Overall Survival Rate Of Patients Research Articles

TBI-Containing with T-Cell Replete Full Haplotype Mismatched Hematopoietic Stem Cell Transplantation in Adult Patients with De Novo Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the 2nd most frequent developing hematologic malignancy with deep heterogeneity, but unfortunately the majority of patients relapse even after allogeneic hematopoietic stem cell transplantation (HSCT) in complete remission (CR). We have developed allogeneic HSCT from familial mismatched/haploidentical donors (FMT) in adult patients with a single disease entity of AML lacking of both HLA-identical siblings and well-matched unrelated donors (WMUD) from the mid 1990s. Previously, several pilot studies of FMT performed with various total body irradiation (TBI)-based conditioning regimens (2~12 gray) with or without post-transplant cyclophosphamide (PT-Cy) as a graft-versus-host disease (GvHD) prophylaxis were reported. Here, we demonstrate about the encouraging outcomes of FMT using unmanipulated peripheral blood donor stem cells (PBSCs) and de-escalated dose of TBI (4~8 gray) containing conditioning regimen without T-cell depletion manner. Although PT-Cy as a specific GvHD prophylaxis regimen is increasingly used for both adult and pediatric FMT, our group investigated the clinical outcomes in adult patients with de novo AML who received full haplotype mismatched HSCT after TBI containing preparation regimen consisted of fractionated TBI (total 4 gray for elderly and 8 gray for <60 years old), fludarabine (150 mg/m 2/day), busulfex (6.4mg/kg/day), and anti-thymocyte globulin (ATG). For GvHD prophylaxis, rabbit ATG (thymoglobulin, Genzyme, 1.25mg/kg/day for 4 days at D-4 to D-1) and a combination of tacrolimus and short-term methotrexate was used. G-CSF mobilized unmanipulated PBSCs were used with a median CD34+ dose of 6.5 x 10 6/kg (1~25.6). From 2008 to the end of 2022, total 429 adult patients were enrolled, and data demonstrated that our trial of intermediate-dose of ATG and reduced toxicity of TBI-containing conditioning regimen to reduce graft-failure even for high levels of donor-specific antibody titer, early transplant-related mortality, critical cytomegalovirus (CMV) disease, and emerging post-transplant lymphoproliferative disease with rapid immune recovery has shown very successful outcomes. Briefly, the median absolute neutrophil count recovery was 12 days (10~26) and the platelet of 14 days (5~38). There was no either primary or secondary graft-failures at all. With a median follow-up of 36.5 months (2~242) for survivors, overall survival rate (OS) and relapse-free survival (RFS) for patients in any CR (n=338) and relapse/refractory status (n=91) were 62.9% vs. 34.3% and 59.5% vs. 32.2%, respectively. Although there was no significant difference in the subgroup analysis, de novo and young aged patients in any CR showed the best OS 73% (Figure 1). Cumulative incidences of acute GvHD and chronic GvHD were 66% (59-73), 70% (63-76), respectively. The incidences of moderate to severe acute GvHD and chronic GvHD were 16.1%, 30.5%, respectively. By univariate and multivariate analyses, patient's age <54 (p=0.043), pre-HSCT CR1 (p <0.001), absence of mod to severe chronic GvHD (p <0.001), and use of post-transplant iron-chelating agent (p=0.001) were the statistically significant in the study. The GvHD-free and relapse-free survival rate in CR1 was 62.4% for younger patients (age <54) and 47.9% for older patients (p=ns). The non-relapse mortality rate was 27.2% for all enrolled patients and 16% for CR patients. The rapidity of immune recovery was also compared with our old control cohort when we performed T-cell depletion using the CliniMACS system, and it showed a significant reconstitution of CD4+ cells (>300/ul) at 3 months post-FMT compared to the much delayed T-cell depleted FMT. Of note, CMV DNAemia was relatively higher (76.9%) than reported in other studies, likely due to the use of ATG and the endemic region of our country. Therefore, we suggest that the strategic reduction of fractionated TBI 4~8 gray-based conditioning with unmanipulated PBSCs graft without PT-Cy seems feasible with favorable outcomes for adult patients with de novo AML undergoing FMT in CR, especially even in a certain subgroup of elderly patients with AML.

Combining Selinexor with R-CHOP in the Treatment of Newly Diagnosed High-Risk (IPI 3-5) GCB Subtype DLBCL Patients: A Multicenter, Open Label Phase 2 Study

