Combination therapy with oncolytic viruses and immune checkpoint inhibitors in head and neck squamous cell carcinomas: an approach of complementary advantages.

Squamous cell carcinomas are the most common head and neck malignancies. Significant progress has been made in standard therapeutic methods combining surgery, radiation, and chemotherapy. Nevertheless, the 5-year survival rate remains at 40-50%. Immune checkpoint inhibitors (ICIs) are a new strategy for treating head and neck squamous cell carcinomas (HNSCCs). Still, the overall response and effective rates are poor, as HNSCCs are 'cold' tumors with an immunosuppressive tumor microenvironment (TME), limiting ICI's beneficial effects. In this case, transforming the tumor suppression microenvironment before using ICIs could be helpful. Oncolytic viruses (OVs) can transform cold tumors into hot tumors, improving the situation. Talimogene laherparepvec (T-VEC), oncolytic immunotherapy authorized for advanced melanoma, also showed good safety and antitumor activity in treating head and neck cancer and pancreatic cancer. In combination with pembrolizumab, T-Vec may have more anticancer efficacy than either drug alone. Therefore, understanding the mechanisms underpinning OVs and their potential synergism with ICIs could benefit patients with HNSCC.

The correlation of fibrinogen-like protein-1 expression with the progression and prognosis of hepatocellular carcinoma.

BACKGROUND: Fibrinogen-like-protein 1 (FGL1), a member of the fibrinogen-related protein (FREP) family, is a major ligand of the immune inhibitory receptor lymphocyte-activation gene 3 (LAG-3). While FGL1 is strongly implicated in the development and prognosis of a variety of diseases, its role in hepatocellular carcinoma (HCC) is still disputed. Therefore, the role of FGL1 expression in the progression and prognosis of HCC was investigated. METHODS AND RESULTS: In the present study, bioinformatics analysis was first used to probe the expression profile of FGL1 in multiple malignant tumor tissues and paired normal tissues, and to explore the possible relationship between FGL1 and prognosis of HCC patients. Thereafter, the expression levels of FGL1 were determined and compared in human HCC cell lines, HCC tissues, peri-tumor tissues and normal liver tissues by western blot analysis. Furthermore, tissue microarrays were used to detect the expression of FGL1 through immunohistochemical staining and to verify whether the FGL1 expression level was associated with clinicopathological features and the prognosis of HCC patients. The results showed that FGL1 was downregulated significantly in most of the HCC cells lines and HCC tissues, corresponding to the results of the bioinformatics and western blot analyses. FGL1 expression level in HCC was found to be correlated to Edmondson grade and metastasis of the HCC. Additionally, high FGL1 expression was associated with better overall survival in HCC patients, suggesting that FGL1 could function as a tumor suppressor. CONCLUSIONS: The expression level of FGL1 can be correlated with the progression and prognosis of HCC, suggesting its potential as a prognostic biomarker.

Nanocarriers surface engineered with cell membranes for cancer targeted chemotherapy.

BACKGROUND: Inspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells. KEY SCIENTIFIC CONCEPTS OF REVIEW: Nanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems. AIM OF REVIEW: This review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects.

Primary Renal BCOR-CCNB3 Fusion Sarcoma: A Case Report and Review of the Literature.

BCOR-CCNB3 fusion sarcoma is a recently described undifferentiated sarcoma with a novel recurrent inversion of 2 nearby genes BCOR and CCNB3. It typically affects bone and soft tissues of the pelvis, extremity, and paraspinal region and pursues variable clinical course. Primary renal BCOR-CCNB3 fusion sarcoma is very rare, and only a small number of cases have been documented. Accurate diagnosis is often challenging, and there is not any agreement for the treatment of this entity due to its rarity. We report findings of primary renal BCOR-CCNB3 fusion sarcoma in a 16-year-old boy with a brief review of the literature.

Primary Adrenal Glomus Tumor: The First Case Report.

