Replantation of multiple fingertip amputations using super microsurgery: A case report and literature review.

Background: The fingertip amputation is an amputation type of the finger beyond the proximal nail fold. There is no vein available for anastomoses on the dorsal side of the finger, and the palmar vein of the finger is small and tightly attached to the skin. Therefore, it is relatively difficult to implement surgical anastomoses, which poses challenges to the clinical treatment of fingertip amputations. Case report: A 29-year-old male was admitted to the hospital due to "the amputation of the fingertips of the right index, middle, and ring fingers caused by a heavy object compression 3 h ago". The admission examination revealed that the right index, middle, and ring fingers were completely severed at the 1/2 plane of the nail bed, with irregular sections, severe contusion, and pollution. The X-ray examination showed comminuted fractures of the distal phalanges of the right index, middle, and ring fingers. Based on these findings, the patient was diagnosed with multiple severed fingertips of the right hand (Tamai Zone 1). The patient underwent debridement, vascular exploration, and replantation of the right index, middle, and ring fingertips under emergency general anesthesia. After surgery, anti-inflammatory, spasmolytic, and anticoagulant treatment and regular dressing changes were conducted. The patient did not receive a blood transfusion, and all three fingers survived. The appearance of these fingers was favorable 3 months after surgery, and the flexion and extension of these fingers were normal. Eventually, the patient achieved excellent Chen's hand function scores. Conclusions: To the best of our knowledge, this may be the first successful case regarding the replantation of three fingertips after amputations in Tamai Zone 1 with favorable outcomes. It can be maintained that super microsurgery can be used for the replantation of multiple fingertip amputations.

Decreased RNA-binding protein heterogeneous nuclear ribonucleoprotein U improves multiple myeloma sensitivity to lenalidomide.

Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3'-untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU-binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn-humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation.

Long-term quality of life between duodenum-preserving pancreatic head resection and pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: The authors aimed to compare the differences in quality of life (QOL) and overall survival (OS) between duodenum-preserving pancreatic head resection (DPPHR) and pancreatoduodenectomy (PD) during long-term follow-up. DPPHR and PD have been shown to be effective in alleviating symptoms and controlling malignancies, but there is ongoing debate over whether DPPHR has an advantage over PD in terms of long-term benefits. METHOD: The authors searched the PubMed, Cochrane, Embase, and Web of Science databases for relevant studies comparing DPPHR and PD published before 1 May 2023. This study was registered with PROSPERO. Randomised controlled trials and non-randomised studies were included. The Mantel-Haenszel model and inverse variance method were used as statistical approaches for data synthesis. Subgroup analyses were conducted to evaluate the heterogeneity of the results. The primary outcome was the global QOL score, measured using the QLQ-C30 system. RESULTS: The authors analysed ten studies involving 976 patients (456 DPPHR and 520 PD). The global QOL score did not differ significantly between the DPPHR and PD groups [standard mean difference (SMD) 0.21, 95% CI (-0.05, 0.46), P =0.109, I2 =70%]; however, the OS time of patients with DPPHR was significantly improved [hazard ratio 0.59, 95% CI (0.44, 0.77), P <0.001, I2 =0%]. The follow-up length may be an important source of heterogeneity. Studies with follow-up length between two to seven years showed better global QOL for DPPHR than for PD [SMD 0.43, 95% CI (0.23, 0.64), P <0.001, I2 =0%]. There were no significant differences between the two groups in any of the functional scales of the QLQ-C30 system (all P >0.05). On the symptom scale, patients in the DPPHR group had lower scores for fatigue, nausea and vomiting, loss of appetite, insomnia, and diarrhoea than those in the PD group (all P <0.05). CONCLUSIONS: There were no significant differences in global QOL scores between the two surgeries; however, DPPHR had advantages over PD in terms of safer perioperative outcomes, lower long-term symptom scores, and longer OS times. Therefore, DPPHR should be recommended over PD for the treatment of benign pancreatic diseases and low-grade malignant tumours.

RNA-binding protein hnRNPU regulates multiple myeloma resistance to selinexor.

