Objective:To investigate the relationship between the BCL2 family protein BIM and ibrutinib resistance in chronic lymphocytic leukemia (CLL) and to analyze its regulatory mechanisms on apoptosis and autophagy.Methods:RNA sequencing (RNA-seq) was used to examine changes in the expression of BCL2 family proteins in samples from patients with CLL, MEC1 cell lines, and ibrutinib-resistant cell lines (MR). Western blot was used to analyze changes in BIM protein expression during apoptosis in MR. shRNA knockdown was used to assess the effects of BIM on cell proliferation and apoptosis. RNA-seq and the autophagy inhibitor chloroquine treatment were used to study autophagy-related changes in MR.Results:BIM expression was significantly downregulated before and after drug resistance in CLL primary cells and MEC1 cell lines ( P<0.0001). Knockdown of BIM in CLL cells inhibited ibrutinib-induced apoptosis and promoted cell proliferation ( P<0.05 for both). In addition, protective autophagy was increased in MR and apoptosis was increased after administration of chloroquine and small interfering RNA. The increased expression of LC3-Ⅱ protein in BIM-knockdown cell lines ( P<0.01) suggested that reduction of BIM may mediate autophagy activation. Conclusion:Downregulation of BIM may be a key factor in promoting ibrutinib resistance in CLL by activating protective autophagy. These findings provided a potential target for improving CLL treatment.

Objective:To evaluate the efficacy and safety of the pegaspargase, etoposide, methotrexate, and dexamethasone (PEMD) regimen in patients with early-stage nonupper respiratory digestive tract or advanced extranodal natural killer/T-cell lymphoma (ENKTL) .Methods:This retrospective analysis included 38 patients with newly diagnosed early-stage non-upper respiratory digestive tract or advanced ENKTL who received PEMD regimen for induction chemotherapy at the First Affiliated Hospital of Nanjing Medical University from January 2016 to December 2022. Survival outcomes and prognostic factors were examined by Kaplan-Meier, and the Log-rank test was used to compare survival.Results:The study population had a median age of 48 years (range, 26-72 years) and included 30 males (78.9%) and 8 females (21.1%). 7 patients’ age >60 years (18.4%). The Eastern Cooperative Oncology Group (ECOG) performance score was >1 in 7 patients (18.4%) ; 20 patients (52.6%) had elevated lactate dehydrogenase levels; and 37 patients (97.4%) exhibited extranodal involvement. Using the Ann Arbor staging system, 37 patients (97.4%) were classified as stage Ⅲ-Ⅳ. The median number of treatment cycles was 5 (1-6), and the median follow-up duration was 60 months (24 - 101 months). Interim efficacy assessment revealed an overall response rate of 52.7%. At 2 and 4 years, the progression-free survival (PFS) rates were 34.2% (95% CI 22.0%-53.2%) and 25.5% (95% CI 14.7%-44.4%), respectively, and the overall survival rates were 50.0% (95% CI 36.4%-68.7%) and 45.5% (95% CI 31.4%-65.7%), respectively. The risk factors for worse PFS were ECOG performance score >1 [ HR=3.711 (95% CI 1.494-9.218), P=0.005]; bone marrow infiltration [ HR=2.251 (95% CI 1.026 - 4.938), P=0.043]; and Prognostic Index for Natural Killer/T-Cell Lymphoma score of 3 - 5 [ HR=2.350 (95% CI 1.009 - 5.476), P=0.048]. Multivariate analysis identified ECOG performance score >1 as an independent risk factor for PFS [ HR=7.971 (95% CI 2.222 - 28.591), P=0.001]. The main adverse effect was anemia in 31 patients (81.6%) . Conclusion:The PEMD regimen was safe and effective for patients with newly diagnosed early-stage non-upper respiratory digestive tract or advanced ENKTL.