We report a unique case of a 25-year-old man who was incidentally identified to have a mass in the left adrenal gland region by computerized tomography scan. The image revealed a 1.8 × 1.6 cm, well-defined adrenal mass with moderately homogeneous enhancement. The mass was laparoscopically completely removed, and the diagnosis of a solid variant glomus tumor of the adrenal gland was rendered. There were no histologic features indicating atypia or malignance and no primary tumors anywhere else. The patient was free of disease at the 6-month follow-up. To our knowledge, this is the first case of primary adrenal glomus tumor described in the literature.

Surface Engineering of Titanium Dioxide Nanoparticles for Silicone-Based Transparent Hybrid Films with Ultrahigh Refractive Indexes.

We report a newly developed surface engineering approach for TiO2 nanoparticles toward transparent TiO2/silicone nanocomposites with high refractive index (RI) values. Zirconate coupling agents are adopted on the TiO2 nanoparticles for surface passivation and to enhance the dispersibility of the nanoparticles in organic substrates. The modified TiO2 nanoparticles can be uniformly dispersed in silicone, forming transparent hybrid films with an ultrahigh RI of 2.01. The preparation technique of colloidal TiO2 and polymer-based nanocomposites is simple and suitable for scalable production, which is promising for expanding the application of TiO2 materials in photonic devices.

A Highly Controlled Organic-Inorganic Encapsulation Nanocomposite with Versatile Features toward Wearable Device Applications.

Ultraviolet-curable polyurethane acrylate (PUA) materials can be used in a number of important applications spanning from microfluidics, surface patterning to wearable technology. For the first time, the potential of encapsulation of modified zirconia (ZrO2 ) nanoparticles is reported in PUA-based hybrid films aimed to facilitate profoundly enhanced hardness and refractive index. By successfully manipulating the interfacial reaction conditions between ZrO2 nanoparticles and PUA film, the PUA-based nanocomposites exhibit an ultrahigh hardness of 9 and superior refractive index of 1.64 (589.3 nm). The outcomes obtained pave the way for seamless application of nanozirconia/PUA as a potent encapsulating material that provides structurally morphable, water resistant, and optically transparent light emitting diodes toward wearables devices in healthcare.

Cavernous lymphangioma of the urinary bladder in an adult woman: an additional case report of a rare lesion and literature review.

BACKGROUND: Urinary bladder lymphangioma is a rare and benign lesion that is often causes symptoms related to irritation and urinary tract obstruction. Because a lymphangioma may resemble a true neoplasm of the urinary bladder clinically, the lesion must be removed for accurate histologic diagnosis and to rule out malignancy. CASE PRESENTATION: We present a case of a 40-year-old female who was evaluated for painless gross hematuria. Clinical and diagnostic work up revealed a sharply defined mass involving the wall and bulging into the cavity on the dome of the bladder. Partial cystectomy was performed and histologic findings were compatible with cavernous lymphangioma. The symptom of hematuria relieved after the procedure and the patient was in good status without evidence of recurrence by cystoscopy at follow-up 6 months later. CONCLUSIONS: Lymphangioma of the urinary bladder is treated with surgical excision and seems to have no recurrence once completely resected, but long-time follow-up may be needed.

An oncolytic adenovirus delivering TSLC1 inhibits Wnt signaling pathway and tumor growth in SMMC-7721 xenograft mice model.

