A predictive model for therapy failure in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor therapy.

Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.

Efficient isolation and proteomic analysis of cell plasma membrane proteins in gastric cancer reveal a novel differentiation and progression related cell surface marker, R-cadherin.

Cell plasma membrane proteins, playing a crucial role in cell malignant transformation and development, were the main targets of tumor detection and therapy. In this study, CyDye/biotin double-labeling proteomic approach was adopted to profile the membrane proteome of gastric cancer cell line BGC-823 and paired immortalized gastric epithelial cell GES-1. Real-time PCR, Western blotting, and immunohistochemical staining were used to validate the differential expression of a novel identified cell surface marker R-cadherin in gastric cancer cells and tissues. Clinicopathological study and survival analysis were performed to estimate its roles in tumor progression and outcome prediction. Real-time PCR and Western blotting showed that the expression level of R-cadherin in gastric cancer were significantly lower than non-cancerous epithelial cell and tissues. Clinicopathological study indicated that R-cadherin was dominantly expressed on cell surface of normal gastric epithelium, and its expression deletion in gastric cancer tissues was associated with tumor site, differentiation, lymph node metastasis, and pTNM (chi-square test, P < 0.05). Those patients with R-cadherin positive expression displayed better overall survivals than negative expression group (log-rank test, P = 0.000). Cox multivariate survival analysis revealed lacking the expression of R-cadherin was a main independent predictor for poor clinical outcome in gastric cancer (RR = 5.680, 95 % CI 2.250-14.341, P < 0.01). We have established a fundamental membrane proteome database for gastric cancer and identified R-cadherin as a tumor differentiation and progression-related cell surface marker of gastric cancer. Lacking the expression of R-cadherin indicates poor prognosis in patients with gastric cancer.

Zuberitamab, an innovative anti-CD20 monoclonal antibody, for patients with primary immune thrombocytopenia in China: a randomized, double-blind, placebo-controlled, phase 2 study.

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease, and rituximab (RTX) induces long-term effect as second-line treatments. Zuberitamab is an innovative anti-CD20 monoclonal antibody, which was first developed in China and launched in diffuse large B lymphoma. This study aimed to investigate the safety, efficacy, and anticipated therapeutic dose of zuberitamab in Chinese ITP patients. Methods: This randomised, double-blind, placebo-controlled, phase 2 study was conducted at 26 hospitals in China. Eligible patients were aged 18-70 years, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous treatment and had a pre-treatment platelet count of <30 × 109/L. Patients randomly received zuberitamab in a dose escalation (100/300/600 mg) or placebo once-weekly for 4 weeks and followed up to 24 weeks. The primary endpoint is the proportion of patients with a platelet count ≥50 × 109/L at week 8. Secondary endpoints include the proportion of patients with platelet counts ≥50 × 109/L or ≥100 × 109/L at least once within week 12/24, the proportion of patients experiencing platelets increased twice more than baseline as well as ≥30 × 109/L at least once during the treatment. Adverse events, pharmacokinetic, B cell depletion and immunogenicity were also assessed. This study is registered with https://www.chictr.org.cn/as ChiCTR2100050513. Findings: From October 2021 to March 2023, 50 patients were screened for eligibility, of whom 32 patients were enrolled and randomly assigned to placebo (n = 4), zuberitamab 100 mg (n = 10), 300 mg (n = 8) and 600 mg (n = 10) groups. The primary endpoint (PLT ≥50 × 109/L at week 8) was achieved by 40% of patients in the 100 mg group, while none in the other groups. Within 12 weeks, the proportions of patients in each treatment group achieving at least one instance of platelet count ≥50 × 109/L or ≥100 × 109/L or an increase twice more than baseline as well as ≥30 × 109/L were (70%, 38%, 50%), (60%, 13%, 30%), and (80%, 50%, 70%) in zuberitamab 100/300/600 mg groups, respectively. By week 24, the proportions of patients achieving these secondary endpoints remained relatively stable or showed a mild increase of around 10%. The anticipated therapeutic dose of zuberitamab was 100 mg. The plasma concentration of zuberitamab showed an increasing trend with dose (100 mg-600 mg) and linear pharmacokinetic behavior. CD19+ B cells and CD20+ B lymphocytes rapidly declined to 0% within one week and consistently maintained reduced levels throughout the entire treatment phase in three groups. Adverse events occurred in all patients with most of them were mild to moderate, no severe infections occurred. A slight decrease in immunoglobulins was observed in the 600 mg group, but gradually recovered at week 20. Three patients (2 in 100 mg and 1 in 600 mg group) were tested positive for anti-zuberitamab antibodies. We also observed that women, disease duration <12 months, and MAIPA + patients may have higher response rates. Interpretation: This study preliminarily confirmed that 100 mg zuberitamab was safe and effective in treating ITP and was recommended to support further investigation. Funding: National Natural Science Foundation of China and Zhejiang Bioray Biopharmaceutical Co. Ltd.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study.

BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.

Olanzapine 5 mg for Nausea and Vomiting in Patients with Nasopharyngeal Carcinoma Receiving Cisplatin-Based Concurrent Chemoradiotherapy.

Purpose: To explore the efficacy and safety of adding olanzapine (5 mg or 10 mg) to 5-hydroxytryptamine type 3 receptor antagonists (5-HT3 RA), neurokinin-1 receptor antagonists (NK1 RA), and dexamethasone for nausea and vomiting in patients with nasopharyngeal carcinoma (NPC) receiving cisplatin-based concurrent chemoradiotherapy. Methods: Patients receiving olanzapine 5 mg or 10 mg combined with 5-HT3 RA, NK1 RA, and dexamethasone during the cisplatin-based concurrent chemoradiotherapy were included. The primary endpoint was the complete response (CR) (no vomiting) rate, and the secondary endpoint was the incidence of no nausea. Results: A total of 150 chemotherapy cycles were administrated for 88 patients (75 in the olanzapine 5 mg group and 75 in the olanzapine 10 mg group). The proportions of CR in the olanzapine 5 mg group were comparable to those in the olanzapine 10 mg group in acute (93.3% vs. 94.7%, P = 0.731), delayed (76% vs. 78.7%, P = 0.697), and overall phase (73.3% vs. 77.3%, P = 0.570). Moreover, no nausea rates were also comparable between the two groups in acute (76% vs. 78.7%, P = 0.697), delayed (54.7% vs. 60%, P = 0.509), and overall period (50.7% vs. 57.3%, P = 0.111). Regarding the adverse effects, the incidence of somnolence in the 10 mg group (58.6%) was significantly higher than that in the 5 mg group (41.3%) (P = 0.034), while constipation (20.0% vs. 24.0%, P = 0.554) and hiccups (9.3% vs. 10.6%, P = 0.785) rates were comparable in two groups. Conclusions: Patients receiving olanzapine plus standard antiemetic therapy has excellent antiemetic effect in NPC patients receiving cisplatin-based concurrent chemoradiotherapy, and patients with olanzapine 5 mg have a similar antiemetic effect and lower adverse effects compared with those with olanzapine 10 mg.

68Ga-fibroblast activation protein inhibitor PET/CT on gross tumour volume delineation for radiotherapy planning of oesophageal cancer.

BACKGROUND AND PURPOSE: To compare 68Ga-fibroblast activation protein inhibitor (FAPI) and 18F-FDG PET/CT in imaging locally advanced oesophageal cancer, and evaluate the potential usefulness of 68Ga-FAPI PET/CT on gross target volume (GTV) delineation aimed at radiotherapy planning for oesophageal cancer as compared with contrast-enhanced CT (CE-CT) and 18F-FDG PET/CT. MATERIALS AND METHODS: Twenty-one patients with newly diagnosed oesophageal cancer who underwent both 18F-FDG and 68Ga-FAPI PET/CT scans were selected. GTVs of the primary tumours based on CE-CT (GTVCT), PET/CT, and CE-CT plus PET/CT were delineated. Gross tumour lengths were measured by GTVs and endoscopy and recorded. RESULTS: The 68Ga-FAPI PET showed significantly higher radiotracer uptake than 18F-FDG PET (median SUVmax 16.71 vs. 11.23; P = 0.002) in the primary tumours. SUV thresholds of FAPI ×20%, 30%, 40%, and FDG ×40% showed similar lesion lengths compared with that in endoscopic examination (P > 0.05). GTVCT demonstrated the largest volume (median: 48.80 mm3, range: 14.83-162.23 mm3) than PET-based GTVs. For PET/CT-guided complementary contouring of GTVCT, four patients (19%) were increased by FAPI ×20% and 30%, two patients (9.5%) were increased by FAPI ×40%, and only one patient was increased by FDG ×40%. Furthermore, the volume of GTV based on CE-CT plus FAPI ×20%, 30%, and 40% showed no significant difference with GTVCT and planning target volume based CE-CT plus FAPI-PET and meets the organ at risk standard. CONCLUSION: The 68Ga-FAPI PET/CT methodology showed favourable tumour-to-background contrast in oesophageal cancer and might provide additional information for target volume delineation and help avoid tumour geographic misses.

[The study of relationship between platelet function and thrombus in patients with essential thrombocythaemia].