Multiple myeloma (MM) is an incurable haematological cancer. Selinexor is the first-in-class selective inhibitor of nuclear export (SINE) and was newly approved for the treatment of MM. Until now, very few studies have investigated selinexor resistance in MM. Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is an RNA-binding protein and a component of hnRNP complexes. Here we found that hnRNPU regulates MM sensitivity to selinexor. Cell apoptosis assays were performed to compare selinexor-induced cell death in control knockdown (CTR-KD) and hnRNPU knockdown (hnR-KD) MM cells. HnRNPU knockdown-induced nuclear protein retention was examined by proteomics array. HnRNPU-conferred mRNA translation regulation was evaluated by sucrose gradient assay, RNA electrophoresis mobility shift assay, and RNA pull-down assay. We found that hnR-KD MM cells were more sensitive to selinexor-induced cell death in vitro and in mouse model. MM patients who responded to selinexor had relatively low hnRNPU expression. In brief, hnRNPU comprehensively regulated MM sensitivity to selinexor by affecting the localization of LTV1 and NMD3, and mRNA translation of MDM2 and RAN, which were involved in XPO1-mediated nuclear export of ribosome subunits and tumor suppressors. Our discoveries indicate that hnRNPU might be a possible marker to categorize MM patients for the use of Selinexor.

Methylcrotonyl-CoA carboxylase subunit 1 (MCCA) regulates multidrug resistance in multiple myeloma.

AIMS: This study aimed to investigate the effect and mechanism of methylcrotonyl-CoA carboxylase subunit 1 (MCCA) on multidrug resistance in multiple myeloma (MM). MATERIALS AND METHODS: The apoptosis kit and CCK-8 reagent were used to detect drug-induced cell apoptosis and viability. Immunoprecipitation, immunofluorescence staining, and protein structural simulation were used to detect the interaction between MCCA and Bad. Immunodeficient mice were injected with ARD cells and treated with bortezomib. Changes in tumor burden were recorded by bioluminescence imaging, and κ light chain content in the blood of mice was detected by enzyme-linked immunoassay. KEY FINDINGS: Patients with high MCCA expression from a primary MM dataset had superior overall survival. After treatment with different anti-MM drugs, MCCA knockdown MM (MCCA-KD) cells had higher survival rates than control knockdown (CTR-KD) cells (p < 0.05). Mechanistic studies have revealed that MCCA-KD cells had dysfunctional mitochondria with decreased Bax and Bad levels and increased Bcl-xl and Mcl-1 levels. Furthermore, that MCCA and Bad demonstrated protein-protein interactions. The half-life of Bad in MCCA-KD cells is significantly shorter than that in CTR-KD cells (7.34 vs. 2.42 h, p < 0.05). In a human MM xenograft mouse model, we confirmed that MCCA-KD tumors had a poor response to anti-MM drugs in vivo. Finally, we showed that MCCA might contribute to multidrug resistance in different human cancers, particularly in solid tumors. SIGNIFICANCE: Our findings demonstrated a novel function of MCCA in multidrug resistance. The lack of MCCA expression promoted antiapoptotic cell signaling in MM cells.

Valproic acid increases CAR T cell cytotoxicity against acute myeloid leukemia.

The treatment of B cell malignancies has dramatically changed with the introduction of immunotherapy, especially chimeric antigen receptor T (CAR-T) cell therapy. However, only limited efficacy is observed in acute myeloid leukaemia (AML). In the study, We detected CD123 and CLL-1 expression on leukaemia cells from Relapsed/Refractory AML (R/R AML) patients. Then, we constructed anti-CD123 CAR and CLL-1 CAR with different co-stimulation domains (CD28 or 4-1BB) and detected their anti-AML effects. To increase the efficacy of CAR-T cell therapy, we tested different strategies, including application of combined checkpoint inhibitors and histone deacetylase inhibitors (HDACi) in vivo and in vitro We found CD123 and CLL-1 were highly expressed on AML cells. The proportions of T cell subsets and NK cells involved in anti-tumour or anti-inflammation processes in AML patients significantly decreased when compared with healthy donors. Both CD123 CAR and CLL-1 CAR displayed specific anti-AML effects in vitro To improve the lysis effects of CAR-T cells, we combined CAR-T cell therapy with different agents. PD-1/PD-L1 antibodies only slightly improved the potency of CAR-T cell therapy (CD123 CAR-T 60.92% ± 2.9087% vs. 65.43% ± 2.1893%, 60.92% ± 2.9087% vs. 67.43% ± 3.4973%; 37.37% ± 3.908% vs. 41.89% ± 5.1568%, 37.37% ± 3.908% vs. 42.84% ± 4.2635%). However, one HDACi (valproic acid [VPA]) significantly improved CAR-T cell potency against AML cells (CLL-1 CAR-T 34.97% ± 0.3051% vs. 88.167% ± 1.5327%, p < 0.0001; CD123 CAR-T 26.87% ± 2.7010% vs. 82.56% ± 3.086%, p < 0.0001 in MV411; CLL-1 CAR-T 78.77% ± 1.2061% vs. 93.743% ± 1.2333%, p < 0.0001; CD123 CAR-T 64.10% ± 1.5130% vs. 94.427% ± 0.142%, p = 0.0001 in THP-1). Combination therapy prolonged the overall survival of mice when compared with single CD123 CAR-T cell therapy (median survival: 180 days vs. unfollowed). A possible mechanism is that activated CD8+T cells upregulate natural-killer group 2 member D (NKG2D), and VPA upregulates NKG2D ligand expression in AML cells, contributing to NKG2D-mediated cytotoxicity of CAR-T cells against tumour cells. In conclusion, CD123 and CLL-1 are promising targets for AML CAR-T cell therapy. A combination of VPA pre-treatment and CAR-T against AML exhibits synergic effects.

