Genetically determined telomere length as a risk factor for hematological malignancies: evidence from Mendelian randomization analysis.

BACKGROUND: Over the past years, the exact correlation between telomere length and hematological malignancies was still not fully understood. METHODS: We performed a two-sample Mendelian randomization study to investigate the causal relationship between telomere length and hematological malignancies. We selected genetic instruments associated with telomere length. The genetic associations for lymphoid and hematopoietic malignant neoplasms were obtained from the most recent publicly accessible FinnGen study R9 data. Inverse variant weighted (IVW) analysis was adopted as the primary method, and we also performed the weighted-median method and the MR-Egger, and MRPRESSO methods as sensitive analysis. RESULTS: Significant associations have been observed between telomere length and primary lymphoid (IVW: OR = 1.52, P = 2.11 × 10-6), Hodgkin lymphoma (IVW: OR = 1.64, P = 0.014), non-Hodgkin lymphoma (IVW: OR = 1.70, P = 0.002), B-cell lymphoma (IVW: OR = 1.57, P = 0.015), non-follicular lymphoma (IVW: OR = 1.58, P = 1.7 × 10-3), mantle cell lymphoma (IVW: OR = 3.13, P = 0.003), lymphoid leukemia (IVW: OR = 2.56, P = 5.92E-09), acute lymphocytic leukemia (IVW: OR = 2.65, P = 0.021) and chronic lymphocytic leukemia (IVW: OR = 2.80, P = 8.21 × 10-6), along with multiple myeloma (IVW: OR = 1.85, P = 0.016). CONCLUSION: This MR study found a significant association between telomere length and a wide range of hematopoietic malignancies. But no substantial impact of lymphoma and hematopoietic malignancies on telomere length has been detected.

A phase II study of sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy as first-line therapy in patients with newly diagnosed, stage I-II extranodal natural-killer/T-cell lymphoma.

Novel highly effective and low-toxicity combination therapy for localized extranodal natural-killer/T-cell lymphoma (ENKTL) remains a clinically unmet need. This phase II trial (NCT03936452) investigated the efficacy and safety of sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy as first-line treatment in patients with newly-diagnosed stage I-II ENKTL. The patients received sintilimab 200 mg plus pegaspargase 2500 U/m2 on day 1 and anlotinib 12 mg once daily on days 1-14 for three 21-day cycles, followed by intensity-modulated radiotherapy and another three cycles of systemic therapy. The primary endpoint was the complete response rate (CRR) after six treatment cycles. The secondary endpoints included progression-free survival (PFS), overall survival (OS), CRR after two cycles, overall response rate (ORR) after six cycles, duration of response (DOR), and safety. Between May 2019 and July 2021, 58 patients were enrolled. The CRR was 55.1% (27/49) after two cycles and 87.8% (43/49) after six cycles. The ORR was 87.8% (43/49; 95% CI, 75.2-95.4) after six cycles. After a median follow-up of 22.5 months (95% CI, 20.4-24.6), the median PFS, OS, and DOR were not reached. The 2-year PFS, OS, and DOR rates were 87.6% (95% CI, 78.8-97.4), 97.9% (95% CI, 94.0-100), and 91.1% (95% CI, 83.2-99.8), respectively. Grade 3-4 treatment-related adverse events occurred in 41.4% (24/58) of patients, with the most common being hypertension (15.5%), hypertriglyceridemia (8.6%), oral mucositis (6.9%), and anemia (5.2%). No treatment-related deaths occurred. First-line sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy demonstrated promising efficacy in treatment-naïve early-stage ENKTL patients with a favorable safety profile.

Clinicopathologic characteristics, outcomes, and prognostic factors of angioimmunoblastic T-cell lymphoma in China.

