Broadening Eligibility Criteria and Diversity among Patients for Cancer Clinical Trials.

BACKGROUND: Certain populations have been historically underrepresented in clinical trials. Broadening eligibility criteria is one approach to inclusive clinical research and achieving enrollment goals. How broadened trial eligibility criteria affect the diversity of eligible participants is unknown. METHODS: Using a nationwide electronic health record-derived deidentified database, we identified a retrospective cohort of patients diagnosed with 22 cancer types between April 1, 2013 and December 31, 2022 who received systemic therapy (N=235,234) for cancer. We evaluated strict versus broadened eligibility criteria using performance status and liver, kidney, and hematologic function around first line of therapy. We performed logistic regression to estimate odds ratios for exclusion by strict criteria and their association with measures of patient diversity, including sex, age, race or ethnicity, and area-level socioeconomic status (SES); estimated the impact of broadening criteria on the number and distribution of eligible patients; and performed Cox regression to estimate hazard ratios for real-world overall survival (rwOS) comparing patients meeting strict versus broadened criteria. RESULTS: When applying common strict cutoffs for eligibility criteria to patients with complete data and weighting each cancer type equally, 48% of patients were eligible for clinical trials. Female (odds ratio, 1.30; 95% confidence interval [CI], 1.25 to 1.35), older (age 75+ vs. 18 to 49 years old: odds ratio, 3.04; 95% CI, 2.85 to 3.24), Latinx (odds ratio, 1.46; 95% CI, 1.39 to 1.54), non-Latinx Black (odds ratio, 1.11; 95% CI, 1.06 to 1.16), and lower-SES patients were more likely to be excluded using strict eligibility criteria. Broadening criteria increased the number of eligible patients by 78%, with the strongest impact for older, female, non-Latinx Black, and lower-SES patients. Patients who met only broadened criteria had worse rwOS versus those with strict criteria (hazard ratio, 1.31; 95% CI, 1.27 to 1.34). CONCLUSIONS: Data-driven evaluation of clinical trial eligibility criteria may optimize the eligibility of certain historically underrepresented groups and promote access to more inclusive trials. (Sponsored by Flatiron Health.).

Response- and Progression-Based End Points in Trial and Observational Cohorts of Patients With NSCLC.

Importance: Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making. Objective: To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC. Exposure: All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed. Main Outcomes and Measures: End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR. Results: A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment. Conclusions and Relevance: In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.

Bleeder's Femur: The Proximal Femoral Morphology in Hemophilic Patients Who Underwent Total Hip Arthroplasty.

INTRODUCTION: Patients with hemophilia (PWH) constantly suffer hemarthrosis, which leads to deformity of the hip joint. Therefore, PWH who are going to receive total hip arthroplasty (THA) should be exclusively treated before the surgery with careful measurement of their proximal femur. Hence, we conducted a retrospective study to explore the anatomical parameters of and differences in the proximal femur in hemophilic patients who underwent THA. METHODS: The retrospective study comprised data of adult patients who received total hip arthroplasty from 2020 to 2022 in the research center. Patients having a diagnosis of hemophilic arthritis and received THA were included in experimental group, and patients with hip arthritis or femoral head necrosis were taken as control group. Parameters including femoral offset, neck-shaft angle (NSA), medullary cavity of 20 mm above mid-lesser trochanter level (T+20), mid-lesser trochanter level (T), and 20 mm blow it (T-20), and canal flare index (CFI), femoral cortical index (FCI) were measured on X-ray and CT images with PACS by two independent doctors. Data was analyzed by SPSS 20. Kolmogorov-Smirnov test was used to test data normality. Student's t-test was performed between PWH and control group. p < 0.05 was considered statistically significant. RESULTS: Among the 94 hips, 39 (41.5%) were included in group hemophilia and 55(58.5%) in control group. The mean age of the patients was 49.36 ± 12.92 years. All cases were male patients. Data demonstrated significantly smaller femoral cortical index (FCI), femoral offset, medullary cavity of 20 mm above mid-lesser trochanter level, mid-lesser trochanter level, and 20 mm below it, and neck-shaft angle (NSA) was obviously larger in PWH than control group (p < 0.05). No significant difference was found in canal flare index (CFI). CONCLUSION: Hemophilic patients undergoing THA were prone to longer and thinner proximal femur. Preoperative morphological analysis of femur is recommended.