A novel PEGylated form of granulocyte colony-stimulating factor, mecapegfilgrastim, for peripheral blood stem cell mobilization in patients with hematologic malignancies.

BACKGROUND: The Pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) has longer half-life and is given once only, which is more comfortable for patients. We aimed to evaluate the efficacy of mecapegfilgrastim for hematopoietic stem cell (HSC) mobilization in patients with hematologic malignancies and to explore the potential factors related to HSC mobilization. METHODS: A retrospective analysis was performed on patients who underwent HSC mobilization in the hematology department of Mianyang Central Hospital from April 2016 to November 2022. The number of CD34 + cells collected was compared between the patients receiving mecapegfilgrastim (PEG group) and those receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF group), and the possible factors for mobilization failure were analyzed. RESULTS: The success rates of collecting CD34 + cells in the PEG group and rhG-CSF group were 80.6% and 67.7%, respectively (χ = 1.444, P = 0.229). The median CD34 + cell counts were 3.62 × 10^6/kg and 2.92 × 10^6/kg (P = 0.178), respectively. After combination with plerixafor for mobilization, the median number of CD34 + cells collected in the PEG group and rhG-CSF group were 3.64 × 10^6/kg and 3.92 × 10^6/kg, respectively, with no significant difference (P = 0.754). There was no significant difference in hematopoietic cell recovery or infection between the groups (P > 0.05). Multivariate analysis showed that more than 5 cycles of chemotherapy (OR = 15.897, 95% CI: 1.766-143.127, P = 0.014), a precollection WBC count < 32 × 10^9/L (OR = 14.441, 95% CI: 2.180-95.657, P = 0.006) and a precollection to premobilization lymphocyte ratio < 1.7 (OR = 11.388, 95% CI: 2.129-60.915, P = 0.004) were independent risk factors for HSC mobilization failure. CONCLUSIONS: The HSC mobilization efficacy of mecapegfilgrastim in patients with hematologic malignancies was comparable to that of rhG-CSF, and combination with plerixafor for mobilization was feasible and effective. Patients with more than 5 cycles of chemotherapy before HSC mobilization, a precollection WBC count lower than 32 × 10^9/L, and a precollection lymphocyte count less than 1.7 times the premobilization lymphocyte count have a high probability of HSC mobilization failure.

Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia.

PURPOSE: Most patients with acute lymphoblastic leukemia (ALL) are treated with chemotherapy as primary care. Although the treatment response is usually positive, resistance and relapse often occur via unknown mechanisms. The purpose of this study was to identify factors associated with chemotherapy resistance in ALL. Here, we present clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL. METHODS: NCL mRNA and protein levels were compared between cell lines and patient samples using qRT-PCR and immunoblotting. NCL mRNA levels were compared between patients of different disease stages from our clinic patients' specimens and publicly available ALL patient datasets. Cells and patient-derived xenograft mouse experiments were performed to assess the effect of NCL inhibition on ALL chemotherapy effectiveness. RESULTS: Analysis of patient specimens, and publicly available RNA-sequencing datasets revealed a strong correlation between the abundance of NCL and disease relapse or poor survival in B-ALL. Altering NCL expression results in changes in drug sensitivity in ALL cell lines. High levels of NCL upregulated components of the ATP-binding cassette transporters via activation of the ERK pathway, resulting in a decrease in drug accumulation inside the cells. Targeting NCL with AS1411, an NCL-binding oligonucleotide aptamer, significantly increased the sensitivity of ALL cell lines and cells/patient-derived ALL xenograft mice to chemotherapeutic drugs and prolonged mouse survival. CONCLUSION: Our results highlight NCL as a prognostic marker in B-ALL and a potential therapeutic target to combat chemotherapy resistance in ALL.

Clinical study of falls among inpatients with hematological diseases and exploration of risk prediction models.