Tumor suppressor in lung cancer-1 (TSLC1) was first identified as a tumor suppressor for lung cancer, and frequently downregulated in various types of cancers including hepatocellular carcinoma (HCC). The Wnt pathway plays a critical role in tumorigenesis, migration, and invasion in HCC. However, the function of TSLC1 in modulating Wnt signaling in HCC is unclear. In this study, we evaluated the effect of TSLC1-armed oncolytic adenovirus (S24-TSLC1) on the Wnt/ß-catenin pathway, cell viability, invasion and migration abilities of HCC in vitro and the growth of SMMC-7721-xenografted tumor in mice model. We detected the expression of TSLC1 in tumor samples and HCC cell lines. The results showed that TSLC1 expression was low in HCC, but high in pericarcinomatous tissue and normal cells, which implied that TSLC1 is a tumor suppressor of liver cancer. S24-TSLC1 exhibited an antitumor effect on HCC cell growth in vitro, but did little damage to normal liver cells. Overexpression of TSLC1 downregulated the transcriptional activity of TCF4/ß-catenin and inhibited the mRNA or protein expression of Wnt target genes cyclinD1 and c-myc. S24-TSLC1 also inhibited the invasion and migration of HCC cells. Animal experiments further confirmed that S24-TSLC1 significantly inhibited tumor growth of the SMMC-7721-xenografted tumor. In conclusion, TSLC1 could downregulate the Wnt signal pathway and suppress HCC cell growth, migration and invasion, suggesting that S24-TSLC1 may be a potent antitumor agent for future clinical trials in liver cancer treatment.

Elevated expression of AGGF1 predicts poor prognosis and promotes the metastasis of colorectal cancer.

BACKGROUND: Angiogenic factor with G-patch and FHA domains 1 (AGGF1) can promote angiogenesis and increasing evidence has highlighted the important roles of AGGF1 in tumorigenesis. However, the differential expression as well as the biological functions of AGGF1 in colorectal cancer (CRC) remain to be established. The purpose of the present study is therefore to identify the effect of AGGF1 on prognosis and metastasis in CRC patients. METHODS: The expression level of AGGF1 in CRC was examined by qPCR, western blot and immunohistochemistry in a tissue microarray containing 236 CRC specimens and paired normal mucosae. And the effect of AGGF1 on CRC cell malignance was investigated in our established stable AGGF1 upregulated and knockdown CRC cell lines. RESULTS: The expression level of AGGF1 in CRC tissue was not significantly different to that in adjacent normal mucosa at the mRNA level. However, at the protein level, AGGF1 expression in CRC tissues was significantly higher than in paired normal mucosa, which showed a clear association with TNM stage, AJCC stage, vascular invasion, and differentiation. Further, we revealed an apparent correlation between AGGF1 expression and poorer disease-free survival and overall survival of CRC patients. In addition, we discovered that AGGF1 significantly promoted CRC cell wound healing, migration, and invasion in vitro and distant metastasis in vivo. CONCLUSIONS: Our study demonstrates the aberrant overexpression of AGGF1 in CRC and provides a basis on which to explore the application of AGGF1 as a potential therapeutic target for CRC patients, especially for CRC patients with distant metastasis.

Benign ependymoma with extensive intracranial and spinal cerebrospinal fluid dissemination: case report and literature review.

Myxopapillary ependymoma (MPE) is a rare variant of ependymoma that is most commonly located in the cauda equina and filum terminale. We present a case of 23-year-old man diagnosed with MPE in the fourth ventricle and sacral canal area with extensive disseminated lesions along the cerebrospinal ventricular system. Additionally, a molecular pathological diagnosis was performed. The patient underwent a craniotomy and a lumbar laminectomy. In the course of 18 months of follow-up, the patient have recovered very well.

Hand-spinning chrysotile exposure and risk of malignant mesothelioma: A case-control study in Southeastern China.

While chrysotile has been commonly used by Chinese textile industry for many years, investigations on the association of chrysotile exposure with risk of mesothelioma in China are scarce. We conducted a case-control study in a county located at Southeastern China, including 46 cases and 230 individually matched controls. A semi-quantitative method based on experts' assessment was used for evaluating hand-spinning chrysotile exposure. Conditional logistic regression models were used to assess the association of asbestos exposure with risk of mesothelioma. We found that hand-spinning chrysotile exposure was associated with significantly elevated risk of mesothelioma, reaching OR =10 (95% CIs: 1.4-65) for possible exposure and 64 (12-328) for definite exposure. Our data suggested a dose-response relationship of chrysotile exposure duration with risk of mesothelioma, reaching 28 (6-134) for <6 years, 51 (11-247) for 7-17 years and 56 (9-351) for ≥18 years. A dose-response relationship of cumulative exposure index (CEI) with risk of mesothelioma was found, reaching 28 (6-137) for CEI at 0-0.5 fibers per milliliter years (f/mL-year), 36 (7-184) for CEI at 0.5-28.6 f/mL-years and 79 (14-451) for CEI > 28.6 f/mL-years. We found a dose-response relationship of chrysotile exposure duration and CEI with risk of mesothelioma in Southeastern China, adding valuable information on health hazards of chrysotile exposure in China where chrysotile is still used nationwide.

Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview.

The knowledge of cellular mechanisms in malignances of the bladder has grown exponentially. Molecular technologies have led to the discovery of the molecular pathways distinguishing low-and high-grade urothelial neoplasms. This trend portends the future in which the classification and diagnosis of the bladder tumors through morphologic analysis will be supported by molecular information correlating with prognosis and targeted therapy. This article outlines tumor molecular pathology of bladder cancer with an emphasis on several promising candidate biomarkers that may soon make their transition to the realm of clinical management of bladder cancer.

Primary Squamous Cell Carcinoma of the Thyroid Has a Molecular Genetic Profile Distinct From That of Anaplastic Thyroid Carcinoma: A Whole Exome Sequencing and Gene Expression Profiling Study.

BACKGROUND: Primary squamous cell carcinoma (SCC) of the thyroid and anaplastic thyroid carcinoma (ATC) show significant clinical and histologic overlap. Their biological behaviors are so similar that the fifth WHO updates SCC as a morphologic pattern of ATC rather than a separate entity. However, molecular genomic evidence that determines them as the same histologic type is limited. We aimed to explore whether they belong to the same classification from a molecular-typing perspective. METHODS: A cohort enrolled 15 SCCs and 15 ATCs was collected. Whole exome sequencing (WES) and RNA-sequencing were performed to analyze molecular genetic and gene-expression profiles. RESULTS: Significantly differential-mutant genes were BRAF, DPCR1, PCYOX1L, BRSK2, NRG1, PRR14L, TET1, VAMP4 suggesting differences in mutation level, as well as differences in high-frequency mutated genes, and SCC had a much lower tumor mutation burden than ATC. Mutational co-occurrence and mutual exclusion were less frequent in SCC than in ATC. 2047 differential-express genes were screened, indicating differences in gene expression were extremely strong. In principal component analysis, ATC and SCC could be notably clustered together, respectively, meanwhile they could be explicitly distinguished. Unsupervised clustering analysis validated they can indeed be clearly separated from each other which demonstrated that they may be two distinctive entities. CONCLUSIONS: It is controversial yet SCC is classified as a morphologic pattern of ATC. We revealed that SCC exhibited molecular genetic characteristics distinct from ATC. Although the fifth WHO categorizes them together, this study may provide strong molecular genetic evidence for the next edition of WHO classification that may allow for the separation of thyroid SCC from ATC.

Oncogenic Roles of Laminin Subunit Gamma-2 in Intrahepatic Cholangiocarcinoma via Promoting EGFR Translation.

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal biliary epithelial cancer in the liver. Here, Laminin subunit gamma-2 (LAMC2) with important oncogenic roles in iCCA is discovered. In a total of 231 cholangiocarcinoma patients (82% of iCCA patients) across four independent cohorts, LAMC2 is significantly more abundant in iCCA tumor tissue compared to normal bile duct and non-tumor liver. Among 26.3% of iCCA patients, LAMC2 gene is amplified, contributing to its over-expression. Functionally, silencing LAMC2 significantly blocks tumor formation in orthotopic iCCA mouse models. Mechanistically, it promotes EGFR protein translation via interacting with nascent unglycosylated EGFR in the endoplasmic reticulum (ER), resulting in activated EGFR signaling. LAMC2-mediated EGFR translation also depends on its interaction with the ER chaperone BiP via their C-terminus. Together LAMC2 and BiP generate a binding "pocket" of nascent EGFR and facilitate EGFR translation. Consistently, LAMC2-high iCCA patients have poor prognosis in two iCCA cohorts. LAMC2-high iCCA cells are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs) treatment both in vitro and in vivo. Together, these data demonstrate LAMC2 as an oncogenic player in iCCA by promoting EGFR translation and an indicator to identify iCCA patients who may benefit from available EGFR-targeted TKIs therapies.