Background Diffuse large B-cell lymphoma (DLBCL) is an aggressive and highly heterogeneous lymphoma, and for high-risk group who has an International Prognostic Index (IPI) score of 3-5 it is more difficult to treat (Teras LR,2016; Ziepert M,2010). Under the standard R-CHOP-like immunochemotherapy, the 3-year overall survival (OS) rate of patients with IPI score of 0-1, 2, 3, 4-5 were 91%, 81%, 65% and 59%, respectively (Ziepert M,2010). The efficacy for high-risk population (IPI 3-5) was limited even after intensive chemotherapy, with an ORR of 74.5% and CR of 47.3% under R-CODOX-M/R-IVAC (McMillan AK,2020). Nonetheless, adding new agents to R-CHOP shows better efficacy in patients with IPI 3-5(Tilly H,2022; Nowakowski GS,2021). GCB subtype has better prognosis, but 20% of patients still relapsed after R-CHOP therapy (Nowakowski GS,2015), and no more benefit was achieved by modifying regimen with new agents like polatuzumab-R-CHP (Tilly H,2022), adding on lenalidomide (Nowakowski GS,2015) or ibrutinib (Wilson WH,2021). Selinexor is the only approved oral selective nuclear export inhibitor which demonstrated a 34% ORR in GCB subgroup as a monotherapy in relapsed/refractory DLBCL (Kalakonda N,2020). Selinexor combined with R-CHOP showed a CR rate of 58.8% and ORR of 94.1% in 17 high risk GCB DLBCL patients in a real-world setting (Zhiming Li,2023). This phase 2 study (NCT05422066) further explored the benefit and safety of Selinexor plus R-CHOP in the treatment of newly diagnosed (ND) GCB DLBCL patients with IPI 3-5. Methods This is a multicenter, open label, single arm phase 2 study enrolled 18~75 years old ND GCB DLBCL patients with IPI 3-5. Patients were administered selinexor 60mg QW in combination with standard R-CHOP therapy for 6 cycles (Rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2, doxorubicin 50 mg/m 2 IV, vincristine 0.5 mg/kg on day 1, prednisone 100 mg PO on days 1-5 in a 21-day cycle). The primary endpoint is complete remission (CR) rate. Secondary endpoints include objective response Rate (ORR), progression free survival (PFS), disease free survival (DFS), overall survival (OS), safety and tolerability. Results The median age of 15 patients was 59 years (range 25-71), with 10 males (66.7%). All patients were in advanced stage according to Ann Arbor staging system, with 13 patients in stage IV, and 2 in stage III. 11(73.3%) patients had ≥2 extranodal lesions and 9 (60%) patients had higher LDH level at baseline. 1 patient had TP53 mutation, and 6 patients (40%) had double expressor lymphoma (DEL) (Table 1). The overall best ORR and CR were 100% and 60%, respectively. The CR rate in 6 DEL patients were 50%; Patients with ≥2 extranodal lesions reached a CR of 54.5% (n=11), while 3 out of 4 patients with≤1 extranodal lesions completely responded. The CR rates of patients with Ki-67≥80% vs＜80% were 50% vs 62.5%, respectively. Median PFS and OS were not reached yet with a median follow-up of 8 months (range 2-11 months). 2 patients had progressive disease with 1 progressed after C4 and the other 1 after C6. 4 patients with viral hepatitis (3 HBV, 1 HCV) were administered both anti-tumor and antiviral therapy, and their HBV-DNA and HCV-RNA levels continuously declined (till undetectable) along with their tumor load (3 CR ,1 PR). Common treatment-relate adverse events (grade 3/4, all grades) included: leukopenia (80%, 93%), neutropenia (73%, 87%), anemia (27%, 93%), thrombocytopenia (27%, 67%), lymphopenia (20%, 27%), anorexia (13%, 40%), pneumonia (13%,40%), hypertriglyceridemia (7%, 40%), diarrhea (7%, 20%). All AEs were managed with appropriate supportive care and dose adjustments. 8 out of 15 patients had a dose reduction of selinexor to 40mg (initial dose 60mg QW) due to AE, 3 in C2 and the other 5 in C4-C5. All patients were continuously treated after dose reduction, and no treatment-related deaths occurred. Overall, 6 patients completed 6 cycles of selinexor+R-CHOP treatment with sustained remission, and 6 patients were still receiving therapy at time of writing this abstract (4 in C6, 2 in C3). 3 patients ended study, 2 PD and 1 withdrew informed consent after PR at the end of C4 (Figure 1). Conclusion Once weekly 60mg selinexor can be safely combined with R-CHOP in ND high risk (IPI 3-5) GCB subtype DLBCL patients with ORR of 100% and CR of 60%. No viral reactivation was observed in patients with viral hepatitis with simultaneous antiviral therapy.

Correlation between pre-treatment serum total blood bilirubin and unconjugated bilirubin and prognosis in patients with colorectal cancer.

Epidemiological studies have found that unconjugated bilirubin (UCB) levels are positively correlated with the incidence of colorectal cancer (CRC). Therefore, bilirubin may also play an important role in the prognosis of CRC. To investigate the predictive value of total bilirubin (TBIL) and UCB in the prognosis of patients with CRC. A total of 142 CRC patients were selected as the research subjects in Jingxian Hospital, from October 2014 to May 2021. General and tumour-related clinical data at admission and the overall survival at 3 years after surgery were collected. The optimal cut-off values of TBIL and UCB were determined by receiver operating characteristic curve analysis. Univariate and multivariate Cox regression were used to analyse the effect of bilirubin level on the survival of CRC patients. The Kaplan-Meier method was used to assess the survival time. The 3-year overall survival rate of CRC patients was significantly higher in the high TBIL (> 13.45 μmol/L) group than in the low TBIL (≤ 13.45 μmol/L) group (76.4% vs 37.1%; P < 0.05). The 3-year overall survival rate of CRC patients in the high UCB (> 10.75 μmol/L) group was significantly higher than that in the low UCB (≤ 10.75 μmol/L) group (83.3% vs 34.2%; P < 0.05). Multivariate Cox regression analysis showed that higher TBIL levels were an independent predictor of better prognosis in CRC patients (hazard ratio = 0.360, 95% confidence interval: 0.159-0.812, P = 0.014). TBIL levels can be used as a prognostic indicator for CRC patients.

