Efficacy and safety of a novel polytetrafluoroethylene-coated self-expandable metal stent for distal malignant biliary obstruction.

Background: Stent migration and sludge formation remain significant problems associated with covered self-expandable metal stents (CSEMSs). The EGIS biliary stent fully covered flare type (EGIS biliary stent), a new type of polytetrafluoroethylene-coated self-expandable metal stent with low axial force and an anti-migration system, was developed to overcome these disadvantages. We conducted this study to evaluate the efficacy and safety of this stent in comparison with conventional CSEMS (c-CSEMS). Methods: We retrospectively analyzed consecutive patients with unresectable pancreatic cancer who received initial CSEMS for distal malignant biliary obstruction. The primary outcome was time to recurrent biliary obstruction (RBO). Secondary outcomes included technical success rate, functional success rate, stent-related adverse events, causes of RBO, and re-intervention. Results: A total of 40 patients were included (EGIS group: 20; c-CSEMS group: 20). The technical and functional success rates were similar between the two groups. Stent-related adverse event rates (20% vs. 15%, p > 0.99) and overall RBO rates (56% vs. 50%, p > 0.99) were not significantly different between the two groups. Stent migration was the most common cause of RBO in the EGIS group, while stent occlusion was in the c-CSEMS group. The median time to RBO (102 vs. 434 days, p = 0.10) was not significantly different between the two groups. Endoscopic transpapillary re-intervention was successful in most patients in both groups. Conclusions: The EGIS biliary stent was not associated with a longer time to RBO compared to c-CSEMS. Further improvements, especially against stent migration, are needed to improve its efficacy.

Local delivery of carboplatin-loaded hydrogel and calcium carbonate enables two-stage drug release for limited-dose radiation to eliminate mouse malignant glioma.

Postoperative radiotherapy remains the gold standard for malignant glioma treatment. Clinical limitations, including tumor growth between surgery and radiotherapy and the emergence of radioresistance, reduce treatment effectiveness and result in local disease progression. This study aimed to develop a local drug delivery system to inhibit tumor growth before radiotherapy and enhance the subsequent anticancer effects of limited-dose radiotherapy. We developed a compound of carboplatin-loaded hydrogel (CPH) incorporated with carboplatin-loaded calcium carbonate (CPCC) to enable two-stage (peritumoral and intracellular) release of carboplatin to initially inhibit tumor growth and to synergize with limited-dose radiation (10 Gy in a single fraction) to eliminate malignant glioma (ALTS1C1 cells) in a C57BL/6 mouse subcutaneous tumor model. The doses of carboplatin in CPH and CPCC treatments were 150 µL (carboplatin concentration of 5 mg/mL) and 15 mg (carboplatin concentration of 4.1 µg/mg), respectively. Mice receiving the combination of CPH-CPCC treatment and limited-dose radiation exhibited significantly reduced tumor growth volume compared to those receiving double-dose radiation alone. Furthermore, combining CPH-CPCC treatment with limited-dose radiation resulted in significantly longer progression-free survival than combining CPH treatment with limited-dose radiation. Local CPH-CPCC delivery synergized effectively with limited-dose radiation to eliminate mouse glioma, offering a promising solution for overcoming clinical limitations.

Unilateral drainage and chemotherapy prolong the patency of a plastic stent placed above the sphincter of Oddi in patients with malignant hilar biliary obstruction.

Objectives: To evaluate the results of inside stent therapy for unresectable malignant hilar biliary obstruction and identify factors related to stent patency duration. Methods: Of 44 patients who underwent initial inside-stent placement above the sphincter of Oddi from April 2017 to December 2022, 42 with the resolution of jaundice (clinical success rate, 95.5%) were retrospectively analyzed. Univariate and multivariate logistic regression analysis identified factors associated with stent patency duration. Results: Univariate analysis revealed significant differences in the drainage method (406 days for unilateral drainage vs. 305 days for bilateral drainage of the right and left liver lobes, p = 0.022) with or without chemotherapy (406 days with vs. 154 days without, p = 0.038). Multivariate analysis (Cox proportional hazards analysis) revealed similar results, with unilateral drainage (p = 0.031) and chemotherapy (p = 0.048) identified as independent factors associated with prolonged stent patency. Early adverse events were observed in two patients (4.8%; one cholangitis, one pancreatitis). Conclusions: Inside-stent therapy was safely performed in patients with malignant hilar biliary obstruction. Simple unilateral drainage and chemotherapy may prolong stent patency.