Background: Falls are serious health events that can cause life-threatening injuries, especially among specific populations. This study assessed the risk factors associated with falls among inpatients with hematological diseases and explored the predictive value of fall risk assessment models. Methods: Clinical data from 275 eligible hematology disease patients who visited Mianyang Central Hospital with or without falls from September 2019 to August 2022 were retrospectively analyzed. Fall risk scores were determined in all included patients. Clinical characteristics were compared between patients with and without falls. Binary logistic regression models were used to screen for potential fall-specific risk factors among hospitalized patients with hematology diseases. Results: Falls occurred in 79 cases. Patients in the fall group had a higher Charlson Comorbidity Index (CCI), a higher incidence of diabetes mellitus, visual impairment, hematological malignancies, and maintenance of stable disease stage, higher glucose levels, and a greater proportion of dizziness, nocturnal defecation, and receipt of intensive chemotherapy than those in the non-fall group (all P < 0.05). Fall patients were also more likely to have used diuretics, laxatives, sedative-sleeping drugs, analgesics, albumin, and calcium, and to have had catheters placed. The Barthel Index, grade of nursing care, support of chaperones, body temperature, nutrition score, and pain score also differed significantly between the two groups (all P < 0.05). Multivariable logistic regression analysis showed that the maintenance of stable disease stage (OR = 4.40, 95% CI 2.11-9.18, P < 0.001), use of sedative and sleeping drugs (OR = 4.84, 95% CI 1.09-21.49, P = 0.038), use of diuretics (OR = 5.23, 95% CI 2.40-11.41, P < 0.001), and intensive chemotherapy (OR = 10.41, 95% CI 3.11-34.87, P < 0.001) were independent risk factors for falls. A high Barthel Index (OR = 0.95, 95% CI 0.93-0.97, P < 0.001), a high level of nursing care (OR = 0.19, 95% CI 0.04-0.98, P = 0.047), and availability of family accompaniment (OR = 0.15, 95% CI 0.06-0.34, P < 0.001) were protective factors for falls. A ROC curve analysis was used to evaluate the predictive value of different fall-specific risk scales among inpatients with hematological diseases. The Johns Hopkins Fall Risk Rating Scale had high sensibility and specificity with an area under the curve of 0.73 (95% CI 0.66-0.80, P < 0.001). Conclusion: The Johns Hopkins Fall Risk Scale had a strong predictive value for falls among hospitalized patients with hematology diseases and can be recommended as a valid tool for clinical use.

[Application of Mecapegfilgrastim for Peripheral Blood Hematopoietic Stem Cell Mobilization in Patients With Hematologic Neoplasms and Analysis of Predictors for Poor Mobilization].

Objective: To evaluate the efficacy of applying mecapegfilgrastim for peripheral blood hematopoietic stem cell (PBSC) mobilization in patients with hematologic neoplasms, and to investigate the influencing factors of PBSC collection. Methods: Patients who underwent PBSC mobilization in the Department of Hematology, Mianyang Central Hospital between April 2016 and May 2022 were retrospectively analyzed. The CD34 + cell collection results of two groups, the mecapegfilgrastim group ( n=28), or the PEG group, and the recombinant human granulocyte colony-stimulating factor (rhG-CSF) group ( n=30), were compared, and the influencing factors of collection failure were analyzed. Results: The success rates of CD34 + cells collection in the PEG group and the rhG-CSF group were 75.0% and 63.3%, respectively ( P>0.05). The median CD34 + cell counts were 3.37×10 6/kg and 2.68×10 6/kg, respectively, showing no significant difference. After combined mobilization with plerixafor, the median counts of CD34 + cells collected in the PEG group and rhG-CSF group were 4.23×10 6/kg and 3.26×10 6/kg, respectively, showing no significant difference ( P>0.05). There was no significant difference in hematopoietic system reconstruction and infections between the two groups ( P>0.05). Multivariate analysis found non-plasma cell disease (odds ratio [ OR]=19.697, 95% confidence interval [ CI] : 1.501-258.537, P=0.023), anemia before collection ( OR=18.571, 95% CI: 1.354-254.775, P=0.029) and white blood cell count before collection under 32×10 9 L -1 ( OR=85.903, 95% CI: 4.947-1491.807, P=0.002) to be independent risk factors for PBSC collection failure. Conclusion: The effect of PBSC mobilization with mecapegfilgrastim was comparable to that of rhG-CSF in patients with hematologic neoplasms. Furthermore, combined mobilization with plerixafor was feasible and effective. Patients with leukemia or lymphoma, anemia, and WBC<32×10 9 L -1 before stem cell collection have a high probability of PBSC collection failure.