TRIM29 promotes antitumor immunity through enhancing IGF2BP1 ubiquitination and subsequent PD-L1 downregulation in gastric cancer

Tripartite motif-containing protein 29 (TRIM29) is a member of TRIM family protein which has been reported to play a role in the progress of inflammatory and cancer diseases. However, its specific role in gastric cancer (GC) has yet to be fully understood. Here, we investigated the expression of TRIM29 in gastric cancer and its functions in the antitumor immunity. TRIM29 expression was lower in tumor tissues than that in paired normal tissues. Lower expression of TRIM29 was related to aberrant hypermethylation of CpG islands in TRIM29 gene. Comprehensive proteomics and immunoprecipitation analyses identified IGF2BP1 as TRIM29 interactors. TRIM29 interacted with IGF2BP1 and induced its ubiquitination at Lys440 and Lys450 site by K48-mediated linkage for protein degradation. IGF2BP1 promoted PD-L1 mRNA stability and expression in a 3′UTR and m6A-dependent manner. Functionally, TRIM29 enhanced antitumor T-cell immunity in gastric cancer dependent on the IGF2BP1/PD-L1 axis in vivo and in vitro. Clinical correlation analysis revealed that TRIM29 expression in patient samples was associated with CD8+ immune cell infiltration in the GC microenvironment and the overall survival rates of GC patients. Our findings revealed a crucial role of TRIM29 in regulating the antitumor T-cell immunity in GC. We also suggested that the TRIM29/IGF2BP1/PD-L1 axis could be used as a diagnostic and prognostic marker of gastric cancer and a promising target for GC immunotherapy.

Long non-coding RNA SNHG17 may function as a competitive endogenous RNA in diffuse large B-cell lymphoma progression by sponging miR-34a-5p.

We investigated the functional mechanism of long non-coding small nucleolar host gene 17 (SNHG17) in diffuse large B-cell lymphoma (DLBCL). lncRNAs related to the prognosis of patients with DLBCL were screened to analyze long non-coding small nucleolar host gene 17 (SNHG17) expression in DLBCL and normal tissues, and a nomogram established for predicting DLBCL prognosis. SNHG17 expression in B-cell lymphoma cells was detected using qPCR. The effects of SNHG17 with/without doxorubicin on the proliferation and apoptosis of DoHH2 and Daudi were detected. The effects of combined SNHG17 and doxorubicin were analyzed. The regulatory function of SNHG17 in DLBCL was investigated using a mouse tumor xenotransplantation model. RNA sequencing was used to analyze the signaling pathways involved in SNHG17 knockdown in B-cell lymphoma cell lines. The target relationships among SNHG17, microRNA, and downstream mRNA biomolecules were detected. A higher SNHG17 level predicted a lower survival rate. SNHG17 was highly expressed in DLBCL patient tissues and cell lines. We established a prognostic model containing SNHG17 expression, which could effectively predict the overall survival rate of DLBCL patients. SNHG17 knockdown inhibited the proliferation and induced the apoptosis of B-cell lymphoma cells, and the combination of SNHG17 and doxorubicin had a synergistic effect. SNHG17, miR-34a-5p, and ZESTE gene enhancer homolog 2 (EZH2) had common hypothetical binding sites, and the luciferase reporter assay verified that miR-34a-5p was the direct target of SNHG17, and EZH2 was the direct target of miR-34a-5p. The carcinogenic function of SNHG17 in the proliferation and apoptosis of DLBCL cells was partially reversed by a miR-34a-5p inhibitor. SNHG17 increases EZH2 levels by inhibiting miR-34a-5p. Our findings indicate SNHG17 as critical for promoting DLBCL progression by regulating the EZH2 signaling pathway and sponging miR-34a-5p. These findings provide a new prognostic marker and therapeutic target for the prognosis and treatment of DLBCL.

PYCR1, BANF1, and STARD8 Expression in Gastric Carcinoma: A Clinicopathologic, Prognostic, and Immunohistochemical Study.

It will be important to understand the molecular pathways of gastric cancer (GC) occurrence and progression, thus detecting predictive and prognostic biomarkers of GC. Pyrroline-5-carboxylate reductase 1 (PYCR1) was upregulated in many cancers, suggesting its possible roles in carcinogenesis and tumor metastases. Barrier-of-autointegration factor 1 (BANF1) is a protein family that plays essential roles in maintaining the integrity of an intact cellular genome. Rho-GTPs are molecular switches that control many signal transduction pathways in normal cells, including 3 subgroups from 1 to 3 (DLC1-3). DLC-3, known as StAR-related lipid transfer domain protein 8 (STARD8), and its role in cancers were not sufficiently studied. The study aimed to investigate the significance of PYCR1, BANF1, and STARD8 protein expression in GC tissues and normal gastric mucosa retrieved from patients with GC to detect prognostic roles of expression. Specimens were collected from 100 patients with gastric carcinoma. After the application of the inclusion criteria of the study, we prepared 100 paraffin blocks from samples of the 100 included patients; each block included samples from gastric carcinoma and adjacent non-neoplastic gastric mucosa. We assessed the expression of PYCR1, BANF1, and STARD8 using immunohistochemistry in all studied samples. We followed patients for the detection of disease progression and survival rates. We correlate PYCR1, BANF1, and STARD8 expression with clinical, pathologic, and prognostic parameters. Overexpression of PYCR1 and BANF1 and decreased expression of STARD8 was found in gastric carcinoma tissues than adjacent non-neoplastic gastric mucosa ( P <0.001), and was positively associated with high grade ( P =0.006), depth of tumor invasion, presence of lymph nodes metastases and advanced stage ( P =0.001), high incidence of GC progression, recurrence, unfavorable disease-free survival ( P =0.003) and unfavorable overall survival rates ( P <0.001). Thus, it was revealed that; in univariate and multivariate analyses, levels of PYCR1, BANF1, and STARD8 are associated with the overall survival rate of GC patients. We showed that overexpression of PYCR1 and BANF1 and decreased expression of STARD8 in GC tissues was associated with poor prognosis and GC progression.

