A novel role of acellular hemoglobin in hemolytic thrombosis.

BACKGROUND: Hemolytic thrombosis has been associated with acellular hemoglobin released from damaged red blood cells during hemolysis. However, the precise molecular mechanism underlying acellular hemoglobin-induced thrombosis remains arguable. In this study, we examined the interaction between hemoglobin and the A1 domain of von Willebrand factor (VWF), which is a critical mediator of platelet activation. METHODS: Previous studies have suggested that the interaction between hemoglobin and the A1 domain of VWF enhances VWF's hemostatic activity. We employed a multidisciplinary investigation to re-examine this interaction, and identified significant differences in binding affinity between the active and inactive forms of A1. RESULTS: We found that hemoglobin binds more strongly to the active A1 than the inactive form. Using hydrogen­deuterium exchange mass spectrometry, we identified the specific residues involved in this interaction, which are located on the α1-ß2 and ß3-α2 loops that are typically covered by the "autoinhibitory module" in the inactive A1. This observation provides a structural explanation for the differential binding affinity between the active and inactive forms of A1. We demonstrated that the binding of hemoglobin to A1 blocks the interaction between GPIbα and VWF, and inhibits VWF-mediated thrombosis in vivo. Furthermore, we found that administration of hemoglobin led to similar levels of thrombocytopenia and microthrombosis in both wildtype and VWF-deficient mice, indicating that the mechanism underlying acellular hemoglobin-induced thrombosis is VWF-independent. CONCLUSIONS: These findings challenge the previous theory that hemoglobin-induced thrombosis occurs solely through binding with VWF, and provide evidence supporting a novel role for hemoglobin in hemolytic thrombosis.

Identification and functional analysis of non-coding regulatory small RNA FenSr3 in Bacillus amyloliquefaciens LPB-18.

Bacillus amyloliquefaciens is an interesting microbe in the food processing and manufacturing industries. Non-coding small RNAs (sRNAs) have been shown to play a crucial role in the physiology and metabolism of bacteria by post-transcriptionally regulating gene expression. This study investigated the function of novel sRNA FenSr3 by constructing fenSr3 deficient strain and complementary strains in B. amyloliquefaciens LPB-18 , which were named LPN-18N and LPB-18P, respectively. The result showed significant differences in fengycin yield between strain LPB -18N and LPB-18P. The production of fengycin was significantly enhanced in B. amyloliquefaciens LPB-18N, compared with that of the strain LPB-18 from 190.908 mg/L to 327.598 mg/L. Moreover, the production of fengycin decreased from 190.464 mg/L to 38.6 mg/L in B . amyloliquefaciens LPB-18P. A comparative transcriptome sequencing was carried out to better understand the complex regulatory mechanism. Transcription analysis revealed that 1037 genes were differentially expressed between B. amyloliquefaciens LPB-18 and B. amyloliquefaciens LPB-18N, including the key regulatory genes in fatty acid, amino acid biosynthesis, and central carbon metabolism, which could provide sufficient quantities of building precursors for fengycin biosynthesis. The biofilm formation and sporulation was also enhanced in the strain LPB-18N, which indicates that FenSr3 could play a vital role in stress resistance and promotes survival in B. amyloliquefaciens. Some sRNAs involved in stress response have been identified in the literature, but their regulatory roles in fengycin production remain unclear. The study will contribute a novel perspective to the regulation mechanism of biosynthesis and the optimization of key metabolites of B. amyloliquefaciens.

Sovleplenib (HMPL-523), a novel Syk inhibitor, for patients with primary immune thrombocytopenia in China: a randomised, double-blind, placebo-controlled, phase 1b/2 study.

BACKGROUND: Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia. METHODS: This randomised, double-blind, placebo-controlled, phase 1b/2 study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 × 109 platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT03951623. FINDINGS: Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40·0 years (IQR 33·0-50·0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded. INTERPRETATION: Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3 trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia. FUNDING: HUTCHMED.

Immune Co-inhibitory Receptors CTLA-4, PD-1, TIGIT, LAG-3, and TIM-3 in Upper Tract Urothelial Carcinomas: A Large Cohort Study.