Combinations of ivermectin with proteasome inhibitors induce synergistic lethality in multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Ivermectin is a US Food and Drug Administration-approved drug for antiparasitic use. Here, we showed that ivermectin exerted anti-MM effects and significantly synergized with proteasome inhibitors in vitro and in vivo. Ivermectin alone exhibited mild anti-MM activity in vitro. Further investigation suggested that ivermectin inhibited proteasome activity in the nucleus by repressing the nuclear import of proteasome subunits, such as PSMB5-7 and PSMA3-4. Therefore, ivermectin treatment caused the accumulation of ubiquitylated proteins and the activation of the UPR pathway in MM cells. Furthermore, ivermectin treatment caused DNA damage and DNA damage response (DDR) signaling pathway activation in MM cells. Ivermectin and bortezomib exhibited synergized anti-MM activity in vitro. The dual-drug treatment resulted in synergistic inhibition of proteasome activity and increased DNA damage. An in vivo study using a human MM cell line xenograft mouse model showed that ivermectin and bortezomib efficiently repressed MM tumor growth in vivo, while the dual-drug treatment was well tolerated by experimental animals. Overall, our results demonstrated that ivermectin alone or cotreated with bortezomib might be promising in MM treatment.

Loss of MiR-155 Sensitizes FLT3-ITD+AML to Chemotherapy and FLT3 Inhibitors via Glycolysis Blocking by Targeting PIK3R1.

FLT3 tyrosine kinase inhibitors in combination with chemotherapy have shown some success in patients with FLT3 mutations. But a variety of mechanisms have led to the rapid resistance to the treatment. One of the most prominent is the metabolic alteration on aerobic glycolysis. We aim to explore the role of a high expressing microRNA, miR-155, in mediating resistance to chemotherapy and FLT3 inhibitor treatment. The deep sequencing data mining revealed the connection between glycolysis and drug resistance. MV411 cells with miR-155 knockout (KO) not only had increased sensitivity to FLT3 inhibitors but also Adriamycin (ADM) treatment. When combined with glycolysis inhibition the treatment response in MV411 cells further increased. Whereas in miR-155 KO cells, a lower glucose consumption level and lactic acid level were observed, and western blotting showed a decreased expression of key enzymes in glycolysis pathways. A negative correlation between PIK3R1 and miR-155 level can be observed in the sequencing data from FLT3-ITD+ AML patients. Moreover, luciferase reporter assay revealed that the 3'UTR of PIK3R1 mRNA can interact with the seed sequence of miR-155-5p. In conclusion, the loss of miR-155 increased treatment sensitivity to both chemotherapy and FLT3 inhibitors in FLT3-ITD+ AML cells via glycolysis blocking by targeting PIK3R1.

Effects of peripheral blood leukocyte count and tumor necrosis factor-alpha on early death in acute promyelocytic leukemia.

BACKGROUND: Early death remains a major factor in survival in APL. We aimed to analyze the risk factors for differentiation syndrome and early death in acute promyelocytic leukemia (APL). METHODS: The clinical data of APL patients who were newly diagnosed at Mianyang Central Hospital from January 2013 to January 2022 were retrospectively analyzed. RESULTS: Eighty-six newly diagnosed APL patients (37 males and 49 females) were included in this study. The median age was 46 (17-75) years. Sixty-one patients (70.9%) had low/intermediate-risk APL, and 25 patients (29.1%) had high-risk APL. The incidence of differentiation syndrome (DS) was 62.4%. The multivariate analysis showed that a peak white blood cell (WBC) count ≥16 × 10^9/L was an independent risk factor (OR = 11.000, 95% CI: 2.830-42.756, P = 0.001) for DS in all APL patients, while a WBC count ≥10 × 10^9/L on Day 5 was an independent risk factor for DS in low-intermediate risk APL patients (OR = 9.114, 95% CI: 2.384-34.849, P = 0.001). There were 31 patients (36.5%) with mild DS and 22 patients (25.9%) with severe DS. The multivariate analysis showed that WBC count ≥23 × 10^9/L at chemotherapy was an independent risk factor for severe DS (OR = 10.500, 95% CI: 2.344-47.034, P = 0.002). The rate of early death (ED) was 24.4% (21/86). The multivariate analysis showed that male gender (OR = 7.578,95% CI:1.136-50.551, P = 0.036), HGB < 65 g/L (OR = 16.271,95% CI:2.012-131.594, P = 0.009) and WBC count ≥7 × 10^9/L on Day 3(OR = 23.359,95% CI:1.825-298.959, P = 0.015) were independent risk factors for ED. The WBC count at diagnosis, WBC count on Day 3 and WBC count on Day 5 had moderate positive correlations with tumor necrosis factor-α (TNF-α) at diagnosis, and the correlation coefficients were 0.648 (P = 0.012), 0.615 (P = 0.033), and 0.609 (P = 0.035), respectively. The WBC count had no correlation with IL-6. CONCLUSION: During induction treatment, cytotoxic chemotherapy may need to be initiated to reduce the risk of DS for APL patients with a low-intermediate risk WBC count ≥10 × 10^9/L on Day 5 or for all patients with a peak WBC count ≥16 × 10^9/L. Patients with WBC > 7 × 10^9/L on Day 3 have a higher risk of ED. Leukocyte proliferation is associated with TNF-α rather than IL-6, and TNF-α may be a potential biomarker for predicting ED.