Unique endoscopic features of primary biliary diffuse large B-cell lymphoma: A case report with literature review (with video).

A 67-year-old man visited our hospital complaining of dark-colored urine and upper abdominal pain. Magnetic resonance cholangiopancreatography showed stricture of the distal bile duct, and contrast-enhanced computed tomography showed irregular thickening of the distal bile duct wall. However, no enlarged lymph nodes, pancreatic tumors, or other neoplastic lesions were apparent around the bile duct. Endoscopic ultrasonography and intraductal ultrasonography showed irregular thickening of the inner hypoechoic layer without the disappearance of the innermost thin hyperechoic layer. On the basis of these findings, we considered that the bile duct lesion was of non-epithelial origin. Thus, we repeatedly performed bile duct biopsies from the same site under fluoroscopy to obtain a sample of the submucosal tissue. The pathological diagnosis was diffuse large B-cell lymphoma, and the patient received systemic chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). After six courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, positron emission tomography-computed tomography showed the disappearance of 18-fluorodeoxyglucose uptake in the bile duct and endoscopic retrograde cholangiography showed improvement of the bile duct stricture. Endoscopic findings and repeated biopsies were useful in making the diagnosis of primary biliary diffuse large B-cell lymphoma.

Outcomes of multi-hole self-expandable metal stents versus fully covered self-expandable metal stents for malignant distal biliary obstruction in unresectable pancreatic cancer.

Objectives: The multi-hole self-expandable metal stent (MHSEMS) is a novel SEMS with multiple small side holes on the covering membrane to prevent stent migration while minimizing tumor ingrowth. This study aimed to evaluate the clinical outcomes of MHSEMS in comparison with conventional covered SEMS (c-CMS). Methods: Consecutive patients with unresectable pancreatic cancer who underwent initial SEMS placement (MHSEMS or c-CMS) for malignant distal biliary obstruction were analyzed. Technical success, clinical success, causes of recurrent biliary obstruction (RBO), non-RBO adverse events, time to RBO (TRBO), and endoscopic reintervention were compared between groups. Results: A total of 65 patients were included (MHSEMS: 27, c-CMS: 38). The technical success, clinical success, and non-RBO adverse event rates were similar between groups. Although stent migration was less frequently observed in the MHSEMS group (0% vs. 17.6%, p = 0.032), overall RBO rates were similar between groups (53.8% vs. 55.9%, p > 0.99). The most common cause of RBO within 14 days in the MHSEMS group was non-occlusion cholangitis. Median TRBO was significantly shorter in the MHSEMS group (101 vs. 227 days, p = 0.030) and MHSEMS was an independent predictor for shorter TRBO in multivariate analysis (hazard ratio, 2.27; 95% confidence interval, 1.06-4.86; p = 0.034). Outcomes after endoscopic interventio were not significantly different between groups. Stent removal was successful in all attempted cases in both groups. Conclusions: MHSEMS was associated with a significantly shorter TRBO compared to c-CMS. Further modifications of the present MHSEMS may be needed.

An Overview of Research Advances in Oncology Regarding the Transcription Factor ATF4.

This review provides a comprehensive overview of the recent advancements in research on ATF4 (Activating Transcription Factor 4) within the field of oncology. As a crucial transcription factor, ATF4 has garnered increasing attention for its role in cancer research. The review begins with an exploration of the regulatory mechanisms of ATF4, including its transcriptional control, post-translational modifications, and interactions with other transcription factors. It then highlights key research findings on ATF4's involvement in various aspects of tumor biology, such as cell proliferation, differentiation, apoptosis and survival, invasion and metastasis, and the tumor microenvironment. Furthermore, the review discusses the potential of targeting ATF4 as a novel therapeutic strategy for cancer treatment. It also explores how ATF4's interactions with existing anticancer drugs could inform the development of more effective therapeutic agents. By elucidating the role of ATF4 in tumor biology and its potential clinical applications, this review aims to provide new insights and strategies for cancer treatment.

Metastatic Malignant Pseudomyogenic Hemangioendothelioma: An Exceedingly Rare Entity That Challenges Conventional Paradigms.