Effect of low visceral fat area on long-term survival of stage I–III colorectal cancer

ObjectiveThe prognostic significance of a low visceral fat area (VFA) in colorectal cancer (CRC) remains unclear. The aim of this study was to evaluate the prognostic effects of a low VFA on the long-term outcomes of patients with CRC after laparoscopic surgery. MethodsThis retrospective study included 306 patients with stages I–III CRC who underwent R0 resection. VFA was preoperatively measured via computed tomography using image processing software. Relapse-free survival (RFS) and overall survival (OS) rates were analyzed using the Cox proportional hazards model and Kaplan–Meier curves. ResultsLow VFA was identified in 153 patients. The low VFA group had significantly lower RFS and OS rates than did the high VFA group (5-y RFS rates: 72 versus 89%, P = 0.0002; 5-y OS rates: 72 versus 92%, P = 0.0001). The independent significant predictors of RFS were T3 or T4 disease (hazard ratio [HR], 2.75; 95% confidence interval [CI], 1.12–6.76; P = 0.027), stage III CRC (HR, 3.49; 95% CI, 1.82–6.69; P < 0.001), low psoas muscle index (PMI; HR, 2.12; 95% CI, 1.19–3.79; P = 0.011), and low VFA (HR, 2.12; 95% CI, 1.16–3.86; P = 0.014). The independent significant predictors of OS were age ≥65 y (HR, 2.59; 95% CI, 1.13–5.92, P = 0.024), carbohydrate antigen 19-9 levels ≥37 ng/mL (HR, 2.32; 95% CI, 1.18–4.58; P = 0.015), stage III CRC (HR, 2.66; 95% CI, 1.37–5.17; P = 0.004), low PMI (HR, 2.00; 95% CI, 1.06–3.77; P = 0.031), and low VFA (HR, 2.42; 95% CI, 1.24–4.70; P = 0.009). ConclusionA low preoperative VFA was significantly associated with worse RFS and OS rates in patients who underwent CRC resection.

Construction and validation of a prognostic model for tongue cancer based on three genes signature.

Tongue squamous cell carcinoma (TSCC) has a poor prognosis and destructive characteristics. Reliable biomarkers are urgently required to predict disease outcomes and to guide TSCC treatment. This study aimed to develop a multigene signature and prognostic nomogram that can accurately predict the prognosis of patients with TSCC. We screened differentially expressed genes associated with TSCC using The Cancer Genome Atlas dataset. Based on this, we developed a new multi-mRNA gene signature using univariate Cox regression, Least Absolute Shrinkage and Selection Operator regression, and multivariate Cox regression. We used the concordance index to evaluate the accuracy of this new multigene model. Moreover, we performed receiver operating characteristic and Kaplan-Meier survival analyses to assess the predictive ability of the new multigene model. In addition, we created a prognostic nomogram incorporating clinical and pathological characteristics, with the aim of enhancing the adaptability of this model in practical clinical settings. We successfully developed a new prognostic model based on the expression levels of these 3 mRNAs that can be used to predict the prognosis of patients with TSCC. This prediction model includes 3 genes: KRT33B, CDKN2A, and CA9. In the validation set, the concordance index of this model was 0.851, and the area under the curve was 0.778 and 0.821 in the training and validation sets, respectively. Kaplan-Meier survival analysis showed that regardless of whether it was in the training or validation set, the prognosis of high-risk patients was significantly worse than that of low-risk patients (P < .001). Multivariate Cox regression analysis revealed that this model was an independent prognostic factor for patients with TSCC (P < .001). Our study suggests that this 3-gene signature model has a high level of accuracy and predictive ability, is closely related to the overall survival rate of patients with TSCC, and can independently predict the prognosis of TSCC patients with high accuracy and predictive ability.

Integrated untargeted and targeted proteomics to unveil plasma prognostic markers for patients with acute paraquat poisoning: A pilot study

Paraquat (PQ) is a widely used but strongly toxic herbicide, which can induce multiple organ failure. The overall survival rate of the poisoned patients was only 54.4% due to lack of specific antidotes. Besides, the definite pathogenic mechanism of PQ is still not fully understood. In this pilot study, untargeted and targeted proteomics were integrated to explore the expression characteristics of plasma protein in PQ poisoned patients, and identify the differentially expressed proteins between survivors and non-survivors. A total of 494 plasma proteins were detected, and of which 47 were upregulated and 44 were downregulated in PQ poisoned patients compared to healthy controls. Among them, five differential plasma proteins (S100A9, S100A8, MB, ACTB and RAB11FIP3) were further validated by multiple reaction monitoring (MRM)-based targeted proteomic approach, and three of them (S100A9, S100A8 and ACTB) were confirmed to be correlated with PQ poisoning. Meanwhile, 84 dysregulated plasma proteins were identified in non-survivors compared with survivors. Moreover, targeted proteomic and ROC analysis suggested that ACTB had a good performance in predicting the prognosis of PQ poisoned patients. These findings highlighted the value of label-free and mass spectrometry-based proteomics in screening prognostic biomarkers of PQ poisoning and studying the mechanism of PQ toxicity.