Structural insights into branch site proofreading by human spliceosome.

Selection of the pre-mRNA branch site (BS) by the U2 small nuclear ribonucleoprotein (snRNP) is crucial to prespliceosome (A complex) assembly. The RNA helicase PRP5 proofreads BS selection but the underlying mechanism remains unclear. Here we report the atomic structures of two sequential complexes leading to prespliceosome assembly: human 17S U2 snRNP and a cross-exon pre-A complex. PRP5 is anchored on 17S U2 snRNP mainly through occupation of the RNA path of SF3B1 by an acidic loop of PRP5; the helicase domain of PRP5 associates with U2 snRNA; the BS-interacting stem-loop (BSL) of U2 snRNA is shielded by TAT-SF1, unable to engage the BS. In the pre-A complex, an initial U2-BS duplex is formed; the translocated helicase domain of PRP5 stays with U2 snRNA and the acidic loop still occupies the RNA path. The pre-A conformation is specifically stabilized by the splicing factors SF1, DNAJC8 and SF3A2. Cancer-derived mutations in SF3B1 damage its association with PRP5, compromising BS proofreading. Together, these findings reveal key insights into prespliceosome assembly and BS selection or proofreading by PRP5.

Facile fabrication of hydrophilic covalent organic framework composites for highly selective enrichment of N-glycopeptides.

The development of facilely synthetic materials acts an essential role in glycoproteome analysis, especially for the highly efficient enrichment of N-linked glycopeptides. In this work, a facile and timesaving route was introduced in which COFTP-TAPT served as a carrier and poly (ethylenimine) (PEI) and carrageenan (Carr) were successively coated on the surface via electrostatic interaction. The resultant COFTP-TAPT@PEI@Carr showed remarkable performance in glycopeptide enrichment with high sensitivity (2 fmol µL-1), high selectivity (1:800, molar ratio of human serum IgG to BSA digests), large loading capacity (300 mg g-1), satisfactory recovery (102.4 ± 6.0%) and reusability (at least eight times). Due to the brilliant hydrophilicity and electrostatic interactions between COFTP-TAPT@PEI@Carr and positively charged glycopeptides, the prepared materials could be applied in the identification and analysis in the human plasma of healthy subjects and patients with nasopharyngeal carcinoma. As a result, 113 N-glycopeptides with 141 glycosylation sites corresponding to 59 proteins and 144 N-glycopeptides with 177 glycosylation sites corresponding to 67 proteins were enriched from 2 µL plasma trypsin digests of the control groups and patients with nasopharyngeal carcinoma, respectively. 22 glycopeptides were identified only from the normal controls and 53 glycopeptides were detected only from the other set. The results demonstrated that this hydrophilic material was promising on a large scale and further N-glycoproteome research.

LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia.

BACKGROUND: Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins (e.g., interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome. METHODS: First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2, were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting. RESULTS: Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2, prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice. CONCLUSIONS: Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia.

A rare lymphoplasmacyte-rich meningioma involving the dura of the skull base and cervical spinal cord: A case report.

Lymphoplasmacyte-rich meningioma (LPRM) is a rare subtype of meningioma, the specific pathogenesis of which remains unclear. Herein, we report the case of a 48-year-old Asian man who experienced progressive deafness and limb weakness. Magnetic resonance imaging revealed extramedullary masses diffusely growing, wrapping, and compressing the cervical spinal cord. The dural lesion was partially excised by surgery, and postoperative pathological examination confirmed the diagnosis of LPRM. Diffuse LPRM is extremely rare, and its treatment is challenging owing to difficulties associated with surgery and the uncertain efficacy of traditional therapies. Therefore, further clinical practice and basic research are needed to improve the prognosis of diffuse LPRM.