Programmed cell death 1 ligand 1), programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3, lymphocyte activation gene-3, and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in upper tract urothelial carcinoma (UTUC). The aim of this Cohort Study was to provide evidence concerning expression profiles and the clinical significance of CIRs among Chinese UTUC patients. A total of 175 UTUC patients who received radical surgery in our center were included. We used immunohistochemistry to evaluate CIR expressions in tissue microarrays (TMAs). Clinicopathological characteristics and prognostic correlations of CIR proteins were retrospectively analyzed. TIGIT, T-cell immunoglobulin and mucin-domain containing-3, PD-1, CTLA-4, Programmed cell death 1 ligand 1, and lymphocyte activation gene-3 high expression was examined in 136(77.7%), 86(49.1%), 57(32.6%), 18(10.3%), 28(16.0%), and 18(10.3%) patients, respectively. Log-rank tests and Multivariate Cox analysis both implied CTLA-4 and TIGIT expression was associated with worse relapse-free survival. In conclusion, this is the largest Chinese UTUC cohort study, and we analyzed the Co-inhibitory receptor expression profiles in UTUC. We identified CTLA-4 and TIGIT expression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced UTUCs are probably immunogenic, for which single or combined immunotherapy may be potential therapeutic approaches in the future.

Efficacy and safety of LY01005 versus goserelin implant in Chinese patients with prostate cancer: A multicenter, randomized, open-label, phase III, non-inferiority trial.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04563936.

Inherited mutations in Chinese patients with upper tract urothelial carcinoma.

Upper tract urothelial carcinoma (UTUC) accounts for 10% of urothelial carcinomas (UCs) and has a substantial hereditary component. However, the majority of our knowledge of germline spectrum comes from bladder cancer (BCa) data in White populations. Here, we sequence 309 Chinese UTUC cases and identify 71 germline pathogenic/likely pathogenic (P/LP) mutations in 62 patients (20.1%). Compared with White cases, we observe disparities and similarities in inherited mutational profiles. Association analysis reveals that germline P/LP mutations in MSH2, BRCA2, BRCA1, and BRIP1 significantly increase UTUC risk in Chinese populations. Furthermore, germline P/LP mutation in homologous recombination genes indicates poor prognosis for non-metastatic UTUC. Finally, we perform paired sequencing and observe significant correlations between germline mutation patterns and tumor subtypes. This study highlights the importance of genetic testing in patients with UTUC and calls for germline data from various ethnicities to better understand this disease.

The expression and prognostic value of transporter 1, ATP binding cassette subfamily B member in clear cell renal cell cancer with experimental validation.

Transporter associated with antigen processing 1(TAP1) serves as a protein to transport antigenic peptides from the surface of the endoplasmic reticulum to the lumen of the endoplasmic reticulum when the antigens are presented by major histocompatibility complex type I (MHC-I), which has been identified to play a critical role in antigen presentation in innate immunity. In tumors, the role of TAP1 seems to remain controversial. On the one hand, given the role of TAP1 in antigen presentation, it is indicated that high TAP1 expression corresponds to the emergence of more neoantigens epitopes that facilitate the recognition for phagocytes, T cells and other cells. On the other hand, the genetic ablation of transporter associated with antigen processing (TAP) results in the presentation of new class I-restricted epitopes encoded in house-keeping products. Opposite result has been revealed by studies in other tumors suggest, which implies a more complex function of TAP1. Therefore, it's significant to clarify the role of TAP1 in clear cell renal cell carcinoma (ccRCC). In this study, we found the elevated expression levels in mRNA and protein of TAP1 in ccRCC tissues, which indicated a relatively worse prognosis. Transwell assay and Scratch assay in vitro demonstrated the promotive role of TAP1 in ccRCC migration as well as a significant role in metastasis. And the increased expression of TAP1 resulted in more immune cells infiltrated in cancer tissues. TAP1 was also demonstrated to be related to immune regulator genes, as gene set enrichment analysis (GSEA) indicated its significant role in immune regulation. The results of CancerSEA indicated the positive association of the high-level TAP1 expression with epithelial-mesenchymal transition (EMT) and the inverse association with Cell Cycle. The effective drugs were also predicted based on TAP1 expression, of which the high level was indeed associated with resistance to multiple drugs, but some effective drugs still identified based on high TAP1 expression. According to the analysis of various databases, the role of TAP1 in ccRCC was explored, especially in relationship of TAP1 with tumor microenvironment. These results indicate that TAP1 can serve as a potential target for treatment of ccRCC.

Clinicopathological characteristics and loss of mismatch repair protein expression in Chinese upper tract urothelial carcinomas.