Identification of cancer-associated fibroblasts signature for predicting the prognosis and immunotherapy response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies globally with poor prognosis. Cancer-associated fibroblasts (CAFs) play multiple functions in the regulation of tumorigenesis, metastasis and therapeutic resistance of cancer. The current study aimed to explore the role of CAFs-related genes in the prognosis and immunotherapy response in HCC. CAFs-related genes were identified by using single-cell RNA-sequencing analysis. Least absolute shrinkage and selection operator (LASSO) analysis was conducted to develop a CAFs-related prognostic signature (FRPS) in TCGA dataset and verified in ICGC, GSE14520 and GSE76427 cohorts. Several tools, including Tumor Immune Dysfunction and Exclusion (TIDE) score, immunophenoscore, and Tumor Mutation Burden (TMB) score were used to evaluate the value of FRPS in predicting immunotherapy benefits. The FRPS constructed based on 10 genes (RGS5, CNN3, PALLD, FLNA, KLHL23, MYC, NDRG2, SERPINE1, CD151 CALU) served as an independent risk factor and showed stable and powerful performance in predicting the overall survival rate of HCC patients with an AUCs of 0. 734, 0.727, and 0.717 in 2-, 3-, and 4-year ROC curve in TCGA cohort. Low risk score indicated a higher abundance of CD8+ T cells and NK, and lower abundance of Treg. Moreover, HCC patients with low risk score had a higher PD1&CTLA4 immunophenoscore, higher TMB score, and lower TIDE score. Moreover, high risk score indicated a lower IC50 value of 5-fluorouracil, camptothecin, cisplatin, docetaxel, gemcitabine, paclitaxel, afatinib, crizotinib, dasatinib, erlotinib, erlotinib, gefitinib, lapatinib, and osimertinib in HCC. Our study develops a novel FRPS HCC. The FRPS acts as a risk factor for the prognosis of HCC patients and it can predict the immunotherapy benefits of HCC patients.

Circular RNA from Tyrosylprotein Sulfotransferase 2 Gene Inhibits Cisplatin Sensitivity in Head and Neck Squamous Cell Carcinoma by Sponging miR-770-5p and Interacting with Nucleolin.

Chemoresistance poses a significant challenge in the treatment of advanced head and neck squamous cell cancer (HNSCC). The role and mechanism of circular RNAs (circRNAs) in HNSCC chemoresistance remain understudied. We conducted circRNA microarray analysis to identify differentially expressed circRNAs in HNSCC. The expression of circRNAs from the tyrosylprotein sulfotransferase 2 (TPST2) gene and miRNAs was evaluated through qPCR, while the circular structure of circTPST2 was verified using Sanger sequencing and RNase R. Through Western blotting, biotin-labeled RNA pulldown, RNA immunoprecipitation, mass spectrometry, and rescue experiments, we discovered miR-770-5p and nucleolin as downstream targets of circTPST2. Functional tests, including CCK8 assays and flow cytometry, assessed the chemoresistance ability of circTPST2, miR-770-5p, and Nucleolin. Additionally, FISH assays determined the subcellular localization of circTPST2, miR-770-5p, and Nucleolin. IHC staining was employed to detect circTPST2 and Nucleolin expression in HNSCC patients. circTPST2 expression was inversely correlated with cisplatin sensitivity in HNSCC cell lines. Remarkably, high circTPST2 expression correlated with lower overall survival rates in chemotherapeutic HNSCC patients. Mechanistically, circTPST2 reduced chemosensitivity through sponge-like adsorption of miR-770-5p and upregulation of the downstream protein Nucleolin in HNSCC cells. The TCGA database revealed improved prognosis for patients with low circTPST2 expression after chemotherapy. Moreover, analysis of HNSCC cohorts demonstrated better prognosis for patients with low Nucleolin protein expression after chemotherapy. We unveil circTPST2 as a circRNA associated with chemoresistance in HNSCC, suggesting its potential as a marker for selecting chemotherapy regimens in HNSCC patients. Further exploration of the downstream targets of circTPST2 advanced our understanding and improved treatment strategies for HNSCC.

Incidence and Survival of Testicular Cancers in a Province in Northern Italy and Their Association with Second Tumors.

This study investigated the incidence, mortality, and 5-year survival rates of testicular cancers diagnosed in a northern Italian province, which were eventually associated with previous or subsequent extratesticular neoplasms. Cases from 1996 to 2020 were examined by age and histotype (seminoma vs. non-seminoma). The standardized incidence rate was calculated using the European population, and the annual percent change (APC) was reported. The five-year relative survival was estimated using the Pohar Perme method. The association with the second neoplasm was also evaluated. In our study, 385 patients with testicular cancer were included, most of whom were aged between 30 and 40 years. The non-seminoma and seminoma groups accounted for 44% and 18% of younger adults, respectively. The incidence rate increased during the study period (APC 1.6*); however, it increased in seminomas (APC 2.3*) but not in non-seminomas (APC -0.1). Conversely, the mortality rate remained constantly low either overall or in each of the two groups. The overall 5-year survival rate of testicular cancer patients was 95% (99% and 88% for seminomas and non-seminomas, respectively). Primary extratesticular tumors were documented in 37 cases, 18 after and 19 before the testicular cancer diagnosis. Our study confirms that the increased incidence and excellent survival rate are the prerogative of seminomas.

Construction of a Nomogram to Predict Overall Survival in Patients with Early-Onset Hepatocellular Carcinoma: A Retrospective Cohort Study.

Hepatocellular carcinoma (HCC) is a widespread and impactful cancer which has pertinent implications worldwide. Although most cases of HCC are typically diagnosed in individuals aged ≥60 years, there has been a notable rise in the occurrence of HCC among younger patients. However, there is a scarcity of precise prognostic models available for predicting outcomes in these younger patients. A retrospective analysis was conducted to investigate early-onset hepatocellular carcinoma (EO-LIHC) using data from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2018. The analysis included 1392 patients from the SEER database and our hospital. Among them, 1287 patients from the SEER database were assigned to the training cohort (n = 899) and validation cohort 1 (n = 388), while 105 patients from our hospital were assigned to validation cohort 2. A Cox regression analysis showed that age, sex, AFP, grade, stage, tumor size, surgery, and chemotherapy were independent risk factors. The nomogram developed in this study demonstrated its discriminatory ability to predict the 1-, 3-, and 5-year overall survival (OS) rates in EO-LIHC patients based on individual characteristics. Additionally, a web-based OS prediction model specifically tailored for EO-LIHC patients was created and validated. Overall, these advancements contribute to improved decision-making and personalized care for individuals with EO-LIHC.