GARP-mediated active TGF-ß1 induces bone marrow NK cell dysfunction in AML patients with early relapse post-allo-HSCT.

Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow-derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor ß1 (TGF-ß1) were associated with impaired effector function of BMNK cells in these AML patients. TGF-ß1 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-ß1 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-ß1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-ß1 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-ß1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell-based immunotherapy.

Opportunistic osteoporosis screening using chest CT with artificial intelligence.

Osteoporosis has a high incidence and a low detection rate. If it is not detected in time, it will cause osteoporotic fracture and other serious consequences. This study showed that the attenuation values of vertebrae on chest CT could be used for opportunistic screening of osteoporosis. This will be beneficial to improve the detection rate of osteoporosis and reduce the incidence of adverse events caused by osteoporosis. INTRODUCTION: To explore the value of the attenuation values of all thoracic vertebrae and the first lumbar vertebra measured by artificial intelligence on non-enhanced chest CT to do osteoporosis screening. METHODS: On base of images of chest CT, using artificial intelligence (AI) to measure the attenuation values (HU) of all thoracic and the first vertebrae of patients who underwent CT examination for lung cancer screening and dual-energy X-ray absorptiometry (DXA) examination during the same period. The patients were divided into three groups: normal group, osteopenia group, and osteoporosis group according to the results of DXA. Clinical baseline data and attenuation values were compared among the three groups. The correlation between attenuation values and BMD values was analyzed, and the predictive ability and diagnostic efficacy of attenuation values of thoracic and first lumbar vertebrae on osteopenia or osteoporosis risk were further evaluated. RESULTS: CT values of each thoracic vertebrae and the first lumbar vertebrae decreased with age, especially in menopausal women and presented high predictive ability and diagnostic efficacy for osteopenia or osteoporosis. After clinical data correction, with every 10 HU increase of CT values, the risk of osteopenia or osteoporosis decreased by 32 ~ 44% and 61 ~ 80%, respectively. And the combined diagnostic efficacy of all thoracic vertebrae was higher than that of a single vertebra. The AUC of recognizing osteopenia or osteoporosis from normal group was 0.831and 0.972, respectively. CONCLUSIONS: The routine chest CT with AI is of great value in opportunistic screening for osteopenia or osteoporosis, which can quickly screen the population at high risk of osteoporosis without increasing radiation dose, thus reducing the incidence of osteoporotic fracture.

Identification of a pyroptosis-related prognosis gene signature and its relationship with an immune microenvironment in gliomas.

BACKGROUND: Glioma is the most common type of primary brain cancer, and the prognosis of most patients with glioma is poor. Pyroptosis is a newly discovered inflammatory programmed cell death. However, the expression of pyroptosis-related genes (PRGs) in glioma and its correlation with prognosis are unclear. METHODS: 27 pyroptosis genes differentially expressed between glioma and adjacent normal tissues were identified. All glioma cases could be stratified into 2 subtypes based on these differentially expressed PRGs. The prognostic value of each PRG was evaluated to construct a prognostic model. RESULTS: A novel 16-gene signature was constructed by using the least absolute shrinkage and selection operator Cox regression method. Then, patients with glioma were divided into low- and high-risk groups in the TCGA cohort. The survival rate of patients in the low-risk group was significantly higher than that in the high-risk group (P = .001). Patients with glioma from the Gene Expression Omnibus (GEO) cohort were stratified into 2 risk groups by using the median risk score. The overall survival (OS) of the low-risk group was longer than that of the high-risk group (P = .001). The risk score was considered an independent prognostic factor of the OS of patients with glioma. Gene ontology and Kyoto Encylopedia of Genes and Genomes analysis showed that the differentially expressed PRGs were mainly related to neutrophil activation involved in immune responses, focal adhesion, cell cycle, and p53 signaling pathway. CONCLUSION: PRGs could predict the prognosis of glioma and play significant roles in a tumor immune microenvironment.