Objective:To observe and compare the application of different scanning fields of view (FOV) in cone beam CT (CBCT) imaging of the temporomandibular joint (TMJ), and to explore the advantages and disadvantages of different CBCT scanning FOV for TMJ imaging. The aim is to provide a reference for the rational selection of CBCT scanning FOV for TMJ imaging in clinical practice.Methods:A total of 46 patients with temporomandibular disorders [22 males, 24 females; median age 24.5 years (range from 12 to 84 years)] were enrolled from the Department of Stomatology,the First Medical Centre, Chinese PLA General Hospital, between January 2023 and January 2025. All patients underwent CBCT scanning of the temporomandibular joints with both large and small fields of view using the same CBCT device, Newtom 5G (QR S.r.l, Italy), including small-field-of-view (sFOV 6 cm×6 cm, 46 cases, 92 sides) and large-field-of-view (lFOV 15 cm×12 cm for 26 cases with 52 sides or 18 cm×16 cm for 20 cases with 40 sides). A self-matched design was used to compare imaging parameters (scan time, exposure time, reconstruction voxel, radiation dose, data volume), image quality, and lesion detection efficacy (articular surface flattening, surface erosion, osteophyte, subcortical sclerosis, subcortical cyst, intra-articular calcification). Additionally, differences in joint spaces, condylar head height, and condylar height were analyzed.Results:In the sFOV group, scan time (72 s vs. 24 s) and exposure time (14.6 s vs. 4.8 s) were significantly longer than those in the lFOV group, with smaller reconstruction voxels (0.15 mm vs. 0.3 mm). Radiation dose in the sFOV group [(199.94±5.52) mGy·cm] was significantly higher than that in the lFOV 15 cm×12 cm subgroup [(96.20±25.34) mGy·cm, t=-20.29, P<0.001] and the 18 cm×16 cm subgroup [(101.73±13.49) mGy·cm, t=-31.34, P<0.001]. In terms of data volume, the sFOV group [(274.18±1.74) MB] was larger than the lFOV 15 cm×12 cm subgroup [(208.83±20.13) MB, t=-16.75, P<0.001], while the lFOV 18 cm×16 cm subgroup [(386.39±1.63) MB] was significantly larger than the sFOV group [(274.83±1.78) MB, t=214.49, P<0.001]. sFOV images showed clearer anatomical margins, distinguishable trabecular bone, and fewer artifacts. The detection rate of subcortical cyst in the sFOV group (50.0%, 46/92) was significantly higher than that in the lFOV group (36.96%, 34/92, χ2=5.61, P=0.018), with a moderate agreement Kappa coefficient of 0.48. Detection rates of articular surface flattening (80.43%, 74/92) and osteophyte (55.43%, 51/92) were identical between groups, with a perfect agreement Kappa coefficient of 1. Detection rates of subcortical sclerosis (69.57% vs. 68.48%) and intra-articular calcification (5.43% vs. 4.34%) were slightly higher in sFOV but without statistical significance ( P>0.05), with high Kappa coefficients of 0.93 and 0.88, respectively. For subcortical erosion, sFOV detection rate (38.04%, 35/92) was higher than lFOV (26.09%, 24/92, Kappa=0.53, moderate agreement), with no significant difference in detection rate (χ2=2.97, P=0.085). There were no statistical differences in joint space or condylar head height measurements between groups ( P>0.05), but condylar height measurements in the sFOV group were significantly greater than those in the lFOV group ( t=4.52, P<0.001). Conclusions:Large FOV provides wide anatomical coverage, optimizes radiation dose and data processing efficiency, and is more convenient for quantitative TMJ measurements.Small FOV offers superior resolution for displaying subtle condylar structures and lesions.Clinically, the choice of scan field should be individualized based on examination objectives (large FOV for holistic assessment/quantitative analysis; small FOV for early bone lesion diagnosis), equipment performance, and patient characteristics.

