetry of the likelihood profile in nonlinear regression. In contrast, a likelihood interval is estimated directly from the likelihood profile and does reflect the shape of the likelihood profile. However, the lack of software for the estimation of likelihood intervals and visualization of likelihood profiles posed an obstacle to the use of likelihood intervals in nonlinear models. There was a need for software implementation to tackle these tasks. Likelihood interval estimation and likelihood profile plotting for nonlinear models had not been previously implemented in R software. This article describes the implementation of likelihood interval estimation and likelihood profile plotting in the wnl R software package. To demonstrate the usage of implemented functions, an example of fitting a nonlinear pharmacokinetic model to concentration-time data is presented.

Pharmacokinetic Interactions Between Bazedoxifene and Cholecalciferol: An Open-Label, Randomized, Crossover Study in Healthy Male Volunteers.

Purpose: The combined administration of bazedoxifene, a tissue-selective estrogen receptor modulator, and cholecalciferol can be a promising therapeutic option for postmenopausal osteoporosis patients. This study aimed to examine the pharmacokinetic interactions between these two drugs and the tolerability of their combined administration in healthy male subjects. Patients and Methods: Thirty male volunteers were randomly assigned to one of the six sequences comprised of three treatments: bazedoxifene 20 mg monotherapy, cholecalciferol 1600 IU monotherapy, and combined bazedoxifene and cholecalciferol therapy. For each treatment, a single dose of the investigational drug(s) was administered orally, and serial blood samples were collected to measure the plasma concentrations of bazedoxifene and cholecalciferol. Pharmacokinetic parameters were calculated using the non-compartmental method. The point estimate and 90% confidence interval (CI) of the geometric mean ratio (GMR) were obtained to compare the exposures of combined therapy and monotherapy. The pharmacokinetic parameters compared were the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast). The safety and tolerability of the combined therapy were assessed in terms of the frequency and severity of adverse events (AEs). Results: For bazedoxifene, the GMR (90% CI) of the combined therapy to monotherapy was 1.044 (0.9263-1.1765) for Cmax and 1.1329 (1.0232-1.2544) for AUClast. For baseline-adjusted cholecalciferol, the GMR (90% CI) of the combined therapy to monotherapy was 0.8543 (0.8005-0.9117) for Cmax and 0.8056 (0.7445-0.8717) for AUClast. The frequency of AEs observed was not significantly different between the combined therapy and monotherapy, and their severity was mild in all cases. Conclusion: A mild degree of pharmacokinetic interaction was observed when bazedoxifene and cholecalciferol were administered concomitantly to healthy male volunteers. This combined therapy was well tolerated at the dose levels used in the present study.

Eflapegrastim versus Pegfilgrastim for Chemotherapy-Induced Neutropenia in Korean and Asian Patients with Early Breast Cancer: Results from the Two Phase III ADVANCE and RECOVER Studies.

PURPOSE: We investigated the consistent efficacy and safety of eflapegrastim, a novel long-acting granulocyte-colony stimulating factor (G-CSF), in Koreans and Asians compared with the pooled population of two global phase 3 trials. Materials and Methods: Two phase 3 trials (ADVANCE and RECOVER) evaluated the efficacy and safety of fixed-dose eflapegrastim (13.2 mg/0.6 mL [3.6 mg G-CSF equivalent]) compared to pegfilgrastim (6 mg based on G-CSF) in breast cancer patients who received neoadjuvant or adjuvant docetaxel/cyclophosphamide. The primary objective was to demonstrate non-inferiority of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN) in cycle 1, in Korean and Asian subpopulations. RESULTS: Among a total of 643 patients randomized to eflapegrastim (n=314) or pegfilgrastim (n=329), 54 Asians (29 to eflapegrastim and 25 to pegfilgrastim) including 28 Koreans (14 to both eflapegrastim and pegfilgrastim) were enrolled. The primary endpoint, DSN in cycle 1 in the eflapegrastim arm was non-inferior to the pegfilgrastim arm in Koreans and Asians. The DSN difference between the eflapegrastim and pegfilgrastim arms was consistent across populations: -0.120 days (95% confidence interval [CI], -0.227 to -0.016), -0.288 (95% CI, -0.714 to 0.143), and -0.267 (95% CI, -0.697 to 0.110) for pooled population, Koreans and Asians, respectively. There were few treatment-related adverse events that caused discontinuation of eflapegrastim (1.9%) or pegfilgrastim (1.5%) in total and no notable trends or differences across patient populations. CONCLUSION: This study may suggest that eflapegrastim showed non-inferior efficacy and similar safety compared to pegfilgrastim in Koreans and Asians, consistently with those of pooled population.

Single-cell characterization of anti-LAG-3 and anti-PD-1 combination treatment in patients with melanoma.

BackgroundRelatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti-LAG-3+anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown.MethodsWe evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαß-Seq) combined with other multiomics profiling.ResultsThe highest LAG3 expression was noted in NK cells, Tregs, and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. LAG3+ Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained a more cytotoxic and NK-like phenotype.ConclusionAnti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.Trial registrationClinicalTrials.gov (NCT01968109)FundingCancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS.