Profilin 1 Induces Tumor Metastasis by Promoting Microvesicle Secretion Through the ROCK 1/p-MLC Pathway in Non-Small Cell Lung Cancer.

Profilin 1 (PFN1), an actin-binding protein, plays contrasting roles in the metastasis of several cancers; however, its role in non-small cell lung cancer (NSCLC) metastasis remains unclear. Here, PFN1 expression was upregulated in metastatic NSCLC tissues. PFN1 overexpression significantly promotes NSCLC metastasis in vitro and in vivo. Proteomics analysis revealed PFN1 involvment in microvesicles (MVs) secretion. In vitro experiments confirmed that PFN1 overexpression increased secretion of MVs. MVs are important mediators of metastasis. Here, we show an increased abundance of MVs in the sera of patients with metastatic NSCLC compared to that in the sera of patients with non-metastatic NSCLC. Both in vitro and in vivo experiments revealed that PFN1 could increase MV secretion, and MVs derived from PFN1-overexpressing cells markedly promoted NSCLC metastasis. We then elucidated the mechanisms underlying PFN1-mediated regulation of MVs and found that PFN1 could interact with ROCK1 and enhance its kinase activity to promote myosin light chain (MLC) phosphorylation for MV secretion. Inhibition of ROCK1 decreased MV secretion and partially reversed the PFN1-induced promotion of NSCLC metastasis. Collectively, these findings show that PFN1 regulates MV secretion to promote NSCLC metastasis. PFN1 and MVs represent potential predictors or therapeutic targets for NSCLC metastasis.

Estrogen receptor beta promotes endometriosis progression by upregulating CD47 expression in ectopic endometrial stromal cells.

Endometriosis is a common estrogen-dependent gynecological disorder that is characterized by endometrial-like tissue being found at extrauterine sites. Aberrant expression and activation of estrogen receptor beta (ERß) in ectopic endometrium are involved in endometriosis development. Here, we used primary tissues and cells from endometriosis patients to investigate the molecular mechanisms involved in ERß's contribution to endometriosis progression. Through RNA-seq, quantitative PCR, and immunohistochemistry analysis, we found that ERß expression is related to the severity of endometriosis; specifically, the ratio of ESR2/ESR1 in ectopic tissues was positively correlated with the severity of endometriosis, which suggests that ERß has a predominant role in endometriosis progression. Furthermore, we found that ERß could bind to the CD47 promoter, increasing CD47 expression levels. CD47 is a critical molecule in "don't eat me" signaling. These data highlight the importance of the ERß-CD47 axis in the pathogenesis of endometriosis. We believe targeting CD47 may be a novel therapeutic approach for treating endometriosis and other ERß-associated diseases.

LncRNA DLGAP1-AS2 promotes the radioresistance of rectal cancer stem cells by upregulating CD151 expression via E2F1.