Pseudomyogenic hemangioendothelioma (PMHE), a rare soft tissue tumor predominantly affecting young adults, often presents as multiple nodules in various tissue planes of a limb. Malignant transformation and metastatic disease are unusual and pose diagnostic and therapeutic challenges. A 17-year-old patient from Western India, with a history of recurrent excisions for a toe swelling presented to our center for evaluation and management. A below-knee amputation was performed, and histopathology revealed PMHE. Adjuvant therapy was deemed unnecessary given the borderline nature of the tumor. Shortly thereafter, he developed features of local recurrence and underwent above-knee amputation. An expert histopathological review confirmed the diagnosis and noted features of malignant transformation-progression to a higher grade with greater cytological atypia, confluent growth, and increased mitotic activity over time. Upon further distant progression in the lung, he was started on a palliative regimen of weekly paclitaxel, vinblastine, and propranolol but eventually succumbed to his illness. In contrast to conventional descriptions of low mitotic activity, minimal nuclear atypia, and absence of necrosis, our patient exhibited increased mitotic rates, nuclear atypia, and evolving necrosis in serial histopathological evaluations. The fulminant clinical progression within a short interval was also atypical. Our patient's clinical course underscores the need for meticulous histopathological and molecular characterization and vigilant clinical surveillance after resection in patients with PMHE. Providing the standard of care for malignant disease in the adjuvant setting is challenging owing to the rarity and the lack of treatment guidelines.

Clinical research progress of fruquintinib in the treatment of malignant tumors.

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.

Neurofibromatosis to neoplasia transition: a rare case report of spindle cell malignant peripheral nerve sheath tumor with literature review.

Introduction and importance: Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue malignant tumor. MPNST in the spinal canal is rarely seen except in cases of neurofibromatosis type 1. However, a long-segment extradural spinal malignant spindle cell neoplasm has not been reported in the current literature. Case presentation: We present the first reported case of spinal malignant spindle cell neoplasm extended along the spine. The detected lesion is responsible for compressing various segments of the spinal cord, causing thinning of the cord and secondary stenosis of the spinal canal, leading to a condition known as multisegment compression myelopathy. Clinical discussion: MPNSTs are typically detected late due to nonspecific symptoms, with a higher incidence in extremities and a notable occurrence in unusual locations. Diagnosis relies on MRI and histopathology, with S_100 positivity as a neural marker. MPNSTs can arise from neurofibromas or Schwann cells, with a significant portion resulting from TP53 mutations or secondary to radiation exposure. Conclusion: This case stands out due to its unique presentation, characterized by a predominantly spindle cell morphology with certain epithelioid features. It is imperative to recognize this condition for an accurate diagnosis, emphasizing the spindle cell-type MPNST and highlighting its exceptionally poor prognosis.

The impact of mindfulness intervention on negative emotions and quality of life in malignant tumor patients: a systematic review and meta-analysis.

Objective: This study aims to assess the effect of mindfulness intervention on negative emotions (anxiety and depression) and quality of life in malignant tumor patients. Methods: The databases, including CNKI, VIP, Wanfang, Chinese Biomedical Literature Database disc (CBMdisc), PubMed, Embase, Cochrane Library, and Web of Science (WoS), were searched from inception to January 2024. Randomized controlled trials examining the effects of mindfulness intervention on negative emotions and quality of life in malignant tumor patients were selected. Meta-analysis was conducted using RevMan 5.1. Results: A total of 11 studies involving 993 patients were included. Compared with usual care, mindfulness intervention effectively reduced anxiety [SMD = -0.81, 95% CI (-1.01, -0.60), p < 0.00001], depression [SMD = -0.86, 95% CI (-1.01, -0.70), p < 0.00001], and improved patients' quality of life [SMD = 0.64, 95% CI (0.50, 0.78), p < 0.00001]. Conclusion: Mindfulness intervention can effectively alleviate negative emotions such as anxiety and depression in malignant tumor patients and positively impact their quality of life.

Adenocarcinoma of Sacrococcygeal Pilonidal Disease: A Report of a Rare Case.

A recurring abscess or draining sinus overlying the sacrococcygeal area is the hallmark of the chronic, well-known condition known as sacrococcygeal pilonidal disease. It is among the most difficult surgical challenges. Rarely, recurrent illness, persistent infection, and associated inflammation result in malignant transformation, most frequently in the form of squamous cell carcinoma (SCC). We report a similar case of an 84-year-old man who presented to our outpatient clinic and had a persistent, recurring sacrococcygeal pilonidal sinus for 28 years. He had already undergone several surgical excisions for the same and now developed an ulceroproliferative growth on his right gluteal cleft since his previous resection when he first appeared.