Abstract 18441: Long-Term Outcomes of Total Arch Replacement With Frozen Elephant Trunk Procedure for Patients With Acute Type A Aortic Dissection: A Single-Center Experience

Introduction: Total arch replacement (TAR) with frozen elephant trunk (FET) is an extensive surgical procedure for patients with acute type A aortic dissection (ATAAD). This study aimed to investigate the long-term outcomes of TAR with FET procedure for patients with ATAAD. Methods: A total of 670 patients with ATAAD who underwent TAR with FET procedure between January 2013 and December 2018 were included in this study. The patients were divided into two groups: the early group (n=245, 2013-2015) and the modern group (n=425, 2016-2018). In-hospital and long-term outcomes were compared between the two groups. Results: The average age and gender distribution were similar between the two groups (P&gt;0.05). The modern group had a higher prevalence of preoperative coma (P&lt;0.001). Patients in the modern group had a shorter mean duration of surgical procedure, including cardiopulmonary bypass time (189.8 ± 53.0 vs 176.0 ± 53.0 min, P=0.001) and hypothetical cardiac arrest time (22.8 ± 5.2 vs 15.1 ± 6.2 min, P&lt;0.001). Although the in-hospital mortality was lower in the modern group, the difference was not statistically significant (6.1% vs 3.3%, P=0.064). The modern group had a significantly lower incidence of postoperative major adverse outcomes compared to the early group (33.9% vs 20.2%, P&lt;0.001). The mean follow-up period was similar between the two groups. The overall long-term survival rate of patients undergoing TAR with FET procedure in this cohort was 92.7%. Patients in the modern group had a significantly lower cumulative incidence of all-cause mortality compared to those in the early group (P&lt;0.001). Cox regression analysis showed that the modern year was an independent protective factor for the long-term survival of ATAAD patients undergoing TAR with FET procedure (HR=0.336, 95% CI: 0.193-0.585, P&lt;0.001). Conclusions: The in-hospital and long-term outcomes of TAR with FET procedure for patients with ATAAD are promising and have improved over time.

Prognostic related gene index for predicting survival and immunotherapeutic effect of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common malignant liver tumor. It is an aggressive disease with high mortality rate. In this study, we investigated a new prognosis-related gene index (PRGI) that can predict the survival and efficacy of immunotherapy in patients with HCC. RNA-seq data and clinical data of HCC samples were obtained from the cancer genome atlas and ICGC databases. Prognosis-related genes were obtained using log-rank tests and univariate Cox proportional hazards regression. Univariate and multivariate analyses were performed on the overall survival rate of patients with prognosis-related genes and multiple clinicopathological factors, and a nomogram was constructed. A PRGI was then constructed based on least absolute shrinkage and selection operator or multivariate Cox Iterative Regression. The possible correlation between PRGI and immune cell infiltration or immunotherapy efficacy was discussed. Eight genes were identified to construct the PRGI. PRGI can predict the infiltration of immune cells into the tumor microenvironment of HCC and the response to immunotherapy. PRGI can accurately predict the survival rate of patients with HCC, reflect the immune microenvironment, and predict the efficacy of immunotherapy.

The Journey to Diagnosis of Light Chain Amyloidosis: A Real-World Experience from a Single Center in Latin America

Light chain (AL) amyloidosis is a form of systemic amyloidosis, causing organ dysfunction; mainly affecting heart and kidneys. Due to the non-specific clinical manifestations, diagnosis is challenging and patients experience a long journey and treatment delay. Consequently, AL amyloidosis patients have extensive organ involvement at the time of diagnosis which implies a poor prognosis. Early diagnosis of AL amyloidosis is of paramount importance. There is limited real-world data from Latin America regarding the time from initial patient reported symptom onset to diagnosis. This retrospective cohort study aimed to assess clinical and laboratory characteristics, diagnostic journey, and outcomes of patients with AL amyloidosis treated in a medical care program in Argentina. AL amyloidosis patients were identified using a 12-year follow-up data (January 1, 2010 to December 31, 2022) from the institutional registry of amyloidosis (IRA).The IRA is registered in ClinicalTrials.gov (NCT01347047) and is approved by the IRB (CEPI 1635). Diagnosis of AL amyloidosis was confirmed by tissue biopsy staining positive with Congo red in addition to the demonstration of a monoclonal plasma cell proliferative disorder and the presence of amyloid-related systemic syndrome.The symptoms and signs related to amyloidosis were selected based on previously reported data in the literature. The number of medical consultations and health care resource utilization was collected from electronic medical records of patients in the medical care program. fThe statistical analyses were performed with Stata version 13.0. The continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR), and the categorical variables were presented as absolute frequencies and percentages. The survival rate was estimated by Kaplan-Meier. From 181807 community patients included in the comprehensive health care program, 28 patients were diagnosed with AL amyloidosis and included in the study. The median age at diagnosis was 73 (IQR, 66.5-80.5) years old and 64% (n=18) were female (Table 1).Heart and kidney were the most frequently affected organs. The median time from the first sign and/or symptom related to AL amyloidosis to diagnosis was 15.9 months (IQR, 8.8-38.2). Only 4 patients (14%) were diagnosed within the first six months since the onset of symptoms. Prior to diagnosis, the median number of symptoms and/or signs presented by the patients was 4 (IQR, 3.5-7). The median number of medical consultations prior to diagnosis was 3 (IQR, 1-5). The most consulted medical specialties were internal medicine (n=24, 86%), cardiology (n=14, 50%) and nephrology (n=10, 36%). Twelve patients (43%) were hospitalized at least once before diagnosis and 4 (14%) were hospitalized at least 3 times. Ten (36%) patients were diagnosed during a hospitalization. Involvement of more than three organs was present in 25% (n=7) of the patients. Fifty-seven percent (n=16) had cardiac involvement, mostly in advanced stages. Out of 23 patients that underwent treatment, 22 patients were treated with bortezomib based regimens in first line; 3 in combination with anti CD38. The median overall survival was 21 months (IQR, 4.6-49.8). The one-year overall survival rate after diagnosis was 55% (95% CI 34-71). The one-year overall survival rate for patients diagnosed within the first 12 months from the onset of symptoms was 70% (95% CI 32-89), while for those diagnosed after 12 months from the onset of symptoms, it was 45% (95% CI 20-67). This study provides real-world evidence about the diagnostic journey of AL amyloidosis patients in Latin America. AL amyloidosis is a complex disease with diverse manifestations, leading to diagnostic challenges even with growing awareness among the medical community. Patients often underwent a diagnostic odyssey involving multiple specialists and hospitalizations before the definitive diagnosis is reached.

