Smoking has been shown to have detrimental effects on KT outcomes and survival. Most units and guidelines advocate for the cessation of smoking prior to a kidney transplant and consider it a general contraindication to listing. Smoking prevalence is higher in disadvantaged groups. Smoking cessation is complex and often takes many years. For those suffering from the burden of chronic kidney disease, a delay in transplantation with a longer dialysis time may result in worse outcomes and accentuate the difficulty of cessation. The objective of this study was to describe the cohort of excluded smokers for kidney transplantation (KT) and further examine the current practices regarding smoking and KT waitlisting. We undertook a retrospective observational study of dialysis patients in Hunter New England Local Health District 2013-2023 <65 years old and assessed but not listed for KT. We examined the reasons for non-transplant listing and divided them into two categories, smoking versus others (comorbidities, patient preference and cancer). We compared the categories in terms of demography, comorbidities and dialysis modality. We also conducted a survey of KT units across Australia and New Zealand regarding their policies towards smoking. We reviewed the records of 333 patients (142 female), 89 of whom were smokers. Patients not listed due to smoking were less comorbid than those rejected for another reason (83% vs 40% having ≤1 comorbid condition, P < 0.001). Patients rejected due to smoking were younger than those rejected for other reasons (47.8 vs 52.1, P = 0.007). There was no difference between the two groups in terms of sex or dialysis modality. All the acute KT units were surveyed (response rate 100%); 72% of units do not list current smokers for KT. Patients not listed for KT due to smoking are generally younger and less comorbid than those not listed for other reasons. Our survey shows variation in practice between units. As smoking is more prevalent in marginalised communities, not listing these patients for KT may be an equity-of-access-to-treatment issue.
Ribosomal protein (RP) L23 is a negative regulator of cellular apoptosis, and RPL23 overexpression is associated with abnormal apoptotic resistance in CD34+ cells derived from patients with higher-risk myelodysplastic syndrome (MDS). However, the mechanism underlying RPL23-induced apoptotic resistance in higher-risk MDS patients is poorly understood. In this study, we showed that reduced RPL23 expression led to suppressed cellular viability, increased apoptosis and G1-S cell cycle arrest. Gene microarray analysis comparing RPL23-knockdown and control cells identified an array of differentially expressed genes, of which, Miz-1, was upregulated with transactivation of the cell cycle inhibitors p15Ink4b and p21Cip1, and Miz-1's functional repressor, c-Myc, was downregulated. Cells derived from higher-risk MDS patients demonstrated consistently increased expression of RPL23 and c-Myc and decreased Miz-1 expression compared with cells from lower-risk patients. In conclusion, Miz-1-dependent induction of p15Ink4b and p21Cip1 was depressed with decreased Miz-1 and increased c-Myc expression under conditions of elevated RPL23 expression, leading to apoptotic resistance in higher-risk MDS patients. Because RPL23 is encoded by a target gene of c-Myc, the RPL23/Miz-1/c-Myc regulatory circuit provides a feedback loop that links efficient RPL23 expression with c-Myc's function to suppress Miz-1-induced Cdk inhibitors and thereby leads to apoptotic resistance in higher-risk MDS patients.
e19032 Background: Myelodysplastic syndrome(MDS) patients may have iron overload due to long-term RBC transfusion or combined with abnormal iron metabolism.what are the differences of iron content detection by magnetic resonance imaging (MRI) and dual energy spectrum computed tomography (DECT)? What are the advantages and disadvantages of the two methods in the state of high and low iron deposition? Can the two methods complement each other? The purpose of this study was to compare the difference of liver/cardiac iron content detection in MDS patients by DECT and MRI under different adjust serum ferritin (ASF) levels. Methods: Liver and cardiac iron content were detected by DECT and MRI. Patients divided into different subgroups according to ASF. Compared the detection rate between DECT and MRI group, and correlation between liver/cardiac iron content detected by DECT/MRI and ASF in each subgroups. Results: The detection rate of iron overload(IO) in DECT group was lower than that of MRI group with ASF < 1000ng/ml subgroup,DECT and MRI had similar detection rates of moderate to severe IO with 1000≤ ASF < 5000ng/ml subgroup, detection rate of severe IO in MRI was lower than that of DECT with 5000ng/ml ≤ ASF subgroup. In patients underwent DECT and MRI examination at the same time, ASF was significantly correlated with hepatic VIC but not with liver iron concentration (LIC), and LIC correlated with ASF after removed these data of ASF > 5000 mg/L. LIC expression are not significantly different among 1000≤ ASF < 5000ng/ml and 5000 ng/ml ≤ASF subgroup. LIC and liver virtual iron content (VIC) were all significant correlation with ASF when ASF < 2500ng/ml, liver VIC was still correlation with ASF but LIC was not when 2500ng/ml≤ ASF. Neither cardiac VIC nor myocardial iron content (MIC) correlation with ASF in these subgroups. Conclusions: This study showed that MRI and DECT can be used complementary to each other. In high iron content, such as ASF ≥5000ng/ml, DECT detection is more reliable. In patients with low iron content, such as SF < 1000 ng/ml, MRI detection is more reliable. According to ASF, the appropriate detection method can be selected to evaluate the iron content more accurately.