Malignant peripheral nerve sheath tumor mimicking carotid body tumor, a rare case report and review of literature.

INTRODUCTION AND IMPORTANCE: Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare type of soft tissue sarcoma. It is an aggressive tumor with high rates of local recurrence and distant metastasis. MPNST rarely occurs in the neck. We present a case of cervical MPNST manifesting as Carotid Body Tumor (CBT). CASE PRESENTATION: A 67-year-old man presented with a neck mass. The mass was rapidly enlarging and imaging studies favored CBT. A previous attempt at surgical resection failed, and the compressive symptoms were progressive during recent weeks. After multidisciplinary discussion, the tumor was resected and pathological evaluation confirmed the diagnosis of MPNST. Post-operative metastatic work-up showed lung metastasis, and the patient died approximately one year after surgery. CLINICAL DISCUSSION: Cervical MPNST is rare, and surgery is the mainstay of its treatment. Pre-operative tissue diagnosis is recommended when possible, and immunohistochemical staining is necessary for prompt diagnosis. Adjuvant therapy may be helpful in metastatic cases or incomplete resection. Nevertheless, local recurrence and distant metastasis especially to the lungs are common, as in our case. CONCLUSION: MPNST is one of the potential causes of cervical masses and considering its invasive behavior, surgical resection is recommended as soon as the diagnosis is made.

Causes of death in Japanese patients with diabetes based on the results of a survey of 68,555 cases during 2011-2020: Committee report on causes of death in diabetes mellitus, Japan Diabetes Society (English version).

The principal causes of death among 68,555 patients with diabetes and 164,621 patients without diabetes who died in 208 hospitals throughout Japan between 2011 and 2020 were determined based on a survey of hospital records. The most frequent cause of death in patients with diabetes was malignant neoplasms (38.9%) (lung 7.8%, pancreas 6.5%, liver 4.1%), followed, in order of descending frequency, by infectious diseases (17.0%) and then vascular diseases (10.9%) (cerebrovascular diseases 5.2%, ischemic heart diseases 3.5%, renal failure 2.3%). The proportion of deaths from malignant neoplasms and vascular diseases has trended upward and downward, respectively. Almost all deaths from ischemic heart diseases were due to myocardial infarction, and the proportion of deaths from heart diseases other than ischemic heart diseases was relatively high (9.0%), with most cases due to heart failure. Diabetic coma associated with hyperglycemia accounted for only 0.3% of deaths. The proportion of deaths from malignant neoplasms, infectious diseases, renal failure, ischemic heart diseases, and heart failure was significantly higher in patients with diabetes than in those without diabetes, and the proportion of deaths from cerebrovascular diseases was significantly lower in patients with diabetes. With regard to the relationship between the age and cause of death in patients with diabetes, malignant neoplasms were the most frequent cause of death in all age groups, and the incidence was around 50% for those in their 50s and 60s. The incidence of death due to infectious diseases was highest in patients older than their 70s. The incidence of death due to vascular diseases for patients in their 40s and 50s was higher than that due to infectious diseases. The highest incidence of death due to ischemic heart diseases was observed for patients in their 40s, and that due to renal failure and heart failure in patients older than their 70s. Compared with patients without diabetes, patients with diabetes demonstrated a higher incidence of death due to pancreatic cancer, infectious diseases, renal failure, ischemic heart diseases, and heart failure, and a lower incidence of death due to cerebrovascular diseases in all age groups. The average age at death of patients with diabetes was 74.4 years old in men and 77.4 years old in women, which were lower than the average lifespan of the Japanese general population in 2020 by 7.2 and 10.3 years, respectively. However, these differences were smaller than in previous surveys. The average age at death due to all causes, especially due to ischemic heart diseases, cerebrovascular diseases, heart failure, infectious diseases, and diabetic coma, was lower in patients with 'poorer' glycemic control than in those with 'better' glycemic control. In the total survey population, the average age at death of patients with diabetes was significantly higher than that of patients without diabetes. The average age at death due to malignant neoplasms and cerebrovascular diseases was higher in patients with diabetes than in those without diabetes and that due to renal failure, ischemic heart diseases, and infectious diseases was lower in patients with diabetes than in those without diabetes.

An uncommon case of anorectal malignant melanoma (ARMM): Clinical presentation and surgical outcome.