Clonal Hematopoiesis Is Associated with Cardiovascular Disease Risk and Worse Survival after Autologous Hematopoietic Cell Transplantation for Lymphoma

Introduction: Autologous hematopoietic cell transplantation (HCT) is an effective treatment for patients with relapsed or refractory lymphoma, and use of HCT has contributed to a growing number of survivors. Despite these improvements in outcomes, long-term survivors of lymphoma are at high risk of developing clinically significant cardiovascular disease (CVD) which, to date, has largely been attributed to pre-HCT cardiotoxic therapeutic exposures (e.g. anthracyclines, radiation) and modifiable risk factors (e.g. hypertension, diabetes, dyslipidemia) after HCT. In the general population, clonal hematopoiesis of indeterminate potential (CHIP), which refers to clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with aging-related health conditions including CVD. Accumulating data suggests CHIP is more prevalent in cancer patients compared to age-matched controls, due in part to clonal selection after genotoxic stressors. There is a paucity of information about the association between CHIP and CVD after HCT, including its interaction with modifiable risk factors and subsequent impact on survival after HCT. Methods: This was a retrospective cohort study of 861 consecutive patients who underwent autologous HCT for lymphoma between 2010 and 2016, with available pre-HCT DNA obtained from peripheral blood stem cells. We performed targeted exome sequencing of DNA (92 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CHIP (variant allele frequency ≥2%). CVD outcomes of interest included de novo heart failure, coronary artery disease and stroke after HCT. Five-year cumulative incidence of CVD was calculated taking into consideration competing risk of death. Fine-Gray multivariable regression was used to evaluate the association between CHIP and CVD, adjusting for demographic, clinical and therapeutic factors. The Kaplan-Meier method was used to examine the effect of CHIP on overall survival after HCT. Results: Median age at HCT was 55.7 years (range 18.4-78.1 years); 63.3% were male; race/ethnicity: non-Hispanic White (56.9%), Hispanic (26.1%), Asian (10.8%), Black (5.1%); 78.0% had non-Hodgkin lymphoma; comorbidities at HCT: hypertension (32.1%), dyslipidemia (16.4%), diabetes (10.1%), high (≥3) HCT-comorbidity index (CI) score (46.1%). Nearly all patients (94.3%) had received anthracycline-based chemotherapy prior to HCT, and 63.3% were treated with cumulative dose ≥300mg/m 2; 6% had chest radiotherapy. Overall, 186 patients (21.7% of the cohort) had at least one CHIP variant and 57 (6.6%) had ≥2 variants. DNMT3A, PPM1D, TET2 and TP53 were the most frequently mutated genes. In total, 74 patients developed CVD within five years from HCT. The 5-year cumulative incidence of CVD was significantly higher in patients with CHIP (20.9% vs 9.1%, p&amp;lt;0.001), compared to those without CHIP, and there was a graded relationship between number of CHIP variants and incidence of CVD. In the adjusted (age, cancer diagnosis, HCT-CI, modifiable cardiovascular risk factors) multivariable model, CHIP was significantly and independently associated with a nearly two-fold (HR: 1.8, 95% CI=1.1-3.1; P=0.020) risk of CVD, as well as the individual outcome of heart failure (HR: 2.3, 95%CI=1.3-4.3; P=0.008). Patients who had both CHIP and hypertension had a 3-fold (HR: 3.0, 95%CI=1.4-6.5, p=0.006) risk of CVD (reference: no CHIP, no hypertension). Overall 5-year survival after HCT was significantly worse in patients with CHIP, compared to those without CHIP (47.2% vs 68.2%, p&amp;lt;0.001; adjusted HR: 1.9, 95%CI=1.4-2.6), attributed to the higher burden of non-relapse mortality in patients with CHIP. Conclusions: In this well-characterized and demographically diverse cohort of lymphoma patients undergoing HCT, CHIP was highly prevalent and associated with a significantly higher risk of CVD after HCT, with the highest risk among those with CHIP and hypertension. We confirmed the poor overall survival rate in patients with CHIP, independent of patient and disease-related risk factors. These findings highlight the potential role of CHIP as a novel biomarker to better define CVD risk in patients with lymphoma prior to HCT, setting the stage for better screening and implementation of interventions (e.g., aggressive management of modifiable risk factors) to reduce the risk of CVD and to ultimately improve long-term health outcomes after HCT.