Efficacy and safety analysis of bortezomib-based triplet regimens sequential lenalidomide in newly diagnosed multiple myeloma patients.

The aim of this study is to analyze the efficacy and safety of sequential therapy with bortezomib-based triplet regimens without lenalidomide (PXD, including VTD, PAD, and VCD) followed by continuous lenalidomide and dexamethasone (Rd) or bortezomib and dexamethasone (Vd) treatment. The main objective is to evaluate the advantages of PXD followed by Rd compared to the combinations of bortezomib-lenalidomide-dexamethasone (VRd) in newly diagnosed multiple myeloma (NDMM). Fifty-eight nontransplant NDMM patients who were admitted to our department from 2017 to 2019 were included in this study. Bortezomib-based triplet regimens were initially selected and followed by Rd or Vd as continuous treatment once the patients achieved partial remission (PR) or better response. The efficacy and safety of the patients were observed. The Rd continuous treatment cohort was compared with historical data from the EVOLUTION trial on continuous VRd treatment. In our cohort, the overall survival rate was 100%, and progression-free survival (PFS) was 38.5% after a median of 19 (4-36) cycles of Rd continuous therapy was applied. During the follow-up period, the best outcome assessments achieved were 53.8% complete response (CR) and 84.6% excellent partial response (VGPR). A total of 23.1% had grade 3-4 or higher drug-related adverse reactions, mainly hematological toxicity, and no patients died of adverse reactions. Compared with the Vd group, the Rd group had a better PFS and VGPR rate (2-year PFS: 92.3% vs. 56.3%, P = 0.002; 3-year PFS: 69.2% vs. 8.0%, P < 0.001; VGPR: 84.6% vs. 69.2%, P = 0.02). No significant differences were found in ORR (100% vs. 92.3%) or CR (53.8% vs. 35.7%, P = 0.082). Compared with the EVOLUTION study, patients in the Rd group had a more advanced disease stage (stage III rate of 40% vs. 19%, P = 0.039) and worse physical status (KPS 50-60 rate of 25.0% vs. 2.0%, P = 0.000). However, a higher proportion of ORR (100% vs. 73.0%, P < 0.001), VGPR or better (75.0% vs. 32.0%, P < 0.001), and PFS at 12 months (90.0% vs. 68%, P = 0.011) were achieved. Sequential administration of bortezomib-based triplet regimens without lenalidomide as an initial therapy followed by Rd as a continuous treatment may not be inferior to VRd for first-line treatment in NDMM patients.

An E3 ubiquitin-proteasome gene signature for predicting prognosis in patients with pancreatic cancer.

Pancreatic cancer is the seventh leading cause of cancer death worldwide, which is demonstrated with remarkable resistance to radiotherapy and chemotherapy. The identification of prognosis signature and novel prognostic markers will facilitate patient stratification and an individualized precision therapy strategy. In this study, TCGA-PAAD was used to screen prognostic E3 ubiquitin ligases and establish prognostic signatures, and GEO database was used to verify the accuracy of prognostic signatures. Functional analysis, in vitro experiments and clinical cohort studies were used to analyze the function and prognostic efficacy of the target gene. An E3 ligase-based signature of 9 genes and the nomogram were developed, and the signature was proved to accurately predict the prognosis of patients with pancreatic cancer. WDR37 might be the most prognostic E3 ubiquitin ligase in pancreatic cancer, and the clinical cohort analyses suggested a tumor-suppressive role. The results of functional analysis and in vitro experiments indicated that WDR37 may promote the degradation of TCP1 complex to inhibit tumor and improve immune cell infiltration. The E3 ligase-based signature accurately predicted the prognosis of patients with pancreatic cancer, so it can be used as a decision-making tool to guide the treatment of patients with pancreatic cancer. At the same time, WDR37, the main gene in E3PMP signature, can be used as the most prognostic E3 ubiquitin ligase in the treatment of pancreatic cancer.