The RNF214-TEAD-YAP signaling axis promotes hepatocellular carcinoma progression via TEAD ubiquitylation.

RNF214 is an understudied ubiquitin ligase with little knowledge of its biological functions or protein substrates. Here we show that the TEAD transcription factors in the Hippo pathway are substrates of RNF214. RNF214 induces non-proteolytic ubiquitylation at a conserved lysine residue of TEADs, enhances interactions between TEADs and YAP, and promotes transactivation of the downstream genes of the Hippo signaling. Moreover, YAP and TAZ could bind polyubiquitin chains, implying the underlying mechanisms by which RNF214 regulates the Hippo pathway. Furthermore, RNF214 is overexpressed in hepatocellular carcinoma (HCC) and inversely correlates with differentiation status and patient survival. Consistently, RNF214 promotes tumor cell proliferation, migration, and invasion, and HCC tumorigenesis in mice. Collectively, our data reveal RNF214 as a critical component in the Hippo pathway by forming a signaling axis of RNF214-TEAD-YAP and suggest that RNF214 is an oncogene of HCC and could be a potential drug target of HCC therapy.

Targeted next-generation sequencing reveals activating CTNNB1 mutations in SMARCA4/BRG1-deficient sinonasal carcinomas: a report of two new cases and a brief review of the literature with an emphasis on histogenesis.

SMARCA4/BRG1 is a catalytic subunit of the SWItch/sucrose non-fermentable (SWI/SNF) complex and its inactivation is known to drive a variety of cancers across different organs. SMARCA4/BRG1-deficient carcinoma is a relatively new entity in the sinonasal region, and a comprehensive molecular investigation of the underlying genetic abnormalities is largely lacking. In this study, we report two new cases of SMARCA4/BRG1-deficient sinonasal carcinoma with targeted next-generation sequencing analysis, both of which revealed activating mutation of CTNNB1 in addition to somatic loss-of-function mutation of SMARCA4, providing further insights into its tumorigenesis and theoretical basis for the potential future targeted therapy. Activating CTNNB1 mutations in our cases may provide further evidence that SMARCA4-deficient sinonasal carcinoma, sinonasal teratocarcinosarcoma, and olfactory carcinoma are genetically closely related lesions, as recently proposed in the literature.

Case Report: Clinicopathological characteristics of patients with gastric cancer with features of a submucosal tumour.

Purpose: To investigate the clinicopathological characteristics, diagnosis and key points in the differential diagnosis of patients with gastric cancer (GC) with features of a submucosal tumour (GCSMT). Methods: The clinical presentation and imaging findings of four GCSMT cases diagnosed at our centre from 2016 to 2021 were observed and their clinicopathological outcomes were analysed. The related literature was reviewed. Based on our collected data and the related literature, a total of 31 cases of GCSMT can be summarized. Results: 22 out of 31 cases did not present obvious symptoms and were accidentally discovered during gastroscopic examination. Only 10 patients experienced symptoms such as gastric discomfort, upper abdominal swelling and pain, haematemesis, or haematochezia. The male to female ratio was 22:9 and the age of onset ranged from 40 to 81 years (median age: 63 years). Tumours were located in the upper and middle third of the stomach (24/31), and in the lower third(7/31). The tumour diameter ranged from 0.6 to 7.3 cm, with an average value of 2.5 cm. Endoscopically, the disease manifested as SMTs, with the gastric mucosal surface appearing normal. Most patients underwent radical gastrectomy for GC (80.6%, 25/31). The pathological diagnoses of the 31 cases of GCSMT included well- and moderately-differentiated adenocarcinoma (6/31), poorly differentiated adenocarcinoma or signet ring cell carcinoma 6/31), mucinous adenocarcinoma (9/31), lymphoepithelioma-like carcinoma (7/31), gastric adenocarcinoma of the fundic gland type (3/31). Stage T1b and T2 tumours accounted for 56.7% (17/30) and 26.7% (8/30) of all cases. Lymph node metastases were found in six cases (20.0%, 6/30), whereas distant metastasis was not observed in any of the cases. For the 16 patients whose follow-up data were available, the follow-up time was 5-66 months, during which recurrence or metastasis was not observed. Conclusion: GCSMT is a rare disease that is often difficult to accurately diagnose through endoscopic biopsy. The importance of gaining an understanding of this disease lies in differentiating it from other SMTs (mostly mesenchymal tumours) to avoid misdiagnosis and missed diagnosis and enable the early diagnosis and treatment of patients.