Combination therapy of niclosamide with gemcitabine inhibited cell proliferation and apoptosis via Wnt/β-catenin/c-Myc signaling pathway by inducing β-catenin ubiquitination in pancreatic cancer

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a type of cancer with high morbidity and mortality rates worldwide. Owing to a lack of therapeutic options, the overall survival rate of patients with pancreatic cancer is low. Gemcitabine has been mainly used to treat patients with pancreatic cancer, but its efficacy is limited by chemoresistance. Therefore, a novel therapeutic agent for PDAC therapy is urgently needed. An anthelminthic drug, niclosamide, has already been researched in breast, lung, colon, and pancreatic cancer as an anti-cancer purpose by re-positioning its original purpose. However, combination therapy of gemcitabine and niclosamide was not informed yet. Here, we found that niclosamide co-administered with gemcitabine significantly inhibited tumorigenesis of pancreatic cancer compared to gemcitabine alone. Further, combining niclosamide and gemcitabine inhibited cell proliferation and induced apoptosis. Niclosamide induced cell cycle arrest at the G1 phase, and the levels of CDK4/6 and cyclin D1 were lowered after gemcitabine treatment. In addition, the combination of these chemical compounds more effectively increased the binding level of activated β-catenin destruction complex and β-catenin to enable phosphorylation, compared to gemcitabine alone. After phosphorylation, niclosamide – gemcitabine upregulated the ubiquitin level, which caused phosphorylated β-catenin to undergo proteasomal degradation; the combination was more potent than gemcitabine alone. Finally, the combination more effectively suppressed tumor growth in vivo, compared to gemcitabine alone. Altogether, our results indicate that niclosamide synergistically enhances the antitumor effect of gemcitabine in pancreatic cancer, by inducing the degradation of β-catenin with ubiquitination. Therefore, this drug combination can potentially be used in PDAC therapy.

Association between cerebrovascular disease and perioperative neurocognitive disorders: a retrospective cohort study.

Previous studies have shown that patients with cerebrovascular disease (CVD) have a significantly increased risk of cognitive decline or dementia; however, the association between preoperative CVD and perioperative neurocognitive disorders (PNDs) remains unclear. This study aimed to explore the correlation between preoperative CVD and PNDs, as well as combine logistic regression and ROC curves to construct a clinical prediction PND model. This retrospective cohort study evaluated 13,899 surgical patients of a large-scale comprehensive hospital between January 2021 and January 2022 to explore the association between preoperative CVD and PNDs, with follow-up to monitor postoperative survival until February 28, 2023, unless the patient died. The study participants comprised all inpatients from the Bone and Joint Surgery, Spine Surgery, Urology, Hepatobiliary Surgery, Gastrointestinal Surgery, and Thoracic Surgery departments. Patients were classified into two groups: the CVD group with a confirmed diagnosis and the non-cerebrovascular disease (NCVD) group. The incidence of PNDs was measured, and potential associations between patient demographic information, preoperative comorbidities, and CVD, as well as the correlation between preoperative CVD and PNDs, were investigated by multivariate logistic regression analysis. Next, we constructed a clinical prediction PND model by drawing the receiver operating characteristic (ROC) curve. The postoperative survival of all patients was tracked, and a survival curve was constructed and incorporated into the Cox proportional hazard regression model to analyze the relationship between preoperative CVD and overall postoperative survival rate. Of the included 13,899 patients, propensity score matching yielded 1006 patient pairs. Multivariate logistic regression analysis revealed that CVD was an independent risk factor for PNDs [Odds ratio: 10.193; 95% confidence interval: 7.454-13.938; P<0.001]. Subsequently, we developed a clinical prediction model for PNDs by multivariate logistic regression analysis. The area under the ROC curve was 0.798 (95% CI: 0.765-0.830). The survival of 11,702 patients was followed up. Multivariate Cox hazard ratio regression analysis revealed that CVD affected the overall postoperative survival rate (Hazard ratio, 1.398; 95% confidence interval: 1.112-1.758; P＜0.001). CVD was an independent risk factor for PNDs and affected the overall postoperative survival rate of surgical patients with preoperative CVD.

Prevalence and predictors of survival among patients with prostate cancer attending Nyeri County and referral hospital, Kenya: a review of records 2017-2022

Background: Prostate cancer is a significant health concern globally. The incidence rate of prostate cancer (PCa) has continued to rise in Kenya. This study aimed to investigate the prevalence of prostate cancer in patients attending Nyeri County and referral hospital in Kenya, identify predictors of survival, and assess the impact of treatment modalities on survival outcomes. Methods: A retrospective observational design was employed, analyzing data from 252 patient records documented between 2017 and 2022. Demographic characteristics, clinical features, treatment modalities, and survival outcomes were extracted and analyzed. Results: The prevalence of prostate cancer among the study population was found to be 10.84%. The majority of patients diagnosed with prostate cancer were aged 70 years or older, with none below 40 years. Most patients were residents of Nyeri County, and some came from neighboring counties in central Kenya. The overall survival rate for prostate cancer patients was 64.29%, indicating that 35.71% of patients died during the study period. Advanced age, comorbidities, and late-stage diagnosis were associated with lower survival rates. Multivariate analysis revealed that prostate cancer cases with hypertension were 2.91 times more likely to die compared to those without comorbidities (p=0.01, CI: 1.285051-6.597691). Conclusions: The study highlights a significant prevalence of prostate cancer in the region and emphasizes the need for enhanced management strategies. Early detection programs, tailored treatment approaches considering comorbidities, and improved access to healthcare services are recommended to enhance survival rates and overall management of prostate cancer in this population.