Predictors of early death and clinical features in newly diagnosed patients with low-intermediate risk acute promyelocytic leukemia.

Background: Although most acute promyelocytic leukemia(APL) with low-intermediate risk could survive the induction treatment, early death still a big problem to have effects on overall survival in real world.This study aimed to analyze the clinical characteristics and possible predictors of early death in newly diagnosed patients with low-intermediate-risk acute promyelocytic leukemia. Methods: Sixty patients with newly diagnosed low/intermediate-risk APL admitted to Mianyang Central Hospital from January 2013 to December 2021 were retrospectively analyzed. Results: Sixty patients with a median age of 46 years (range, 17-75 years) were included. Fourteen patients (23.3%) were in low-risk group, and 46 patients (76.7%) were in intermediate-risk group. Fourteen patients (23.3%) died during induction treatment. Five patients died of hemorrhage, 5 of severe infection and 4 of differentiation syndrome. Multivariate analysis showed that HGB <65g/L at diagnosis (OR=38.474, 95%CI: 2.648~558.923, P=0.008) during induction treatment was an independent risk factors for early death in low- intermediate risk APL patients. In survival group, all patients achieved complete remission, the time to achieve remission was 25.87 ± 5.02 days, the average ATO dosage was 0.16 ± 0.03 mg/kg/day. In univariate analysis, there was no statistically significant difference in time span for remission when ATO dosage was in the 0.11~0.16mg/kg/day range. Compared with patients with low-risk APL, those with intermediate-risk APL had higher white blood cell counts (at diagnosis, day 3, day 5 and peak), higher level of lactate dehydrogenase, higher percentage of bone marrow promyelocytes, more platelet transfusions during treatment, and more early deaths (P<0.05). The overall survival of intermediate-risk APL patients seemed worse than those with low-risk APL (χ=5.033, P =0.025). Conclusions: In patients with low-intermediate risk APL, HGB <65g/L at diagnosis was an independent risk factors for early death. Remission could still be achieved at low-dose ATO without affecting the required time for low-intermediate risk APL patients. Differences in clinical characteristics were found between low-risk and intermediate-risk APL. The intermediate-risk group had higher early mortality risk than the low-risk group.

Comparison of safety and effectiveness between laparoscopic and open pancreatoduodenectomy: A systematic review and meta-analysis.

BACKGROUND: Validity of the laparoscopic approach in pancreatic head lesion remains debatable. This study aims to compare the safety and effectiveness of laparoscopic pancreatoduodenectomy (LPD) and open pancreatoduodenectomy (OPD) and investigate the source of heterogeneity from surgeons' and patients' perspectives. METHOD: We searched PubMed, Cochrane, Embase, and Web of Science for studies published before February 1, 2021. Of 6578 articles, 81 were full-text reviewed. The primary outcome was mortality. Three independent reviewers screened and extracted the data and resolved disagreements by consensus. Studies were evaluated for quality using ROB2.0 and ROBINS-I. According to different study designs, sensitivity and meta-regression analyses were conducted to explore the heterogeneity source. This meta-analyses was also conducted to explore the learning curve's heterogeneity. This study was registered with PROSPERO, CRD42021234579. RESULTS: We analyzed 34 studies involving 46,729 patients (4705 LPD and 42,024 OPD). LPD was associated with lower (P = 0.025) in unmatched studies (P = 0.017). No differences in mortality existed in randomized controlled trials (P = 0.854) and matched studies (P = 0.726). Sensitivity analysis found no significant difference in mortality in elderly patients, patients with pancreatic cancer, and in high- and low-volume hospitals (all P > 0.05). In studies at the early period of LPD (<40 cases), higher mortality (P < 0.001) was found (all P < 0.05).LPD showed non-inferiority in length of stay, complications, and survival outcomes in all analyses. CONCLUSION: In high-volume centers with adequate surgical experience, LPD in selected patients appears to be a valid alternative to LPD with comparable mortality, LOS, complications, and survival outcomes.

Isolated coagulopathy without classic CRAB symptoms as the initial manifestation of multiple myeloma: A case report.