OBJECTIVE: To observe the influence of the plasma thromboxane B2 (TXB2), 6-keto-PGF1alpha, CD62P and PAC-1 and Thrombus in patients with primary thrombocytosis (ET). To observe the effect of sodium ozagrel to prevent and treat thrombosis in patients with ET. METHODS: The subjects including 48 patients with ET. All patients were measured the plasma TXB2, 6-keto-PGF1alpha, CD62P and PAC-1 before and after treatment with or without sodium ozagrel. RESULTS: The plasma levels of CD62P, PAC-1, TXB2, 6-keto-PGF1alpha and TXA2/PGI2 in the patients with ET were significantly higher than the normal people (P < 0.01). The levels of CD62P, PAC-1, TXB2, TXB2/6-keto-PGF1alpha in patients with treatment of sodium ozagrel were higher than patients without treatment of sodium ozagrel (P < 0.01). The plasma levels of CD62P, PAC-1 and TXA2/PGI2 in patients with treatment of sodium ozagrel and that in normal people had no significant distinction (P < 0.01). All the index of conventional therapy group were higher than normal people (P < 0.01) but had no significant distinction with the patients before conventional treating. The incidence of thrombus in patients treated with sodium ozagrel was lower than patients treated without sodium ozagrel (P < 0.05). CONCLUSION: With the treatment of sodium ozagrel in patients with ET, the CD62P, PAC-1, TXB2 and TXA2/PGI2 of plasma could be decreased. And the incidence of thrombus was decreased.

Cognitive dysfunction in patients with nasopharyngeal carcinoma after induction chemotherapy.

OBJECTIVE: This prospective study aimed to assess the incidence, details of the change of cognitive dysfunction, and predictive factors of cognitive function impairment associated with induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC) patients. METHOD: We prospectively included NPC patients who treated with IC from December 2018 to January 2020. Montreal cognitive assessment (MoCA) was used to measure cognitive function, and score less than 26 was defined as cognitive dysfunction. Multivariate logistic regression analysis was applied to assess the independent predictors associated with cognitive function impairment. RESULTS: A total of 76 patients were recruited, 10 patients were excluded due to refusal or unable to finish the questionnaire, and 66 patients were analyzed in this study. The median age of the patients was 48.5 years (range, 24-69 years). There was 89.4% of patients received ≥3 circles of IC. For the entire group, 27.3% had cognitive dysfunction, of which attention, language, short-term memory, and orientation showed significant downward trends, while visuospatial/executive function, naming, and abstraction demonstrated no prominent decrease. In patients having cognitive function impairment, 77.8% of them occurred after the first circle of IC. Gender (P = 0.039) and education (P = 0.03) were significant predictors for cognitive dysfunction. Female patients (female vs. male: 50% vs. 20%) and patients with lower educational levels (lower vs. higher: 37.8% vs. 11.8%) were more likely to suffer cognitive dysfunction. In addition, age (P = 0.572) and chemotherapy circles (P = 0.68) had no association with cognitive dysfunction. CONCLUSION: Approximately 25% of NPC patients suffered cognitive dysfunction after IC, especially in female patients and patients with lower educational levels.

[Effects of sodium ozagrel in primary thrombocytosis combined with thrombosis].

This study was aimed to investigate the incidence of thrombosis in patients with primary thrombocytosis (PT) and its correlation with function changes of platelets, and to explore the effect of thromboxane A2 (TXA2) inhibitor-ozagrel sodium on platelet activity and its efficacy for prevention and treatment of thrombosis. The CD62P and PAC-1 levels on platelet surface were detected by flow cytometry; the levels of TXB2 (metabolic product of TXA2) and 6-keto-PGFIalpha (metabolic product of prostacyclin) were detected by FLISA. The function change of platelets and its correlation with thrombosis were observed and compared in PT patients with and without thrombosis. The results indicated that the TXB2, PAC-1 and CD62P level, and TXB2/6-keto-PGF1alpha ratio in PT patients with thrombosis were higher than those in PT patients without thrombosis before treatment with ozagrel sodium (p<0.01). After treatment with ozagrel sodium, the function indexes of platelets such as CD62P, PAC-1, TXB2 and TXB2/6-keto-PGF1alpha except 6-keto-PGF1alpha in PT patients with and without thrombosis decreased obviously (p<0.01), but there was no significant difference in TXB2, 6-keto-PGF1alpha and TXB2/6-keto-PGF1alpha levels between PT patients with and without thrombosis except CD62P and PAC-1. It is concluded that the multi-index of platelets in PT patients with thrombosis are higher than that in PT patients without thrombosis, the activation of platelet function is a high risk factor for thrombosis of PT patients. The ozagrel sodium can obviously reduce the platelet activation, decrease the production of TXA2 and ameliorate the TXB2/6-keto-PGF1alpha ratio. The ozagrel sodium not only possesses therapeutic effect, but also preventive efficacy for thrombosis.

[Use of Z plasty for ankyloglossia: report of 38 cases].

Z plasty was used in 38 children (male 22, female 16) aged from 0.5 to 6 years with ankyloglossia. There were no infection, dehiscence and tongue adhesion. The wound healed more quickly, and tongue protrusion improved from 13.5 mm preoperatively to 24.6 mm postoperatively. Similarly, tongue elevation improved from 4.8 to 20.6 mm.