BACKGROUND: This study aimed to better characterize the clinicopathologic characteristics, outcomes, and prognostic factors of AITL in China. METHODS: We retrospectively analyzed 312 patients with AITL enrolled between January 2011 and December 2020 from five institutions in China. RESULTS: The median age was 65 years, with 92.6% advanced stage, 59.7% elevated LDH, 46.1% anemia, and 44.0% hypergammaglobulinemia. The majority of patients (84.9%) received anthracycline-based regimens with or without etoposide, and only 6.1% underwent autologous stem cell transplantation following first remission. The 5-year OS and PFS estimates were 43.4% and 25.0% with no significant improvement of survival between patients treated during 2011-2015 and 2016-2020, respectively. Both the International Prognostic Index (IPI) and the prognostic index for PTCL, not otherwise specified (PIT), were predictive for OS. In multivariate analysis, age >70 years, elevated LDH, and albumin level <35 g/L were independent prognostic factors for OS. Combining these three factors, a novel prognostic model (the Chinese AITL score) was constructed, which stratified patients into low-, intermediate-, and high-risk groups, with 5-year OS rates of 69.0%, 41.5%, and 23.7%, respectively. This new model was successfully validated in an independent cohort. CONCLUSIONS: Patients with AITL were mainly treated with anthracycline-based regimens, and the outcomes were still unsatisfactory in China. Our novel prognostic model may improve our ability to identify patients at different risks for alternative therapies.

CDC6 is a prognostic biomarker and correlated with immune infiltrates in glioma.

BACKGROUND: Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it's role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear. METHODS: In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells. RESULTS: As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p < 0.05). Meanwhile, high CDC6 expression was associated with poor overall survival (OS) in glioma patients, especially in different clinical subgroups. Furthermore, a univariate Cox analysis showed that high CDC6 expression was correlated with poor OS in glioma patients. Functional enrichment analysis indicated that CDC6 was mainly involved in pathways related to DNA transcription and cytokine activity, and Gene Set Enrichment Analysis (GSEA) revealed that MAPK pathway, P53 pathway and NF-κB pathway in cancer were differentially enriched in glioma patients with high CDC6 expression. Single-sample gene set enrichment analysis (ssGSEA) showed CDC6 expression in glioma was positively correlated with Th2 cells, Macrophages and Eosinophils, and negative correlations with plasmacytoid dendritic cells, CD8 T cells and NK CD56bright cells, suggesting its role in regulating tumor immunity. Finally, CCK8 assay, flow cytometry and transwell assays showed that silencing CDC6 could significantly inhibit proliferation, migration, invasion, and promoted apoptosis of U87 cells and U251 cells (p < 0.05). CONCLUSION: In conclusion, high CDC6 expression may serve as a promising biomarker for prognosis and correlated with immune infiltrates, presenting to be a potential immune therapy target in glioma.

Local radiotherapy versus nonradiotherapy to distant lesions for metastatic nasopharyngeal carcinoma: Retrospective cohort study.

BACKGROUND: To evaluate the efficiency of local radiotherapy to metastatic lesions in patients with metastatic nasopharyngeal carcinoma (mNPC). METHODS: The overall survival was observed and compared for mNPC patients who received local radiotherapy versus nonradiotherapy to metastatic lesions by using the Kaplan-Meier method and Cox analysis. RESULTS: One hundred and nine patients with NPC were involved in this study, with 61 (56.0%) received radiotherapy to metastatic sites and 48 (44.0%) did not receive radiotherapy to metastatic sites. The 2- and 5-year OS for patients who received local radiotherapy to metastatic lesions were 65.8% and 35.7%, and for patients who did not receive radiotherapy to metastatic lesions were 45.3% and 26.2%. The multivariable adjusted hazard radios for local radiotherapy versus nonradiotherapy to metastatic lesions were 0.482 (95% confidence interval is 0.278-0.834, p = 0.009). CONCLUSIONS: Local radiotherapy to metastatic lesions might be a protective factor for patients with mNPC.

Local treatment of metastases plus systemic chemotherapy on overall survival of patients with metastatic nasopharyngeal carcinoma.

BACKGROUND: To investigate the effect of local treatment of metastases on overall survival (OS) of patients with metastatic nasopharyngeal carcinoma (NPC). METHODS: One hundred and forty-seven patients were included. The association between local treatment and OS was examined with propensity score matching (PSM) method. RESULTS: In entire cohort, the median OS was significantly longer in patients with local treatment of metastases plus chemotherapy compared to those with chemotherapy alone (71.7 vs. 16.2 months; p < 0.001). In PSM cohort, similar OS benefit of patients with local treatment was observed (55.6 vs. 17.6 months; p = 0.011). The survival benefit of local treatment remained regardless of the number of metastatic lesions and metastatic sites. Patients received radiation doses of >60 Gy had longer OS than those who received less. CONCLUSIONS: Local treatment of metastases could improve OS of patients with metastatic NPC and could be considered in their treatment in addition to chemotherapy.