Expression of DNA mismatch repair (MMR) protein (MLH1, PMS2, MSH2, and MSH6) in upper tract urothelial carcinoma (UTUC) has been explored in Western cohorts, but it is rarely reported in Eastern cohorts. We aimed to assess the loss of MMR protein expression among Chinese UTUC patients and study its clinicopathological implications. We enrolled 175 UTUC patients at our center and tested the expression of MMR proteins by immunohistochemistry. Then, we explored these patients' clinicopathological characteristics. We found loss of MMR proteins in 19 (10.9%) of 175 patients in our cohort (6 MSH2 and MSH6, 2 MSH6 alone, 6 MSH2 alone, 3 MLH1 and PMS2, and 2 PMS2 alone). Loss of MMR proteins was not a significant prognostic factor of relapse-free survival for these patients. In addition, patients with lower T stage or with bladder cancer history were more likely to have loss of MMR protein expression. At last, two metastatic patients (MSH2 and MSH6 loss; MSH2 loss) with loss of MMR protein experienced tumor recession after several cycles of anti-PD-1 immunotherapy. In conclusion, this is the largest Chinese UTUC cohort study to date that explores the loss of MMR protein expression. The rate of MMR loss observed was comparable to that in the Western UTUC cohort, supporting universal UTUC screening in China. Furthermore, a subset of advanced UTUCs with MMR protein loss are probably immunogenic, for whom single or combined immunotherapy may be potential therapeutic options in the future.

Application of Internet-based multidisciplinary management in patients with genitourinary cancers in China: A brief introduction to a new model of healthcare service for cancer survivors during COVID-19 pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has triggered multiple global healthcare system crises. Apart from the pandemic itself, the travel restriction and social distance policy for the purpose of epidemic control has cast a shadow on the management of cancer survivors. Cancer survivors suffered a double blow from both the epidemic and cancer. To deal with the challenge, we explored a new Internet-based patient management model. This model has overcome the limitation of time and space and thus can help oncologists to provide remote multidisciplinary healthcare services for cancer survivors. These patients can get high-quality cancer management from multidisciplinary experts without too much transportation. This model has been applied in patients with genitourinary cancers and proved to be effective and efficient. Our study demonstrated that more patients benefited from this model during the pandemic of COVID-19, especially in those affected heavily by COVID-19. These results suggested that it can also give insight into the management of other cancer survivors in China. Given the long-term impact of the COVID-19 pandemic, we would like to introduce our new model of healthcare service and the application of Internet-based multidisciplinary management to our global peers and medical industries to help their cancer survivors who are delayed in treatment due to the COVID-19 pandemic.

Avatrombopag for the treatment of thrombocytopenia post hematopoietic stem-cell transplantation.

Background: Thrombocytopenia post hematopoietic stem-cell transplantation (HCT) usually contributes to poor outcomes with no standardized treatment. Eltrombopag and romiplostim can be feasible for post-HCT thrombocytopenia, but the use of avatrombopag has not yet been evaluated. Objectives: We aimed to evaluate the efficacy and safety of avatrombopag treatment in patients diagnosed with post-HCT thrombocytopenia. Design: In this retrospective study, we evaluated the efficacy and safety of avatrombopag treatment in a cohort of 61 patients diagnosed with thrombocytopenia post HCT in our clinical center. Methods: Avatrombopag was initiated at 20 mg daily, with a dosage adjustment to achieve platelet recovery to >20 × 109/l independent from transfusion for 7 consecutive days (overall response, OR) or to >50 × 109/l free from transfusion for 7 consecutive days (complete response, CR). Factors influencing OR and CR were studied in univariate and multivariate analyses, respectively. Within the follow-up, adverse events like myelofibrosis, thrombosis, and organ toxicities were monitored carefully. Results: The overall response rate (ORR) to avatrombopag was 68.9% and the cumulative incidence (CI) of OR was 69.1%. The complete response rate (CRR) and the CI of CR were both 39.3%. The median days from avatrombopag initiation to OR and CR were 21 and 25 days, respectively. An adequate number of megakaryocytes before the initiation of avatrombopag was an independent protective factor of avatrombopag treatment for OR (hazard ratio, HR = 4.628, 95% confidence interval 1.92-11.15, p = 0.0006) and CR (HR = 4.892, 95% confidence interval 1.58-15.18, p = 0.006). Avatrombopag was well tolerated in all patients with no severe adverse events. Conclusion: Our findings suggested that avatrombopag can be optional for thrombocytopenia post HCT.

Long-term outcomes of cryoablation for biopsy-proven T1 stage renal cell carcinoma.