Concordance between microsatellite instability and mismatch repair protein expression in colorectal cancer and their clinicopathological characteristics: a retrospective analysis of 502 cases.

Microsatellite instability (MSI) is one of the hallmarks of colorectal cancer (CRC). Mismatch repair (MMR) protein expression may reflect MSI status. To analyze the concordance between MSI and MMR expression in CRC and their clinicopathological characteristics, 502 CRC patients were retrospectively collected in this study. Polymerase chain reaction-capillary electrophoresis (PCR-CE) was used to measure MSI, and MMR expression was determined by immunohistochemistry (IHC). The causes of non-concordance were analyzed. Chi-square test was used to find the correlation between MSI and various clinicopathological parameters. PCR-CE results showed 64 (12.7%) patients had high microsatellite instability (MSI-H); low microsatellite instability (MSI-L) and microsatellite stable (MSS) cases were 19 (3.8%)and 419 (83.5%), respectively. With regard to IHC, 430 (85.7%) showed proficient mismatch repair (pMMR) and 72 (14.3%) showed deficient mismatch repair (dMMR). The coincidence rate of MSI and MMR expression in CRC was 98.4% (494/502), with good concordance (Kappa = 0.932). Using PCR-CE as the gold standard, the sensitivity, specificity, positive predictive value, and negative predictive value of IHC were 100%, 98.2%, 88.9%, and 100%, respectively. MSI-H was more common in women, right colon, tumors ≥ 5 cm, ulcerative type, mucinous adenocarcinoma, poor differentiation, T stage I/II, and without lymph node or distant metastasis for CRC patients. In summary, MSI exhibited some typical clinicopathological characteristics. MSI and MMR expression in CRC had good concordance. However, it is still extremely necessary to perform PCR-CE. We recommend that testing packages of different sizes should be developed in clinical practice to create a testing echelon, to facilitate comprehensive selection according to experimental conditions, clinical diagnosis, and treatment needs.

Tislelizumab immunotherapy combined with chemotherapy in the treatment of a patient with primary anterior mediastinal undifferentiated pleomorphic sarcoma with high PD-L1 expression: A case report and literature review.

Undifferentiated pleomorphic sarcoma (UPS) is a rare and aggressive soft tissue tumor with a high degree of malignancy and rapid progression, usually occurring in the extremities, retroperitoneum, and abdomen, whereas it rarely arises in the mediastinum, and is treated mainly by surgical resection. The prognosis of patients with advanced sarcoma is poor, and doxorubicin monotherapy is the standard first-line chemotherapy for most advanced soft tissue sarcomas (STS), but the prognosis is generally unsatisfactory. Immune checkpoint inhibitors (ICIs) have been established as therapies for many solid cancers in recent years; however, evidence on the efficacy of ICIs in undifferentiated sarcoma is scarce, mostly consisting of small studies, and no ICIs are currently approved for use in sarcomas. We report a case of a middle-aged man with primary mediastinal UPS with high PD-L1 expression (TPS was approximately 80%) and TLS positive. The patient was treated with sequential tislelizumab monotherapy maintenance after 6 cycles of tislelizumab combined with epirubicin, efficacy evaluation was partial remission (PR), progression-free survival (PFS) was 8.5 months, and grade 1 fatigue was identified as an adverse event.