Synchronous Metastatic Nasopharyngeal Carcinoma: Characteristics and Survival of Patients Adding Definitive Nasopharyngeal-Neck Radiotherapy to Systematic Chemotherapy.

PURPOSE: To determine the M1 sub-staging in synchronous metastatic nasopharyngeal carcinoma (smNPC) and to examine the effect of nasopharyngeal-neck radiotherapy (RT) and local treatment of metastases on overall survival (OS) of smNPC patients. PATIENTS AND METHODS: A total of 150 patients with smNPC were included. Metastatic characteristics associated with their potential prognostic significance were analyzed. Then, a stratification system of the M1 sub-staging in smNPC was provided according to metastatic features. Moreover, the OS of patients with or without nasopharyngeal-neck RT was compared by Log rank test. The OS of patients who received or did not receive local treatment of metastases was also analyzed. RESULTS: We successfully divided the M1 stage into three sub-staging: M1a (a single site with a single lesion), M1b (a single site with multiple lesions), and M1c (multiple sites with multiple lesions). The median OS was 53.2, 25.8, and 18.9 months for M1a, M1b, and M1c, respectively (p < 0.001). Nasopharyngeal-neck RT plus systematic chemotherapy (CT) significantly improved OS compared to systematic CT (median OS, 34.0 vs 15.2 months, p = 0.002). However, incorporation of local treatment of metastases did not bring survival benefit to smNPC patients who received nasopharyngeal-neck RT plus systematic CT (median OS, 25.8 vs 35.1 months, p = 0.374). CONCLUSION: The sub-staging of the M1 stage in smNPC had promising prognostic value. Adding nasopharyngeal-neck RT on the basis of systematic CT markedly improved the survival of smNPC patients, while addition of local treatment of metastases to nasopharyngeal-neck RT plus systematic CT for smNPC needed further exploration.

Author Correction: A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Real-World Cost-Effectiveness Analysis of Gemcitabine and Cisplatin Compared to Docetaxel and Cisplatin Plus Fluorouracil Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma.

BACKGROUND: Addition of gemcitabine and cisplatin (GP) or docetaxel and cisplatin plus fluorouracil (TPF) to concurrent chemoradiotherapy (CCRT) significantly improved survival in locoregionally advanced nasopharyngeal carcinoma (NPC). However, an economic evaluation of these regimens remains unknown. The purpose of this study is to compare the cost-effectiveness of GP versus TPF regimen in the treatment of locoregionally advanced NPC in China. MATERIALS AND METHODS: A comprehensive Markov model was developed to evaluate the health and economic outcomes of GP versus TPF regimen for patients with locoregionally advanced NPC. Baseline and clinical outcome were derived from 158 patients with newly diagnosed stage III-IVA NPC between 2010 and 2015. We evaluated the quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) from the perspective of the Chinese healthcare system. One-way sensitive analysis explored the impact of uncertainty in key model parameters on results, and probabilistic uncertainty was assessed through a Monte Carlo probabilistic sensitivity analysis. RESULTS: GP regimen provided an additional 0.42 QALYs with incremental cost of $3,821.99, resulting in an ICER of $9,099.98 per QALY versus TPF regimen at the real-world setting. One-way sensitivity analysis found that the results were most sensitive to the cost and proportion of receiving subsequent treatment in two groups. The probability that GP regimen being cost-effective compared with TPF regimen was 86.9% at a willingness-to-pay (WTP) of $31,008.16 per QALY. CONCLUSION: Using real-world data, GP regimen was demonstrated a cost-effective alternative to TFP regimen for patients with locoregionally advanced NPC in China. It provides valuable evidence for clinicians when making treatment decisions to improve the cost-effectiveness of treatment.

Corrigendum: A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

This corrects the article DOI: 10.1038/srep14421.