Objective:To observe and compare the application of different scanning fields of view (FOV) in cone beam CT (CBCT) imaging of the temporomandibular joint (TMJ), and to explore the advantages and disadvantages of different CBCT scanning FOV for TMJ imaging. The aim is to provide a reference for the rational selection of CBCT scanning FOV for TMJ imaging in clinical practice.Methods:A total of 46 patients with temporomandibular disorders [22 males, 24 females; median age 24.5 years (range from 12 to 84 years)] were enrolled from the Department of Stomatology,the First Medical Centre, Chinese PLA General Hospital, between January 2023 and January 2025. All patients underwent CBCT scanning of the temporomandibular joints with both large and small fields of view using the same CBCT device, Newtom 5G (QR S.r.l, Italy), including small-field-of-view (sFOV 6 cm×6 cm, 46 cases, 92 sides) and large-field-of-view (lFOV 15 cm×12 cm for 26 cases with 52 sides or 18 cm×16 cm for 20 cases with 40 sides). A self-matched design was used to compare imaging parameters (scan time, exposure time, reconstruction voxel, radiation dose, data volume), image quality, and lesion detection efficacy (articular surface flattening, surface erosion, osteophyte, subcortical sclerosis, subcortical cyst, intra-articular calcification). Additionally, differences in joint spaces, condylar head height, and condylar height were analyzed.Results:In the sFOV group, scan time (72 s vs. 24 s) and exposure time (14.6 s vs. 4.8 s) were significantly longer than those in the lFOV group, with smaller reconstruction voxels (0.15 mm vs. 0.3 mm). Radiation dose in the sFOV group [(199.94±5.52) mGy·cm] was significantly higher than that in the lFOV 15 cm×12 cm subgroup [(96.20±25.34) mGy·cm, t=-20.29, P<0.001] and the 18 cm×16 cm subgroup [(101.73±13.49) mGy·cm, t=-31.34, P<0.001]. In terms of data volume, the sFOV group [(274.18±1.74) MB] was larger than the lFOV 15 cm×12 cm subgroup [(208.83±20.13) MB, t=-16.75, P<0.001], while the lFOV 18 cm×16 cm subgroup [(386.39±1.63) MB] was significantly larger than the sFOV group [(274.83±1.78) MB, t=214.49, P<0.001]. sFOV images showed clearer anatomical margins, distinguishable trabecular bone, and fewer artifacts. The detection rate of subcortical cyst in the sFOV group (50.0%, 46/92) was significantly higher than that in the lFOV group (36.96%, 34/92, χ2=5.61, P=0.018), with a moderate agreement Kappa coefficient of 0.48. Detection rates of articular surface flattening (80.43%, 74/92) and osteophyte (55.43%, 51/92) were identical between groups, with a perfect agreement Kappa coefficient of 1. Detection rates of subcortical sclerosis (69.57% vs. 68.48%) and intra-articular calcification (5.43% vs. 4.34%) were slightly higher in sFOV but without statistical significance ( P>0.05), with high Kappa coefficients of 0.93 and 0.88, respectively. For subcortical erosion, sFOV detection rate (38.04%, 35/92) was higher than lFOV (26.09%, 24/92, Kappa=0.53, moderate agreement), with no significant difference in detection rate (χ2=2.97, P=0.085). There were no statistical differences in joint space or condylar head height measurements between groups ( P>0.05), but condylar height measurements in the sFOV group were significantly greater than those in the lFOV group ( t=4.52, P<0.001). Conclusions:Large FOV provides wide anatomical coverage, optimizes radiation dose and data processing efficiency, and is more convenient for quantitative TMJ measurements.Small FOV offers superior resolution for displaying subtle condylar structures and lesions.Clinically, the choice of scan field should be individualized based on examination objectives (large FOV for holistic assessment/quantitative analysis; small FOV for early bone lesion diagnosis), equipment performance, and patient characteristics.

Objective:To investigate the relationship between the BCL2 family protein BIM and ibrutinib resistance in chronic lymphocytic leukemia (CLL) and to analyze its regulatory mechanisms on apoptosis and autophagy.Methods:RNA sequencing (RNA-seq) was used to examine changes in the expression of BCL2 family proteins in samples from patients with CLL, MEC1 cell lines, and ibrutinib-resistant cell lines (MR). Western blot was used to analyze changes in BIM protein expression during apoptosis in MR. shRNA knockdown was used to assess the effects of BIM on cell proliferation and apoptosis. RNA-seq and the autophagy inhibitor chloroquine treatment were used to study autophagy-related changes in MR.Results:BIM expression was significantly downregulated before and after drug resistance in CLL primary cells and MEC1 cell lines ( P<0.0001). Knockdown of BIM in CLL cells inhibited ibrutinib-induced apoptosis and promoted cell proliferation ( P<0.05 for both). In addition, protective autophagy was increased in MR and apoptosis was increased after administration of chloroquine and small interfering RNA. The increased expression of LC3-Ⅱ protein in BIM-knockdown cell lines ( P<0.01) suggested that reduction of BIM may mediate autophagy activation. Conclusion:Downregulation of BIM may be a key factor in promoting ibrutinib resistance in CLL by activating protective autophagy. These findings provided a potential target for improving CLL treatment.