BACKGROUND: To summarize our clinical experience of cryoablation in renal cell carcinoma (RCC) of Chinese population and to evaluate the long-term outcomes of laparoendoscopic single-site (LESS) cryoablation (LCA) as well as percutaneous CT-guided cryoablation (PCA) for biopsy-proven T1a and T1b RCC. METHODS: This was a multi-center, retrospective study investigating T1 stage RCC patients from 2011 to 2021. The patients were treated by LCA or PCA according to individual situation. Overall survival (OS), cancer-related survival (CSS), and progression-free survival (PFS) were evaluated for oncological outcomes, and kidney function, complications, and hospital stay were used to estimate technical outcomes. RESULTS: A total of 163 consecutive patients were included. Among them, 59 cases were treated by LCA and PCA was performed in 104 cases. All operations were processed successfully. Mean diameter of the mass was (2.9±1.4) cm; median blood volume was 45ml (10~200 ml). The mean operation time was 84.0 ± 24.5 min. The median postoperative hospital stay was 3 days (1~6 days). Compared with LCA, procedure time of PCA was shortened, the volume of bleeding was reduced, and the hospital stay was decreased. The overall adverse events rate was 9.8% (16/163). The mean preoperative and postoperative eGFR of LCA were 77.6±15.3 ml/min and 75.6±17.4 ml/min, respectively. Analogously, the values of PCA were 78.7±12.9 ml/min and 76.7±14.3 ml/min. Mean follow-up time was 64.2 ± 30.2 months (range, 7-127 months). Local recurrence was observed in 13 patients (8.0%), 4 (6.8%) cases of LCA and 9 (8.7%) cases of PCA. PFS at 5 and 10 years were 95.5% and 69.2% for LCA and 96.7% and 62.8% for PCA. In total, 26 patients (16.0%) (11 patients from LCA and 15 from PCA) died throughout the follow-up period. OS at 5 and 10 years were 93.8% and 31.4% for LCA, and 97.4% and 52.7% for PCA. Six patients (3.7%) (3 cases from LCA and 3 from PCA) died of metastatic RCC. CCS for LCA were 98.0% and 82.8% at 5 and 10 years, while the data were 100% and 86.4% for PCA. CONCLUSION: LCA and PCA for T1 stage RCC provides satisfactory long-term oncological and renal function preservation outcomes, with acceptable complication rates.

The novel transcriptomic signature of angiogenesis predicts clinical outcome, tumor microenvironment and treatment response for prostate adenocarcinoma.

Angiogenesis plays the critical roles in promoting tumor progression, aggressiveness, and metastasis. Although few studies have revealed some angiogenesis-related genes (ARGs) could serve as prognosis-related biomarkers for the prostate cancer (PCa), the integrated role of ARGs has not been systematically studied. The RNA-sequencing data and clinical information of prostate adenocarcinoma (PRAD) were downloaded from The Cancer Genome Atlas (TCGA) as discovery dataset. Twenty-three ARGs in total were identified to be correlated with prognosis of PRAD by the univariate Cox regression analysis, and a 19-ARG signature was further developed with significant correlation with the disease-free survival (DFS) of PRAD by the least absolute shrinkage and selection operator (LASSO) Cox regression with tenfold cross-validation. The signature stratified PRAD patients into high- and low-ARGs signature score groups, and those with high ARGs signature score were associated with significantly poorer outcomes (median DFS: 62.71 months vs unreached, p < 0.0001). The predicting ability of ARGs signature was subsequently validated in two independent cohorts of GSE40272 & PRAD_MSKCC. Notably, the 19-ARG signature outperformed the typical clinical features or each involved ARG in predicting the DFS of PRAD. Furthermore, a prognostic nomogram was constructed with three independent prognostic factors, including the ARGs signature, T stage and Gleason score. The predicted results from the nomogram (C-index = 0.799, 95%CI = 0.744-0.854) matched well with the observed outcomes, which was verified by the calibration curves. The values of area under receiver operating characteristic curve (AUC) for DFS at 1-, 3-, 5-year for the nomogram were 0.82, 0.83, and 0.83, respectively, indicating the performance of nomogram model is of reasonably high accuracy and robustness. Moreover, functional enrichment analysis demonstrated the potential targets of E2F targets, G2M checkpoint pathways, and cell cycle pathways to suppress the PRAD progression. Of note, the high-risk PRAD patients were more sensitive to immune therapies, but Treg might hinder benefits from immunotherapies. Additionally, this established tool also could predict response to neoadjuvant androgen deprivation therapy (ADT) and some chemotherapy drugs, such as cisplatin, paclitaxel, and docetaxel, etc. The novel ARGs signature, with prognostic significance, can further promote the application of targeted therapies in different stratifications of PCa patients.