BACKGROUND: Radiotherapy resistance is one of the major causes of rectal cancer treatment failure. LncRNA DLGAP1-AS2 participates in the progression of several cancers. We explored the role and potential mechanism of DLGAP1-AS2 in the radioresistance of rectal cancer stem cells. METHODS: HR8348-R cells, radioresistant cells from HR8348 after irradiation, were isolated into CD133 negative (CD133-) and positive (CD133+) cells. Cell proliferation, apoptosis, migration and tumorsphere formation were determined by CCK-8, flow cytometry, wound healing assay and tumorsphere formation assay, respectively. CD133, tumor stem cell drug resistance gene (MDR1 and BCRP1), DNA repair marker (γ-H2AX) and AKT/mTOR/cyclinD1 signaling were measured by Western blot. The relationship between DLGAP1-AS2 and E2F1 was verified using RIP. The interaction between E2F1 and CD151 promoter was confirmed using dual-luciferase reporter gene assay and ChIP. AKT inhibitor API-2 was employed for validating the effect of AKT/mTOR/cyclinD1 signaling in the radioresistance of rectal cancer cells. RESULTS: The DLGAP1-AS2 level was increased in CD133+ cells after irradiation. DLGAP1-AS2 knockdown inhibited the proliferation, migration and tumorsphere formation while stimulating apoptosis in CD133+ cells. DLGAP1-AS2 inhibition downregulated the expression of CD133, MDR1, BCRP1 and γ-H2AX and suppressed AKT/mTOR/cyclinD1 activation. DLGAP1-AS2 upregulated the expression of CD151 by interacting with E2F1. API-2 neutralized the promotive effects of overexpressed CD151 on radioresistance. CONCLUSION: DLGAP1-AS2 accelerates the radioresistance of rectal cancer cells through interactions with E2F1 to upregulate CD151 expression via the activation of the AKT/mTOR/cyclinD1 pathway.

Genome-wide map of N6-methyladenosine circular RNAs identified in mice model of severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) is a deadly inflammatory disease with complex pathogenesis and lack of effective therapeutic options. N6-methyladenosine (m6A) modification of circRNAs plays important roles in physiological and pathological processes. However, the roles of m6A circRNA in the pathological process of SAP remains unknown. AIM: To identify transcriptome-wide map of m6A circRNAs and to determine their biological significance and potential mechanisms in SAP. METHODS: The SAP in C57BL/6 mice was induced using 4% sodium taurocholate salt. The transcriptome-wide map of m6A circRNAs was identified by m6A-modified RNA immunoprecipitation sequencing. The biological significance of circRNAs with differentially expressed m6A peaks was evaluated through gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The underlying mechanism of m6A circRNAs in SAP was analyzed by constructing of m6A circRNA-microRNA networks. The expression of demethylases was determined by quantitative polymerase chain reaction and western blot to deduce the possible mechanism of reversible m6A process in SAP. RESULTS: Fifty-seven circRNAs with differentially expressed m6A peaks were identified by m6A-modified RNA immunoprecipitation sequencing, of which 32 were upregulated and 25 downregulated. Functional analysis of these m6A circRNAs in SAP found some important pathways involved in the pathogenesis of SAP, such as regulation of autophagy and protein digestion. In m6A circRNA-miRNA networks, several important miRNAs participated in the occurrence and progression of SAP were found to bind to these m6A circRNAs, such as miR-24-3p, miR-26a, miR-92b, miR-216b, miR-324-5p and miR-762. Notably, the total m6A level of circRNAs was reduced, while the demethylase alkylation repair homolog 5 was upregulated in SAP. CONCLUSION: m6A modification of circRNAs may be involved in the pathogenesis of SAP. Our findings may provide novel insights to explore the possible pathogenetic mechanism of SAP and seek new potential therapeutic targets for SAP.

Profilin 1 Protein and Its Implications for Cancers.

Profilin 1 (PFN1) is a ubiquitous small-molecule protein that exists in all eukaryotes. PFN1 was first identified as a G-actin sequestering molecule, and subsequently, its true functions in actin polymerization and F-actin dynamics were revealed. In the following decades, the structure of PFN1 was recognized to have 3 domains: an actin-binding domain, a poly-L-proline (PLP)-binding domain, and a phosphoinositide-binding domain. PFN1 plays a vital role in many cell functions, including membrane trafficking, endocytosis, cell cycle, motility, proliferation, cell survival, transcription, stemness, and autophagy (Figure 1). Abnormal expression or deletion of PFN1 can affect the normal physiological activity of cells and lead to disease development. PFN1 has been deeply studied in a variety of diseases, some genetic (eg, amyotrophic lateral sclerosis) and some chronic (eg, hypertension). In the past 10 years, PFN1's role in cancer has received increasing attention. In this review, we summarize the studies of PFN1 in cancer that have been completed in recent years, discuss the roles of PFN1 in cancer, and discuss the implications for tumor diagnosis and therapy in the future.

Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm.

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms.

Doxorubicin and CD­CUR inclusion complex co­loaded in thermosensitive hydrogel PLGA­PEG­PLGA localized administration for osteosarcoma.

Combination therapy is a promising and prevalent strategy for osteosarcoma treatment. Curcumin (CUR), as a chemosensitizer, improves the antitumor effect of first­line chemotherapy drugs. However, due to its poor solubility and instability in physiological conditions, the bioavailability of CUR is limited. In order to improve the physicochemical properties of natural CUR, ß­cyclodextrin was adopted to generate a ß­cyclodextrin curcumin (CD­CUR) inclusion complex. A thermosensitive hydrogel, poly(D,L­lactide­co­glycolide)-poly(ethylene­glycol)­poly(D,L­lactide­co­glycolide), was selected and synthesized to co­deliver doxorubicin (DOX) and CD­CUR to tumor sites. The dual­drug delivery system (gel+DOX+CD­CUR) was prepared by mixing drugs with hydrogels and had a perfect sol­gel phase transition temperature (18.3˚C for 20% concentration). Both DOX and CUR were released from hydrogels in a sustained manner in PBS (pH 7.4) medium. The combination therapy based on DOX+CD­CUR exhibited higher antitumor activity than monotherapies in vitro. Combined CD­CUR therapy significantly downregulated Bcl­2 expression and upregulated caspase­3 expression, suggesting that DOX combined with CD­CUR treatment has a higher apoptosis­inducing efficiency. The antitumor efficiency of the gel+DOX+CD­CUR strategy was evaluated in K­7 tumor­bearing mice, and this localized combination therapy demonstrated a higher antitumor efficiency compared with free DOX+CD­CUR or single­drug strategies. There were no significant differences in body weight and histological changes of major organs in each group. Therefore, the present combination treatment based on hydrogel may be a feasible approach to co­deliver DOX and CD­CUR to osteosarcoma tumor sites in clinical practice.

Indirect Treatment Comparison of Nivolumab Versus Observation or Ipilimumab as Adjuvant Therapy in Resected Melanoma Using Pooled Clinical Trial Data.

INTRODUCTION: Nivolumab has been approved in patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting. A pivotal trial compared nivolumab with ipilimumab; however, no head-to-head trial exists comparing nivolumab to observation, a common comparator in the adjuvant setting. Here, we compared the efficacy and cost-effectiveness of nivolumab with observation or ipilimumab as adjuvant therapies in resected stage IIIB/C melanoma. METHODS: Patient data were pooled from the EORTC 18071 and CheckMate 238 trials using propensity score weighting and adjusting for cross-trial differences. Number needed to treat (NNT) and costs per recurrence-free life-month (RFLM) at 12, 16, 18, and 24 months (as data allowed) were estimated. Costs included drug acquisition, administration costs, and direct medical costs. Sensitivity analyses including patients with stage IIIB/C and resected stage IV melanoma were conducted. RESULTS: A total of 1287 patients (278 nivolumab, 365 observation, and 644 ipilimumab) with resected stage IIIB/C melanoma were pooled. NNTs to achieve one additional recurrence-free survivor with nivolumab versus observation were 3.93 at 12 months and 3.42 at 24 months; NNTs for nivolumab versus ipilimumab were 7.97 at 12 months and 6.43 at 24 months. Mean drug costs per RFLM were lower for nivolumab at 12, 18, and 24 months, respectively (nivolumab: $13,447, $9462, and $7370; ipilimumab: $52,734, $40,484, and $33,875). Mean medical costs per RFLM were the lowest for nivolumab versus observation or ipilimumab at 12 months ($449 versus $674 or $1531) and 16 months ($383 versus $808 or $1316). The sensitivity analysis results were consistent with the base case. CONCLUSION: For resected melanoma, adjuvant nivolumab is both clinically effective and cost-effective compared with observation or ipilimumab. Adjuvant nivolumab was associated with a lower drug cost per RFLM compared with ipilimumab, and a lower medical cost compared with observation. Future analyses incorporating long-term follow-up data may help increase understanding of the economic impact of nivolumab in the adjuvant setting. FUNDING: Bristol-Myers Squibb Company.