A Phase II Trial of S-1 and Oxaliplatin in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane (KCSG-BR07-03).

PURPOSE: This single-arm phase II trial investigate the efficacy and safety of S-1 plus oxaliplatin (SOX) in patients with metastatic breast cancer. Materials and Methods: Patients with metastatic breast cancer previously treated with anthracyclines and taxanes were enrolled. Patients received S-1 (40-60 mg depending on patient's body surface area, twice a day, day 1-14) and oxaliplatin (130 mg/m2, day 1) in 3 weeks cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumor 1.1. Secondary endpoints included time-to-progression (TTP), duration-of-response (DoR), overall survival (OS), and adverse events. RESULTS: A total of 87 patients were enrolled from 11 institutions in Korea. Hormone receptor was positive in 54 (62.1%) patients and six (6.9%) had human epidermal growth factor receptor 2-positive disease. Forty-eight patients (85.1%) had visceral metastasis and 74 (55.2%) had more than three sites of metastases. The ORR of SOX regimen was 38.5% (95% confidence interval [CI], 26.9 to 50.0) with a median TTP of 6.0 months (95% CI, 5.1 to 6.9). Median DoR and OS were 10.3 months (95% CI, 5.5 to 15.1) and 19.4 (95% CI, not estimated) months, respectively. Grade 3 or 4 neutropenia was reported in 28 patients (32.1%) and thrombocytopenia was observed in 23 patients (26.6%). CONCLUSION: This phase II study showed that SOX regimen is a reasonable option in metastatic breast cancer previously treated with anthracyclines and taxanes.

Insulin Resistance and Microalbuminuria in Patients with Impaired Fasting Glucose versus Hemoglobin A1c-Defined Prediabetes.

OBJECTIVE: This study investigated differences among patients with impaired fasting glucose (IFG) and hemoglobin A1c (HbA1c)-defined prediabetes (A1c-PDM); we compared insulin resistance and the prevalence of microalbuminuria (MAU) in these individuals. METHODS: A total of 982 patients with newly diagnosed PDM and 455 non-PDM healthy individuals were evaluated. Serum insulin, HbA1c, fasting plasma glucose (FPG), and urine albumin excretion (UAE) levels were measured. The homeostasis model assessment of ß-cell function (HOMA-B) and insulin resistance (HOMA-IR) was calculated. RESULTS: MAU was more prevalent in patients with IFG than in those with A1c-PDM (13.2% versus 6.4%, p=0.003). Patients with MAU had significantly higher FPG than those with normoalbuminuria (99.8 mg/dL versus 97.1 mg/dL, p=0.008). However, there was no significant difference in HbA1c levels between the two groups. Patients with IFG had significantly higher HOMA-IR values than those with A1c-PDM (2.31 versus 2.04, p=0.009). In contrast, there was no significant difference in the HOMA-B between the two groups. After adjusting for potential confounders, UAE was significantly correlated with FPG, but not with HbA1c. An elevated FPG level ≥113 mg/dL led to a 2.1-fold increase in the prevalence of MAU (odds ratio, 2.107; 95% confidence interval, 1.010-4.193; p=0.015). However, an elevated HbA1c level ≥6.1% was not significantly associated with the prevalence of MAU. CONCLUSIONS: Patients with IFG may be at a greater risk of insulin resistance and possible progression to diabetic nephropathy than patients with A1c-PDM.

The SUMO protease SENP1 promotes aggressive behaviors of high HIF2α expressing renal cell carcinoma cells.

While an important role for the SUMO protease SENP1 is recognized in multiple solid cancers, its role in renal cell carcinoma (RCC) pathogenesis, particularly the most dominant subtype, clear cell RCC (ccRCC), is poorly understood. Here we show that a combination of high HIF2α and SENP1 expression in ccRCC samples predicts poor patient survival. Using ccRCC cell models that express high HIF2α but low SENP1, we show that overexpression of SENP1 reduces sumoylation and ubiquitination of HIF2α, increases HIF2α transcriptional activity, and enhances expression of genes associated with cancer cell invasion, stemness and epithelial-mesenchymal transition. Accordingly, ccRCC cells with high HIF2α and SENP1 showed increased invasion and sphere formation in vitro, and local invasion and metastasis in vivo. Finally, SENP1 overexpression caused high HIF2α ccRCC cells to acquire resistance to a clinical mTOR inhibitor, everolimus. These results reveal a combination of high SENP1 and HIF2α expression gives particularly poor prognosis for ccRCC patients and suggest that SENP1 may be an attractive new target for treating metastatic RCC (mRCC).

Implementation of Miettinen-Nurminen score method with or without stratification in R.