Objective:To evaluate the efficacy and safety of the pegaspargase, etoposide, methotrexate, and dexamethasone (PEMD) regimen in patients with early-stage nonupper respiratory digestive tract or advanced extranodal natural killer/T-cell lymphoma (ENKTL) .Methods:This retrospective analysis included 38 patients with newly diagnosed early-stage non-upper respiratory digestive tract or advanced ENKTL who received PEMD regimen for induction chemotherapy at the First Affiliated Hospital of Nanjing Medical University from January 2016 to December 2022. Survival outcomes and prognostic factors were examined by Kaplan-Meier, and the Log-rank test was used to compare survival.Results:The study population had a median age of 48 years (range, 26-72 years) and included 30 males (78.9%) and 8 females (21.1%). 7 patients’ age >60 years (18.4%). The Eastern Cooperative Oncology Group (ECOG) performance score was >1 in 7 patients (18.4%) ; 20 patients (52.6%) had elevated lactate dehydrogenase levels; and 37 patients (97.4%) exhibited extranodal involvement. Using the Ann Arbor staging system, 37 patients (97.4%) were classified as stage Ⅲ-Ⅳ. The median number of treatment cycles was 5 (1-6), and the median follow-up duration was 60 months (24 - 101 months). Interim efficacy assessment revealed an overall response rate of 52.7%. At 2 and 4 years, the progression-free survival (PFS) rates were 34.2% (95% CI 22.0%-53.2%) and 25.5% (95% CI 14.7%-44.4%), respectively, and the overall survival rates were 50.0% (95% CI 36.4%-68.7%) and 45.5% (95% CI 31.4%-65.7%), respectively. The risk factors for worse PFS were ECOG performance score >1 [ HR=3.711 (95% CI 1.494-9.218), P=0.005]; bone marrow infiltration [ HR=2.251 (95% CI 1.026 - 4.938), P=0.043]; and Prognostic Index for Natural Killer/T-Cell Lymphoma score of 3 - 5 [ HR=2.350 (95% CI 1.009 - 5.476), P=0.048]. Multivariate analysis identified ECOG performance score >1 as an independent risk factor for PFS [ HR=7.971 (95% CI 2.222 - 28.591), P=0.001]. The main adverse effect was anemia in 31 patients (81.6%) . Conclusion:The PEMD regimen was safe and effective for patients with newly diagnosed early-stage non-upper respiratory digestive tract or advanced ENKTL.

Objective:To assess the efficacy, safety, and related prognostic factors associated with the P-GemDOx regimen as a first-line treatment for patients with early-stage extranodal natural killer (NK) /T cell lymphoma (ENKTL) .Methods:A retrospective analysis was performed on sixty early-stage ENKTL patients treated with the P-GemDOx regimen who were admitted to the First Affiliated Hospital of Nanjing Medical University between August 2015 and May 2021. The Chi-square test or Fisher's exact test was used to compare group differences, and the Log-rank test was used to compare the differences in survival. Survival outcomes and prognostic factors were examined.Results:After completing 4 to 6 cycles of P-GemDOx chemotherapy, the overall response rate (ORR) was 88.3%, with forty-six patients (76.7% ) achieving complete response (CR). The 4-year progression-free survival (PFS) and overall survival (OS) rates were (66.3±7.1) % and (79.5±6.0) %, respectively. According to the PINK/PINK-E model, there was no significant difference in survival outcomes among risk groups. 23.3% of patients experienced progression of disease within 24 months (POD<24). OS estimates differed significantly ( P<0.001) between the POD<24 group ( n=14) and the POD≥24 group ( n=46). Analysis showed that SUVmax > 12.8 at diagnosis, non-single nasal cavity infiltration, and response less than CR after 4–6 cycles all had a significant association with POD24. We used these data as the basis for predicting POD<24 international prognostic index (POD24-IPI). Patients were stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high risk (two or three risk factors). These groups were associated with 4-year OS rate of 100%, (85.6±9.7) %, and (65.0±10.2) %, respectively ( P=0.014). The P-GemDOx regimen was well tolerated, with hematological toxicity being the main side effect. Conclusion:This study demonstrated that the P-GemDOx regimen is effective and safe in the first-line treatment of early-stage ENKTL, and POD24-IPI is a promising prognostic model.