A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) are common components of the tumor-suppressive microenvironment, and are a major determinant of the poor outcome of therapeutic vaccination. In this study, we modified tumor cells to express the fibroblast activation protein (FAP), which is highly expressed by CAFs, to potentially improve whole-cell tumor vaccines by targeting both tumor cells and CAFs. Tumor cells were transfected with murine FAP plasmids bearing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. Vaccination with tumor cells expressing FAP eliminated solid tumors and tumors resulting from hematogenous dissemination. This antitumor immune response was mediated by CD8+ T cells. Additionally, we found that CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD8+ T lymphocytes, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Our results indicated that the FAP-modified whole-cell tumor vaccine induced strong antitumor immunity against both tumor cells and CAFs and reversed the immunosuppressive effects of tumors by decreasing the recruitment of immunosuppressive cells and enhancing the recruitment of effector T cells. This conclusion may have important implications for the clinical use of genetically modified tumor cells as cancer vaccines.

Metachronous metastasis from the right colon adenocarcinoma to the vulva: an unusual report and literature review.

A 67-year-old woman who was presented to the gynecologist with a two-month history of heavy vaginal bleeding, after an excisional biopsy of vulvar mass, was diagnosed with the right colon adenocarcinoma metachronous metastasis to the vulva. Pathological examination preliminarily revealed by primary adenosquamous carcinoma of vulva. The original submitting pathologist and gynecologist were contacted to obtain the pathological and clinical information whenever possible, combining with a history of the right colon cancer, subsequently, which confirmed the diagnosis of vulvar metastatic adenocarcinoma. Distinguishing metastatic carcinoma from primary vulvar adenocarcinoma is crucial, since these carcinomas are different. Herein reports the second case of the right colon carcinoma presenting as a vulvar metastasis. This report also shows the differentiation, diagnosis and treatment of metastatic colon carcinoma and its metastatic route.

Nasopharyngeal carcinoma mimicking Aspergillosis rhinosinusitis: an unusual case report and review of the literature.

Clinical symptoms and imaging features of fungal infection are confused with those of atypical nasopharyngeal carcinoma (NPC), and therefore development of a more effective diagnostic method is essential. It is a common knowledge that there is a significant association between Epstein-Barr virus (EBV) and nonkeratinizing NPC. However, fungal infection may be considered to be a vital etiologic agent contributing to the NPC and more evidence is needed to be approved this theory. We report on a rare case of a patient with atypical nasopharyngeal carcinoma (NPC) who suffered from chronic fungal infection and was diagnosed initially as Aspergillosis. Following anti-aspergillus infection therapy, the repeated deep biopsy of the maxillary sinus and MRI confirmed the diagnosis of nasopharyngeal carcinoma (NPC).

Expression loss and revivification of RhoB gene in ovary carcinoma carcinogenesis and development.

RhoB, a member of small GTPases belonging to the Ras protein superfamily, might have a suppressive activity in cancer progression. Here, expression of RhoB gene was evaluated in human benign, borderline and malignant ovary tumors by immunostaining, with normal ovary tissue as control. Malignant tumors were assessed according to Federation Internationale de Gynecologie Obstetrique (FIGO) guidelines and classified in stage I-IV. Revivification of RhoB gene was investigated by analyzing the effect of histone deacetylase (HDAC) inhibitor trichostatin (TSA) and methyltransferase inhibitor 5-azacytidine (5-Aza) on ovarian cancer cells via RT-PCR and western blot. Apoptosis of ovary cancer cells was detected using flowcytometry and fluorescence microscopy. Subsequently, RhoB expression is detected in normal ovary epithelium, borderline tumors, and decreases significantly or lost in the majority of ovarian cancer specimen (P<0.05). RhoB expression decreases significantly from stage II (71.4%) to stage III (43.5%) to stage IV (18.2%, P<0.05). TSA can both significantly revive the RhoB gene and mediate apoptosis of ovarian cancer cells, but 5-Aza couldn't. Interference into Revivification of RhoB gene results in reduction of ovary carcinoma cell apoptosis. It is proposed that loss of RhoB expression occurs frequently in ovary carcinogenesis and progression and its expression could be regulated by histone deacetylation but not by promoter hypermethylation, which may serve as a prospective gene treatment target for the patients with ovarian malignancy not responding to standard therapies.