Transcriptome Analysis of Bacillus amyloliquefaciens Reveals Fructose Addition Effects on Fengycin Synthesis.

Fengycin is a lipopeptide produced by Bacillus that has a strong inhibitory effect on filamentous fungi; however, its use is restricted due to poor production and low yield. Previous studies have shown that fengycin biosynthesis in B. amyloliquefaciens was found to be significantly increased after fructose addition. This study investigated the effect of fructose on fengycin production and its regulation mechanism in B. amyloliquefaciens by transcriptome sequencing. According to the RNA sequencing data, 458 genes were upregulated and 879 genes were downregulated. Transcriptome analysis results showed that fructose changed the transcription of amino acid synthesis, fatty acid metabolism, and energy metabolism; alterations in these metabolic pathways contribute to the synthesis of fengycin. In an MLF medium (modified Landy medium with fructose), the expression level of the fengycin operon was two-times higher than in an ML medium (modified Landy medium). After fructose was added to B. amyloliquefaciens, the fengycin-synthesis-associated genes were activated in the process of fengycin synthesis.

Prognostic value of dynamic cardiac biomarkers in patients with acquired refractory thrombocytopenic purpura: A retrospective study in Chinese population.

INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is becoming a curable disease with the introduction of therapeutic plasma exchange (TPE). However, cardiovascular complications remain essential causes of mortality in patients with refractory TTP, while the association of cardiac biomarkers with the prognosis of TTP warrants further investigation. METHODS: Patients admitted to the First Affiliated Hospital of Soochow University for refractory TTP from 2013 through 2020 were included in this retrospective study. Clinical characteristics were collected from electronic health records. Biomarker levels on admission and post TPE were recorded. Logistic regression was adopted to identify risk factors for mortality. RESULTS: A total of 78 patients with refractory TTP were included in this study. Twenty-one patients died during hospitalization, with a mortality rate of 26.9%. High-sensitivity cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ratios (AAR) were increased in deceased patients compared with the survival group. Multivariate analysis showed that AAR after TPE was associated with overall mortality (OR: 4.45, 95% CI 1.09-18.19). The areas under the receiver operator characteristic curve (AUC) of AAR, hs-cTnT, and NT-proBNP for the association with mortality were 0.814, 0.840, and 0.829, respectively. CONCLUSION: Higher post-TPE cardiac biomarker levels are associated with increased in-hospital mortality in patients with refractory TTP.

Successful treatment of acquired amegakaryocytic thrombocytopenia with eltrombopag and immunosuppressant.

Acquired amegakaryocytic thrombocypenia (AAMT) is an extremely rare hematologic disorder and standard treatment strategy has not been established. We described herein two cases of AAMT who were fully responded to eltrombopag and immunosuppressant. Patient 1 was refractory to steroid, IVIG and recombinant human thrombopoietin (rhTPO). Patient 2 did not respond to high dosage of steroid, IVIG, rhTPO and rituximab. Moreover, his AAMT progressed to aplastic anemia in 5 months. Both patients took eltrombopag and immunosuppressant, then they achieved long-term remission without obvious side effects. Our findings suggest that this combination can be a valuable alternative in AAMT.

Prostate Cancer Screening Using Prostate-Specific Antigen Tests in a High-Risk Population in China: A Cost-Utility Analysis.