Objective:This study aimed to assess the efficacy and safety of thioamide as a maintenance therapy for peripheral T-cell lymphoma (PTCL) .Methods:This study retrospectively analyzed the data from 58 patients with PTCL who were treated in the Department of Hematology at the First Affiliated Hospital of Nanjing Medical University from January 2015 to July 2022. Chidamide was orally administered as a maintenance therapy after first-line or salvage treatment. Progression-free survival (PFS), overall survival (OS), and safety were analyzed.Results:Among the 58 patients with PTCL, 43 were males and 15 were females, and the median age was 66 (range: 29-83) years. Thirty-nine patients received thioamide as first-line maintenance therapy, and 19 patients received thioamide as maintenance therapy after salvage treatment. The median maintenance therapy duration was 16 months (range: 1-72 months), with a median PFS time of 33 (2-74) months, and the median OS time had not been reached. Patients who received first-line maintenance therapy with thioamide demonstrated superior PFS and OS outcomes compared with patients who received thioamide maintenance therapy after salvage treatment (median PFS time: not reached vs 7 months, P<0.001; median OS time: not reached vs 67 months, P=0.009). The most prevalent adverse reaction was a hematologic adverse reaction (77.6%). Twelve (20.7%) patients underwent a dose reduction and three patients discontinued treatment. Conclusion:Patients receiving thioamide maintenance therapy demonstrated a promising PFS and OS with a manageable safety profile, especially as the first-line maintenance therapy.

Objective:To investigate the efficacy and safety of orelabrutinib combined with R-CHOP in the treatment of MCD subtype diffuse large B cell lymphoma (DLBCL) .Methods:Twenty-three MCD subtype patients whose gene-subtype classification was based on baseline tumor tissue and/or baseline plasma using the LymphGen algorithm from June 2022 to June 2023 in the First Affiliated Hospital of Nanjing Medical University were retrospectively enrolled in the analysis. All patients were treated with R-CHOP or R-miniCHOP in Course 1, OR-CHOP or OR-miniCHOP (21 days for one course) in Courses 2-6, and R-monotherapy in Courses 7-8.Results:Of the 23 patients, the median age was 58 years (range: 30-81 years), and 11 (47.8% ) aged >60 years. Fifteen cases (65.2% ) had international prognostic index (IPI) scores of 3 to 5. The top 10 mutated genes in the gDNA tissues were PIM1 (78.3% ), MYD88 (69.6% ), ETV6 (43.5% ), BTG1 (39.1% ), CD79B (43.5% ), HIST1H1E (39.1% ), BTG2 (34.8% ), KMT2D (30.4% ), CD58 (26.1% ), and CDKN2B (21.7% ). The consistency rate of the tissue and plasma mutations was 80%, while the baseline plasma ctDNA burden was closely correlated with the LDH levels and IPI scores ( P<0.05). All patients received 5 courses of OR-CHOP regimens. The mid-term (after 3 courses) evaluation showed that the overall response rate (ORR) was 100% (23/23), with 22 patients (95.65% ) achieving complete remission (CR), and 1 patient (4.35% ) achieving partial remission (PR). The ORR after the end of treatment (EOT) was 95.65% (22/23). Moreover, 21 patients (91.30% ) obtained CR, 1 patient (4.35% ) obtained PR, and 1 patient (4.35% ) obtained progression disease (PD). Of the 21 patients who had the dynamic EOT-ctDNA burden, only four patients (19.0% ) did not achieve EOT-ctDNA clearance, while the other 17 patients (81.0% ) achieved EOT-ctDNA clearance. The median follow-up time was 20.8 (15.3-30.0) months, while the median progression-free survival (PFS) and overall survival (OS) were not reached. The 2-year PFS rate was 71.8% (95% CI 54.7% -94.2% ), while the 2-year OS rate was 91.3% (95% CI 80.5% -100.0% ). Furthermore, the OR-CHOP regimen was generally well tolerated during clinical use, with hematological toxicity being the main adverse effect. Conclusion:This study revealed that the OR-CHOP regimen can be used as an effective and safe first-line treatment for MCD subtype DLBCL.