7061 Background: As the first approved Janus kinase inhibitor (JAKi) for pts with symptomatic MF, RUX showed superiority in spleen volume reduction with increased anemia and thrombocytopenia. However, there are few treatment options after RUX intolerance. Jaktinib, an oral novel JAK and ACVR1 inhibitor showed promising efficacy in Jaki-naïve pts with intermediate or high risk MF with mild side effects. Here we present the results of MF pts who were intolerant to RUX and received jaktinib 100 mg bid from a phase 2b study. Methods: Pts who had primary or post-ET/PV MF and were previously treated with RUX for ≥28 days who either required RBC transfusions or required more frequent transfusions on RUX, or had grade 3/4 anemia, thrombocytopenia or hematoma when receiving RUX, and with palpable spleen ≥5 cm were included. The primary endpoint was the proportion of pts with spleen volume reduction of ≥ 35% from baseline (SVR35) at week (wk) 24, assessed centrally on the basis of MRI/CT images. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of pts with ≥ 50% reduction in MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), anemia response, safety, etc. Results: A total of 45 patients received jaktinib 100 mg bid. The full analysis set (FAS) for efficacy included 44 pts who had completed the 24-week treatments and evaluations or terminated prior to wk 24, and excluded one pt because of incorrect diagnosis of MF. The median baseline TSS was 9.5, hemoglobin (Hb) was 79.5 g/L, and platelets was 132.5×10 9 /L. While on RUX, 21 pts (48%) required RBC transfusion and all pts experienced those grade 3 hematological toxicities. In FAS, the SVR35 rate at wk 24 was 43% (19/44). Over the study phase, the best spleen response rate was 55% (24/44). The median time to achieve the first SVR35 was 12 weeks. Response was maintained in 80% pts for at least 24 weeks and median duration was not reached. At wk 24, 62% of the evaluable pts achieved a ≥ 50% improvement in TSS from baseline. Of 31 pts with baseline Hb ≤ 100 g/L, 13 (42%) had a ≥20 g/L Hb increase. Of 19 pts who required RBC transfusion at baseline, 11 (58%) had a 50% decrease in RBC infusion frequency. Of 9 transfusion-dependent pts at baseline, one became transfusion-independent. In the safety set (n = 45), the median jaktinib exposure time was 280 days. The most common grade ≥3 TEAEs were anemia (31%), thrombocytopenia (22%), pneumonia (18%), neutropenia (16%) and leukopenia (16%). Treatment discontinuation due to TEAEs occurred in five pts (11%). A dose reduction or temporary interruption due to TEAEs were reported in 12 pts (27%). Conclusions: Jaktinib demonstrated promising activities in MF pts who was intolerant to RUX by substantially reducing spleen volume, ameliorating MF-related symptom burdens, and elevating Hb levels. Jaktinib could be a viable treatment for MF pts with anemia in this setting. Clinical trial information: NCT04217993 .
Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: MYCN is a member of the MYC proto-oncogene family that also includes MYC and MYCL. Overexpression of MYCN is frequent in several solid cancers and associated with poor prognosis. However, the role of MYCN in acute myeloid leukemia (AML) remains poorly understood. Aims: To investigate the mechanism of MYCN in maintenance of malignant characteristic of leukemia cells. Methods: The expression of MYC family was analyzed in 542 AML patients, 76 chronic myeloid leukemia (CML) patients and 74 non-leukemia/healthy controls from Microarray Innovations in Leukemia (MILE) study. Lentivirus-mediated MYCN knockdown was performed to investigate its biological function in leukemia cell lines. The mechanism of MYCN in leukemia development was investigated by functional experiments. Results: We found that MYCN, not MYC or MYCL, was up-regulated in the AML patients compared with CML or non-leukemia controls. In vitro experiments, knockdown of MYCN impaired growth capacity, elevated autonomously cell apoptosis and increased apoptosis sensitivity to cytotoxic agent. Gene microarray and bioinformatic analysis suggested that MYCN plays a critical role in transcription regulation and apoptosis pathway. Correlation analysis and functional experiments revealed that MSI2 is a target of MYCN. Knockdown of MYCN inhibited the expression of MSI2. Mechanistically, MYCN could directly bind at the promoter of MSI2 and promote its transcription. Summary/Conclusion: MYCN oncogene contributes to the malignant characteristics of leukemia cells through activation of MSI2 in AML. MYCN is required for maintaining an oncogenic characteristics of leukemia cells in acute myeloid leukemia This study was supported by the National Natural Science Foundation of China (Grant No. 81770120 and 81770122) The authors declare no competing financial interests. Keywords: Acute myeloid leukemia, MYC, Oncogene
Topic: 16. Myeloproliferative neoplasms - Clinical Background: As the first approved Janus kinase inhibitor (JAKi) for patients with symptomatic myelofibrosis (MF), ruxolitinib showed superiority in spleen volume reduction with increased anemia and thrombocytopenia. However, there are few treatment options after ruxolitinib intolerance. Jaktinib, an oral novel JAK and ACVR1 inhibitor showed promising efficacy in JAKi-naïve patients with intermediate or high risk MF with mild side effects. Aims: We conducted a single-arm phase 2b study to evaluate jaktinib in MF patients who were intolerant to ruxolitinib. Here we present the results of the cohort of patients who received jaktinib 100 mg twice a day. Methods: Patients who had primary, post-polycythemia vera or post-essential thrombocythemia MF and were previously treated with ruxolitinib for ≥28 days who either required red blood cell (RBC) transfusions or required more frequent transfusions on ruxolitinib, or had grade 3/4 anemia, thrombocytopenia or hematoma when receiving ruxolitinib, and with palpable spleen ≥5 cm were included. Patients were excluded from the study if they had received ruxolitinib ≥20 mg Bid for at least three months and were refractory or relapsed to ruxolitinib. The primary endpoint was the proportion of patients with spleen volume reduction of ≥35% from baseline (SVR35) at week 24, assessed by Independent Review Committee on the basis of MRI/CT images. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of patients with ≥50% reduction in MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), anemia response, safety, etc. Results: In the full analysis set for efficacy, a total of 44 patients received jaktinib 100 mg twice daily and had completed the 24-week treatments and evaluations or terminated prior to week 24. In addition, one patient was excluded from the efficacy analysis due to incorrect diagnosis of MF but included in the safety analysis. The median baseline TSS was 9.5, hemoglobin was 80 g/L, and platelet count was 132.5×109/L. Patient baseline characteristics are summarized in the Table 1. While on ruxolitinib, 21 patients (47.7%) required RBC transfusion and all patients experienced grade 3/4 anemia, thrombocytopenia or both.The SVR35 rate at week 24 was 43.2% (19/44). Over the study phase, the best spleen response rate was 54.5% (24/44). The median time to achieve the first SVR35 was 12.1 weeks. Spleen response was maintained in 80.4% patients for at least 24 weeks and median duration was not reached. At week 24, 61.8% of the evaluable patients achieved a ≥50% improvement in TSS from baseline. Of 31 transfusion-independent patients with hemoglobin ≤100 g/L at baseline, 13 (41.9%) had an increase of hemoglobin ≥20 g/L by week 24. Of 19 patients who required RBC transfusion at baseline, 11 (57.9%) had a 50% decrease in RBC infusion frequency by week 24. Of nine transfusion-dependent patients at baseline, one became transfusion-independent by week 24. In the safety set (n=45), the median jaktinib exposure time was 280 days. The most common grade ≥3 treatment-related adverse events (TEAEs) were anemia (31.1%, n=14), thrombocytopenia (22.2%, n=10), pneumonia (17.8%, n=8), neutropenia (15.6%, n=7) and leukopenia (15.6%, n=7). Treatment discontinuation due to TEAEs occurred in five patients (11.1%). A dose reduction or temporary interruption due to TEAEs were reported in 12 patients (26.7%). Summary/Conclusion: Jaktinib demonstrated promising therapeutic activities in MF patients intolerant to ruxolitinib. Jaktinib 100 mg bid taken orally, not only substantially reduced splenomegaly, but also ameliorated MF-related symptom burdens and anemia. Jaktinib could be a new treatment for patients with anemia after ruxolitinib. Keywords: Janus Kinase inhibitor, Myeloproliferative disorder, Phase II, Myelofibrosis
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