INTRODUCTION AND IMPORTANCE: Anorectal mucosal melanoma (ARMM) is a rare disease with a poor prognosis. However, surgery is often difficult, due to the lentiginous growth pattern of such melanoma. CASE PRESENTATION: A 61 years old lady presented with anal pain for 1 year, associated with painless fresh per rectal bleeding post defecation and altered bowel habit. Physical examination showed hyperpigmentation at the anal verge, extending to the dentate line. CT, MRI and PET imaging showed localised disease. She underwent pelvic exanteration and radical lymph node dissection with gracilis flap coverage. Post operatively, she recovers well, and was discharged well on day 8. HPE came back as malignant melanoma, with 1 out 12 lymph nodes involved. She was subsequently referred to oncology, started on pembrolizumab immunotherapy. CLINICAL DISCUSSION: Anorectal melanoma is an aggressive disease, often present with delayed diagnosis. Multiple imaging has been proposed, however none is standardized to diagnose ARMM. Immunohistochemical stains such as S-100 protein, MelanA and tyrosinase and with HMB-45 help in diagnosis and are sensitive for melanocytic differentiation. Surgery excision remains the most common and superior initial treatment for ARMM. One retrospective study done to compare different treatment modalities has shown that patients with surgical excision and radiation therapy had the highest median survival at 32.3 months but surgical excision remains the single best modality for ARMM. CONCLUSION: Suspicious hyperpigmentation at the anal region should raise clinical awareness. Surgical excision with optimal margin is indicated to achieve favourable symptom control, reduce local recurrence and improve survival rate.

Applications and challenges of photodynamic therapy in the treatment of skin malignancies.

Photodynamic Therapy (PDT), as a minimally invasive treatment method, has demonstrated its distinct advantages in the management of skin malignant tumors. This article examines the current application status of PDT, assesses its successful cases and challenges in clinical treatment, and anticipates its future development trends. PDT utilizes photosensitizers to interact with light of specific wavelengths to generate reactive oxygen species that selectively eradicate cancer cells. Despite PDT's exceptional performance in enhancing patients' quality of life and prognosis, the limitation of treatment depth and the side effects of photosensitizers remain unresolved issues. With the advancement of novel photosensitizers and innovative treatment technology, the application prospects of PDT are increasingly expansive. This article delves into the mechanism of PDT, its application in various skin malignancies, its advantages and limitations, and envisions its future development. We believe that through continuous technological enhancements and integration with other treatment technologies, PDT has the potential to assume a more pivotal role in the treatment of skin malignancies.

Spotlight on the Uncommon: A Rare Case of a Malignant Glomus Tumor of the Skin.

Glomus tumors arise from a neuromyoarterial plexus origin, typically demonstrating branching vascular channels and aggregates of specialized glomus cells. They are characteristically identified in the subungual region of the hand, with the presentation of firm, red or blue nodules that are painful and sensitive to temperature. However, very few cases of malignant glomus tumors of the skin have been reported in the medical literature, making this case quite unique. This case report aims to identify an additional case of this rare condition, discuss the treatment plan pursued, and bring awareness to this distinct oncological entity. A 41-year-old female patient initially presented to her primary care physician with an enlarging and painful nodule on her left temple that had been present for the last two months. The patient was then referred to plastic surgery for excision and pathological workup of the mass. The pathology report of the excised specimen revealed a malignant glomus tumor of the skin. The patient was subsequently scheduled for an oncologic workup with medical oncology and radiation oncology, and a wide excision was performed after the pathologic diagnosis. With negative margins from the wide excision and no evidence of disease spread, it was determined that there was no role for systemic therapy or radiation therapy at that time. Biannual dermatologic examination and monitoring are indicated for follow-up. With very few reports of similar cases and little information in the medical literature on the treatment of this type of neoplasm, this is a unique and rare case that warrants discussion and exposure. Making the correct diagnosis, performing a complete workup, and removing the malignant glomus tumor are all essential parts of medical management in this case, and this type of neoplasm should not be excluded when evaluating the presentation of unusual cutaneous lesions.

PD-L1+ neutrophils induced NETs in malignant ascites is a potential biomarker in HCC.

BACKGROUND: Since differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids. METHODS: Thirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis. RESULTS: Significantly increased pro-tumor PD-L1+ TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites. CONCLUSIONS: Our findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.

Dose-escalation, tolerability, and efficacy of intratumoral and subcutaneous injection of hemagglutinating virus of Japan envelope (HVJ-E) against chemotherapy-resistant malignant pleural mesothelioma: a clinical trial.