Objective:To quantitatively measure the spatial relationship between the temporomandibular joint (TMJ) and surface landmarks such as the tragus and lateral canthus using cone-beam CT (CBCT), as to provide guidance for accurate positioning of CBCT scanning of the TMJ.Methods:DICOM format data from 112 patients (35 males and 77 females with 224 TMJs) were included in this study. The patients were between 12 and 66 years old, with a mean age of (25.6± 9.8) years and they underwent initial visits at the Department of Stomatology, General Hospital of Chinese PLA. CBCT images were imported into Mimics Medical 21.0 software for three-dimensional reconstruction. The distance between selected surface landmarks and corresponding projection points on the same side of the TMJ were measured in both the sagittal and coronal planes. In the frontal view, the distance from the lateral canthus to the perpendicular line passing through the center of the condyle (d x). In the lateral view, the vertical distance from the horizontal line through the rear edge convex of tragus to the roof of glenoid fossa (d y1); the vertical distance from the horizontal line through the rear edge convex of tragus to sigmoid notch (d y2); the distance from the tragus to the perpendicular line through the center of the condyle (d z). The results were compared between different genders and age groups (adolescent group aged 12 to 18 years, 33 cases; adult group aged>18 years, 79 cases). To verify the reliability and stability of the body surface landmarks obtained in this study, a comparison was made between the use of scout view positioning and the auxiliary positioning method that utilizes body surface landmarks to capture the mandibular condyle in a small field of view CBCT of the TMJ (scout view group, 25 cases; surface landmark-assisted positioning group, with 25 cases aged 12-18 years and 25 cases older than 18 years, totaling 50 cases), with regard to the deviation distance from the central point of the field of view to the central point of the mandibular condyle. Results:A total of 112 patients with 224 TMJs were included in this study. In the frontal view, d x was (8.59±3.13) mm, with no significant difference between the left and right sides, between males and females ( P>0.05). Notably, the d x in the adolescent group [(7.43±3.02) mm] was significantly smaller than that in the adult group [(9.07±3.06) mm] ( t=-3.68, P<0.001). In the lateral view, d y1 was (14.80±3.90) mm, showing no significant difference between the left and right sides, males and females, or different age groups( P>0.05). Similarly, d y2 was (6.82±3.95) mm, with no significant differences between the left and right sides or between males and females( P>0.05). However, the d y2 in the adolescent group [(5.88±4.13) mm] was significantly smaller than that in the adult group [(7.22±3.83) mm] ( t=-2.33, P=0.021). Regarding d z, the measurement was (11.73±3.16) mm, with no significant difference between the left and right sides, between males and females ( P>0.05). Meanwhile, the d z in the adolescent group[(10.92± 2.74) mm] was also significantly smaller than that in the adult group [(12.07±3.27) mm] ( t=-2.52, P=0.012). The verification results showed that both positioning methods could fully display the TMJ. The eccentricity in the scout view group [(8.84±3.79) mm ]was slightly greater than that in the body surface landmark-assisted positioning group[ (6.50±2.88) mm], and the difference between the two groups was statistically significant ( t=4.20, P=0.032). Conclusions:The TMJ can be accurately positioned using stable surface landmarks such as the tragus and lateral canthus for reference.