Analysis of a 2 × 2 table for clinical data involves computing the point estimate and confidence interval for risk difference, relative risk, or odds ratio. While point estimates of these comparative parameters are uniquely defined, several statistical methods have been proposed to estimate the confidence interval for each parameter. The Miettinen-Nurminen (MN) score method is expected to be used increasingly over traditional interval estimation methods. The MN score method has not been previously implemented in R software for data with stratification. There is a need for a comprehensive software implementation of the MN score method. This article describes the implementation of the MN score method in the sasLM R software package. To demonstrate the usage of the sasLM functions introduced, recently published clinical data are provided as examples.

The tumor and plasma cytokine profiles of renal cell carcinoma patients.

Renal cell carcinoma (RCC) accounts for 90% of all renal cancers and is considered highly immunogenic. Although many studies have reported the circulating peripheral cytokine profiles, the signatures between the tumor tissue and matching healthy adjacent renal tissue counterparts have not been explored. We aimed to comprehensively investigate the cytokine landscape of RCC tumors and its correlation between the amount and phenotype of the tumor infiltrating lymphocytes (TILs). We analyzed the secretion of 42 cytokines from the tumor (n = 46), adjacent healthy kidney tissues (n = 23) and matching plasma samples (n = 33) with a Luminex-based assay. We further explored the differences between the tissue types, as well as correlated the findings with clinical data and detailed immunophenotyping of the TILs. Using an unsupervised clustering approach, we observed distinct differences in the cytokine profiles between the tumor and adjacent renal tissue samples. The tumor samples clustered into three distinct profiles based on the cytokine expressions: high (52.2% of the tumors), intermediate (26.1%), and low (21.7%). Most of the tumor cytokines positively correlated with each other, except for IL-8 that showed no correlation with any of the measured cytokine expressions. Furthermore, the quantity of lymphocytes in the tumor samples analyzed with flow cytometry positively correlated with the chemokine-family of cytokines, CXCL10 (IP-10) and CXCL9 (MIG). No significant correlations were found between the tumor and matching plasma cytokines, suggesting that circulating cytokines poorly mirror the tumor cytokine environment. Our study highlights distinct cytokine profiles in the RCC tumor microenvironment and provides insights to potential biomarkers for the treatment of RCC.

Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia.

BACKGROUND/AIMS: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. RESULTS: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. CONCLUSION: Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Relationship between Neutrophil Gelatinase-Associated Lipocalin, Eosinophil Cationic Protein, Cytokines, and Atopic Sensitization in Patients with Allergic Diseases.

The effect of neutrophil gelatinase-associated lipocalin (NGAL) on eosinophil activation, atopic sensitization, and systemic inflammation in allergic diseases has rarely been investigated. This study aimed to investigate the relationship between NGAL, eosinophil cationic protein (ECP), cytokines, and allergen-specific immunoglobulin E (sIgE) in allergic diseases. A total of 136 patients with allergies and 58 healthy individuals were evaluated. The concentrations of NGAL, ECP, tumor necrosis factor-α (TNF-α), interleukin-5 (IL-5), sIgE, total IgE (tIgE), and high-sensitivity C-reactive protein (hsCRP) were measured. The transforming growth factor-ß1 (TGF-ß1) level was measured as a profibrotic marker of bronchial asthma. Allergic patients had significantly higher NGAL, ECP, and hsCRP levels than healthy individuals. However, there was no significant difference in NGAL levels between patients with positive and negative ECP tests and those with high and low sIgE scores. Asthmatic patients with elevated NGAL exhibited a significantly higher TGF-ß1 level than those without elevated NGAL. However, no significant difference was observed in the ECP, IL-5, and sIgE levels between the two groups. Among the patients with a positive ECP test, subjects with elevated hsCRP had two times higher NGAL levels than those without elevated hsCRP. NGAL was positively correlated with TNF-α, TGF-ß1, and hsCRP, but not with ECP, IL-5, tIgE, and sIgE. An elevated NGAL level led to a 1.3-fold increase in the prevalence of high TGF-ß1 (odds ratio: 1.31; 95% CI: 1.04-2.58; P < 0.001). In conclusion, NGAL elevation may be more closely linked to allergic inflammation and a possible fibrotic change in the airways than to the severity of eosinophil activation and atopic sensitization.

[Corrigendum] Hwang-Heuk-San induces apoptosis in HCT116 human colorectal cancer cells through the ROS-mediated activation of caspases and the inactivation of the PI3K/Akt signaling pathway.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that certain of the data panels featured in Figs. 1B, 4A, 6A and 8A, showing DAPI or NAC staining of the cells, appeared to contain overlapping data. The authors have consulted their original data, and realize that errors were made during the compilation of these figures; consequently, they have repeated the affected experiments. The revised versions of Figs. 1, 4, 6 and 8, featuring replacement data for Figs. 1B, 4A, 6A and 8A, are shown on the subsequent pages. The authors regret the errors that were made during the preparation of the published figures, and confirm that these errors did not affect the conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [the original article was published in Oncology Reports 36: 205­214, 2016; DOI: 10.3892/or.2016.4812].