The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E's preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345).

[Expression changes of miRNAs and EMT-related genes in human mesothelial cells induced by long-term exposure to asbestos].

Objective: To investigate the effects of long-term exposure to chrysotile and crocidolite on miRNAs and epithelial mesenchymal transformation (EMT) -related gene expression in human pleural mesothelial cells. Methods: In November 2020, fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the expressions of EMT-related genes in human pleural mesothelioma cells (NCl-H2052 cells, NCl-H2452 cells) and human normal mesothelial cells (Met-5A cells). MiRNAs with abnormal expression in human pleural mesothelioma cells were screened out from the previous miRNA chip data of research group, and target genes of differentially expressed miRNAs were predicted using miRWalk database (http: //mirwalk.umm.uni-heidelberg.de). RT-qPCR was used to verify the abnormal expression of EMT-related miRNAs in cell lines. Met-5A cells were treated with 5µg/cm(2) chrysotile and crocidolite respectively for 48 h a time, once a week and a total of 10 times. Chrysotile group, crocidolite group and control group were set up. And the control group was added with the same volume of PBS. The expression changes of EMT-related genes and abnormal expression miRNAs in each group were detected by RT-qPCR. The differences among the groups were compared by one-way ANOVA, and the differences between the control group and the experimental group were compared by dunnet-t test. Results: Compared with Met-5A cells, the expression levels of Vimentin and Twist genes were increased, and the expression level of E-cadherin genes was decreased in NCl-H2052 cells and NCl-H2452 cells (P<0.001). Target genes of miRNAs with abnormal expression in miRNA chip were predicted, and the results showed four abnormally expressed miRNAs associated with EMT and verified the expression of these four miRNAs in the cell lines. Compared with Met-5A cells, the expression level of hsa-miR-155-5p was increased in NCl-H2052 cells and NCl-H2452 cells, the expression levels of hsa-miR-34b-5p, hsa-miR-34c-5p and hsa-miR-28-5p were decreased in NCl-H2052 cells and NCl-H2452 cells (P<0.001), which was consistent with the results of chip analysis. After exposure of Met-5A cells, it was found that compared with the control group, the expression levels of Vimentin and Twist genes, hsa-miR-155-5p, hsa-miR-34b-5p and hsa-miR-34c-5p in the crocidolite group were increased, while the expression level of E-cadherin gene was decreased (P<0.05). Compared with the control group, the expression levels of Vimentin, Twist and E-cadherin genes in chrysotile group were increased, while the expression levels of hsa-miR-34b-5p, hsa-miR-34c-5p and hsa-miR-28-5p were decreased (P<0.05) . Conclusion: Long-term exposure to chrysotile and crocidolite could cause Met-5A cells to produce miRNAs and EMT-related gene expression changes similar to mesothelioma cells.

RNA methyltransferase NSUN2-mediated m5C methylation promotes Cr(VI)-induced malignant transformation and lung cancer by accelerating metabolism reprogramming.

Hexavalent chromium [Cr(VI)], one common environmental contaminant, has long been recognized as a carcinogen associated with lung cancer, but roles and mechanisms of Cr(VI)-induced epigenetic dysregulations in carcinogenesis remain to be investigated. In this study, we identified that RNA m5C methyltransferase NSUN2 was significantly upregulated in Cr(VI)-transformed cells and lung tissues of Cr(VI)-exposed mice. Inhibition of NSUN2 reduced cell proliferation, migration, colony formation and tube formation abilities. We found NSUN2-mediated m5C modification induced metabolic reprogramming and cell cycle by promoting the mRNA stabilities of ME1, GLUT3 and CDK2. In addition, knockdown of NSUN2 attenuated tumorigenesis and angiogenesis in vivo. RNA m5C reader ALYREF was identified to be involved in NSUN2-mediated m5C modification in Cr (VI)-induced carcinogenesis. Further study showed that EP300 induced NSUN2 upregulation through transcriptional activation by inducing histone modification at H3K27ac site for regulating Cr(VI) carcinogenesis. Our findings demonstrated novel role and mechanism of NSUN2 and epigenetic changes by increasing the RNA m5C modification that are important for Cr (VI)-induced carcinogenesis through NSUN2/ALYREF pathway. NSUN2, ALYREF, ME1, GLUT3 or/and CDK2 may be used as potential new biomarkers or/and therapeutic target(s) in the future.