Economic Burden of Switching to Different Biologic Therapies Among Tumor Necrosis Factor Inhibitor-Experienced Patients with Psoriatic Arthritis.

INTRODUCTION: Patients with psoriatic arthritis (PsA) who receive an initial tumor necrosis factor inhibitor (TNFi) may switch to another TNFi or a non-TNFi biologic therapy. This study compared the healthcare resource use (HRU), expenditures, and time to discontinuation among TNFi-experienced patients with PsA who switched to different biologic therapies in the United States (US). METHODS: Adults with PsA who discontinued an initial TNFi (adalimumab, etanercept, infliximab, golimumab, or certolizumab pegol) and switched to another TNFi or a non-TNFi (ustekinumab or secukinumab) were identified in the Symphony Health Solutions database [Quarter (Q)1 2010-Q2 2017]. Eligible patients had claims data activity for ≥ 12 months before (baseline) and after (study period) the switching date. All-cause HRU, costs (2017 US dollars), and time to discontinuation during the study period were compared between patients switching to another TNFi vs. a non-TNFi (index drug). Multivariable regression models adjusted for baseline covariates (index year, age, sex, initial TNFi, comorbidities, baseline HRU, and PsA-related treatment history). RESULTS: Of 2107 patients switching to another TNFi and 253 switching to a non-TNFi, adalimumab and etanercept were the most common initial TNFi in both cohorts. During the study period, patients switching to another TNFi had significantly fewer dermatologists visits (0.43; p < 0.01) but more rheumatologist visits (1.56, p < 0.01) than patients switching to a non-TNFi. Patients switching to another TNFi vs. a non-TNFi incurred significantly lower total average healthcare expenditures (adjusted difference: $17,625; p < 0.01), driven by lower prescription drug (adjusted difference: $17,172; p < 0.01) and hospitalization expenditures (adjusted difference: $5772; p = 0.04). Patients who switched to another TNFi vs. a non-TNFi continued on their index therapy significantly longer (median time to discontinuation: 8.31 vs. 5.68 months; log-rank p < 0.01). CONCLUSIONS: Patients with PsA who switched to another TNFi had lower total healthcare expenditures and longer persistence compared with patients who switched to a non-TNFi biologic. FUNDING: AbbVie.

High NEK2 confers to poor prognosis and contributes to cisplatin-based chemotherapy resistance in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in southern China and Southeast Asia, but the molecular mechanism of its pathogenesis is poorly understood. Our previous work demonstrated that NEK2 is overexpressed in multiple cancers. However, how NEK2 involves in NPC development remains to be elucidated. In this study, we firstly identified NEK2, located at +1q32-q33, a late event in NPC pathogenesis, overexpressed in the stage III-IV and paired sequential recurrent patients with NPC by immunohistochemistry. Furthermore, Kaplan-Meier analysis indicated high NEK2 conferred an inferior overall survival in NPC. In addition, cisplatin experiments with cell counting kit-8, colony formation, and a xenograft mice model of NPC demonstrated that NEK2 contributed to proliferation and cisplatin resistance in vitro and in vivo. On the contrary, downregulation of NEK2 by short hairpin RNA inhibited NPC cell growth and increased the sensitivity of cisplatin treatment in vitro. Thus, increased expression of NEK2 protein could not be predicted for poor survival but used as a novel biomarker for recurrence of NPC. Targeting NEK2 has the potential to eradicate the cisplatin-based chemotherapy resistant NPC cells.