BACKGROUND: Both National Comprehensive Cancer Network and Chinese guidelines recommend beginning prostate-specific antigen (PSA) screening for men aged 50 years or 45 years with a family history because they were at a higher risk of developing prostate cancer. Several model-based economic evaluations of PSA screening studies have been conducted, but with little evidence from China. OBJECTIVE: The aim of this study was to conduct an economic evaluation of the cost-utility of PSA-based prostate cancer screening in Chinese men. METHODS: We developed a decision-tree and Markov model in Excel (Microsoft Corp, Redmond, Washington) to compare 2 strategies that can be used to detect prostate cancer: PSA-based screening followed by a biopsy, and non-PSA screening. We assumed that the patients would repeat screening in subsequent years if their first-year PSA value was higher than 4.0 ng/mL. The model adopted health care system perspective and lifetime horizon. Screening efficacy, cost, utility, and long-term survival of prostate cancer were retrieved from published literature and physician surveys. Both quality-adjusted life year and costs were discounted at an annual rate of 3.5%. Uncertainty was assessed by 1-way and probabilistic sensitivity analyses. Our model also calculated the risk-to-benefit ratio as the ratio of overdiagnosis (biopsy without diagnosed) to prostate cancer-related deaths prevented in different age groups. RESULTS: The results suggested that PSA-based screening was cost-effective compared with no PSA screening, with an incremental cost-utility ratio of ¥11,381 ($1821/€1480) per quality-adjusted life year. This value was less than the threshold of 1-time gross domestic product per capita in China (ie, ¥70,892 [$11,343/€9216]). Sensitivity analyses confirmed the robustness of the results. The risk-to-benefit ratios of the 50 to 65 years and the 65 to 80 years age groups were 1.3 and 2.8, respectively. CONCLUSIONS: PSA-based prostate cancer screening appears to be cost-effective in some high-risk Chinese men. PSA screening (PSA testing followed by magnetic resonance imaging and biopsy if positive) can be recommended for Chinese men aged 50 to 65 years because this approach had the lowest risk-to-benefit ratio. The approach should be further adapted based on future updated data. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX)© 2022 Elsevier HS Journals, Inc.

Elevated Lactate Dehydrogenase Levels Display a Poor Prognostic Factor for Non-Hodgkin's Lymphoma in Intensive Care Unit: An Analysis of the MIMIC-III Database Combined With External Validation.

BACKGROUND: Among the growing number of patients with hematologic neoplasms hospitalized in the intensive care unit (ICU), the largest proportion of these patients are diagnosed with lymphoma. However, less attention has been paid in the past to identifying critically ill patients and assessing the prognosis of patients in ICU. Traditional critical care-related scores have shown limitations and inaccuracy in predicting mortality risk. METHODS: Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) were searched for in the Marketplace for Information in Intensive Care Medicine III (MIMIC-III) database. We searched mortality within 28 days as the primary endpoint. Logistics regression was used to screen risk factors. A calibration curve was used for internal validation, and the ROC curve and AUC were used to compare the new model with traditional scores. RESULTS: 405 patients with DLBCL are enrolled in the project. Multivariate analysis shows the patients with the level of lactate dehydrogenase (LDH) > 327 U/L had an increased risk of 28-day mortality in ICU than others (OR = 13.04, p<0.01). Notably, length of ICU stay, LDH, creatinine, white blood cell counts, and APS III score are independent prognostic factors for patients with DLBCL in the ICU. Then, all these independent prognostic factors are selected into our prediction model. The new model has good accuracy (C-index=0.863) and a calibration curve, which improves clinical status concerning established ratings such as IPI, NCCN-IPI score, SOFA, APS III, and LODS. The results of a multicenter external validation including 124 DLBCL patients also showed that the new model was more accurate than all other models. CONCLUSIONS: The elevated level of LDH indicates a poor prognosis of patients with DLBCL in the ICU. Our risk score with crossed validation based on the level of LDH shows a significant prognostic value and may be a valuable tool for assessing the critically ill as well.

Survival in Metastatic Renal Cell Carcinoma Patients Treated With Sunitinib With or Without Cryoablation.

BACKGROUND: Percutaneous cryoablation (PCA) has emerged as an alternative to extirpative management of small renal masses in select patients. In recent years, the use of targeted therapies has become mainstream, while the role of PCA in treating primary tumor is not well established among patients with metastatic renal cell carcinoma (mRCC). We sought to evaluate how mRCC patients react to PCA in combination with sunitinib. METHODS: We retrospectively identified patients with mRCC (primary tumor diameter ≤ 7 cm) treated with sunitinib between 2013 and 2019. These patients were categorized by initial treatment (cryoablation followed by sunitinib versus sunitinib only). Oncological outcomes and rate of adverse events were compared. RESULTS: Of the 178 patients analyzed, 65 underwent PCA prior to sunitinib. The median overall survival (OS) in the PCA-sunitinib group was 31.7 months (95% CI; 26.1-37.3), better than the sunitinib-only group, which reported a median OS of 19.8 months (95% CI; 17.1-22.4) (p < 0.001). The median progression-free survival (PFS) in patients treated with PCA-sunitinib versus sunitinib alone was 13.8 months (95% CI; 10.0-17.6) versus 7.2 months (95% CI: 6.1-8.3) (p < 0.005). No significant differences in adverse events were observed (p > 0.05). CONCLUSIONS: PCA combined with sunitinib is associated with better survival outcomes than sunitinib alone in patients with mRCC. Careful patient selection remains warranted. These results should inform future prospective trials.