BACKGROUND: Multiple myeloma patients usually present with CRAB symptoms (hypercalcemia, renal disease, anemia and bone diseases) as initial manifestations. Bleeding symptoms are less common, most of which result from thrombocytopenia or infiltration of plasmacytoma. Relatively, coagulopathy is not so common, especially isolated coagulopathy without CRAB manifestations, which is very rare. Herein, we report a 54-year old female who was hospitalized for intermittent and recurrent mild oral mucosal hemorrhage without other bleeding symptoms for almost one month or typical myeloma features. CASE SUMMARY: Two months before admission, the patient underwent implantation of a permanent pacemaker due to sick sinus syndrome. Prothrombin time and activated partial thromboplastin time were significantly prolonged. Factor X deficiency was demonstrated to account for the coagulation dysfunction. An M protein peak was shown by serum protein electrophoresis. 26.11% of abnormal plasma cells were detected in bone marrow by flow cytometry, expressing CD38, CD138, CD56 and intracellular immunoglobulin Kappa light chain. Bone marrow biopsy also proved the presence of abnormal plasma cells, but Congo red stain was negative. The patient was finally diagnosed with multiple myeloma IgA-κ type. A literature review indicated that factor X deficiency was highly related to amyloidosis. Before bleeding signs, the patient had cardiac arrhythmia, enlargement of the heart, and progressive heart failure; thus, cardiac amyloidosis was suspected. CONCLUSION: Bleeding related to coagulation dysfunction is uncommon in multiple myeloma, especially as the initial manifestation. Amyloidosis is a well-recognized cause of isolated acquired factor X deficiency.

Genomic heterogeneity contributed to different prognosis between adult and pediatric acute lymphoblastic.

The prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to that in children. Hence, ALL remains challenging to cure in the adult population. Aberrant genetic alterations have been observed in ALL, although the patterns of differential gene alterations in adult and pediatric ALL have not been comprehensively determined on a genome-wide scale. We investigated the biologic differences in genomic profiles between adults (n = 64) and children (n = 54) with ALL and relationship between genomic heterogeneity and prognosis. The 2 populations showed similar common mutation types but an increased prevalence of genetic alterations in adult ALL. The median numbers of gene mutations were 17 (range: 1-53) and 4.5 (range: 1-19) per sample in adult and pediatric ALL, respectively (p < 0.001). An increased number of gene mutations and age were significantly correlated (R2  = 0.5853, p < 0.001). We identified 122 and 53 driver genes in adult and pediatric ALL samples, respectively. IKZF1, IDH1, and TTN mutations were significantly enriched in adult patients with ALL. KRAS, ARID1A, and CREBBP mutations were significantly enriched in pediatric patients with ALL (p < 0.05). The incidence of relapse was 40.0% and 9.6% in adult and pediatric patients with ALL, respectively (p = 0.003). The overall survival and relapse-free survival of adult patients with ALL were poorer than those of pediatric patients with ALL (p = 0.002 and p < 0.001, respectively). This genomic landscape enhances the understanding of the biologic differences in ALL between the 2 populations and provides insight for developing therapeutic approaches.

CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/ß-catenin axis.

BACKGROUND: Epstein-Barr virus (EBV) represents an important pathogenic factor of lymphoma and is significantly associated with poor clinical outcome of diffuse large B-cell lymphoma (DLBCL). Circular RNAs (circRNAs) play an essential role in lymphoma progression. However, the underlying mechanism of circRNA on DLBCL progression related to EBV remains largely unknown. METHODS: CircRNA was screened by high-throughput sequencing in tumor samples of 12 patients with DLBCL according to EBV infection status. Expression of circEAF2, as well as the relationship with clinical characteristics and prognosis, were further analyzed in tumor samples of 100 DLBCL patients using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted to investigate the biological functions of circEAF2 both in vitro and in vivo. The underlying mechanism of circRNA on DLBCL progression were further determined by RNA sequencing, RNA pull down assay, dual-luciferase reporter assay, rescue experiments and western blotting. RESULTS: We identified a novel circRNA circEAF2, which was downregulated in EBV + DLBCL and negatively correlated with EBV infection and DLBCL progression. In EBV-positive B lymphoma cells, circEAF2 overexpression induced lymphoma cell apoptosis and sensitized lymphoma cells to epirubicin. As mechanism of action, circEAF2 specifically targeted EBV-encoded miR-BART19-3p, upregulated APC, and suppressed downstream ß-catenin expression, resulting in inactivation of Wnt signaling pathway and inhibition of EBV + DLBCL cell proliferation. In EBV-positive B-lymphoma murine models, xenografted tumors with circEAF2 overexpression presented decreased Ki-67 positivity, increased cell apoptosis and retarded tumor growth. CONCLUSIONS: CircEAF2 counteracted EBV + DLBCL progression via miR-BART19-3p/APC/ß-catenin axis, referring circEAF2 as a potential prognostic biomarker. Therapeutic targeting EBV-encoded miRNA may be a promising strategy in treating EBV-associated lymphoid malignancies.