SYVN1 modulates papillary thyroid carcinoma progression by destabilizing HMGB1.

E3 ubiquitin ligase synoviolin (SYVN1) has been reported to participate in many human cancers. This study aimed to investigate SYVN1's roles and molecular pathways in papillary thyroid cancer (PTC). The functions of SYVN1 in PTC were further analyzed using gain- and loss-of-function methods and numerous investigations in cellular function and molecular biology. The findings demonstrated that the overexpression of SYVN1 markedly suppressed the proliferation, migration, and invasion of PTC cell lines (NPA87 and TPC-1). We found that SYVN1 interacted with HMGB1 and promoted its ubiquitination and degradation. In addition, SYVN1 effectively impairs cell proliferation, migration, invasion, and the formation of tumor xenografts in mice models. However, this effect may be partly reversed by overexpressing HMGB1. Thus, SYVN1 may inhibit the proliferation, migration, and invasion of PTC cells by disrupting HMGB1. Consequently, SYVN1 might be considered a promising therapeutic target for PTC.

Promoting Intratumoral Drug Accumulation by Bio-Membrane Regulated Active Targeting for Tumor Photothermal Therapy.

Introduction: Insufficient tumor permeability and inadequate nanoparticle retention continue to be significant limitations in the efficacy of anti-tumor drug therapy. Numerous studies have focused on enhancing tumor perfusion by improvement of tumor-induced endothelial leakage, often known as the enhanced permeability and retention (EPR) effect. However, these approaches have produced suboptimal therapeutic outcomes and have been associated with significant side effects. Therefore, in this study, we prepared tumor cell membrane-coated gold nanorods (GNR@TM) to enhance drug delivery in tumors through homogeneous targeting of tumor cell membranes and in situ real-time photo-controlled therapy. Methods: Here, we fabricated GNR@TM, and characterized it using various techniques including Ultraviolet-Visible (UV-Vis) spectrophotometer, particle size analysis, potential measurement, and transmission electron microscopy (TEM). The cellular uptake and cytotoxicity of GNR@TM were analyzed by flow cytometry, confocal laser scanning microscopy (CLSM), TEM, CCK8 assay and live/dead staining. Tissue drug distribution was determined by inductively coupled plasma mass spectrometry (ICP-MS) and immunofluorescence staining. Furthermore, to evaluate the therapeutic effect, mice bearing MB49 tumors were intravenously administered with GNR@TM. Subsequently, near-infrared (NIR) laser therapy was performed, and the mice's tumor growth and body weight were monitored. Results: The tumor cell membrane coating endowed GNR@TM with extended circulation time in vivo and homotypic targeting to tumor, thereby enhancing the accumulation of GNR@TM within tumors. Upon 780 nm laser, GNR@TM exhibited excellent photothermal conversion capability, leading to increased tumor vascular leakage. This magnification of the EPR effect induced by NIR laser further increased the accumulation of GNR@TM at the tumor site, demonstrating strong antitumor effects in vivo. Conclusion: In this study, we successfully developed a NIR-triggered nanomedicine that increased drug accumulation in tumor through photo-controlled therapy and homotypic targeting of the tumor cell membrane. GNR@TM has been demonstrated effective suppression of tumor growth, excellent biocompatibility, and significant potential for clinical applications.

Fusing Positive and Negative CT Contrast Nanoagent for the Sensitive Detection of Hepatoma.

Positive computed tomography (CT) contrast nanoagent has significant applications in diagnosing tumors. However, the sensitive differentiation between hepatoma and normal liver tissue remains challenging. This challenge arises primarily because both normal liver and hepatoma tissues capture the nanoagent, resulting in similar positive CT contrasts. Here, a strategy for fusing positive and negative CT contrast nanoagent is proposed to detect hepatoma. A nanoagent Hf-MOF@AB@PVP initially generates a positive CT contrast signal of 120.3 HU in the liver. Subsequently, it can specifically respond to the acidic microenvironment of hepatoma to generate H2 , further achieving a negative contrast of -96.0 HU. More importantly, the relative position between the negative and positive signals area is helpful to determine the location of hepatoma and normal liver tissues. The distinct contrast difference of 216.3 HU and relative orientation between normal liver and tumor tissues are meaningful to sensitively distinguish hepatoma from normal liver tissue utilizing CT imaging.

In vivo characterization and analysis of glioblastoma at different stages using multiscale photoacoustic molecular imaging.

Simultaneous spatio-temporal description of tumor microvasculature, blood-brain barrier, and immune activity is pivotal to understanding the evolution mechanisms of highly aggressive glioblastoma, one of the most common primary brain tumors in adults. However, the existing intravital imaging modalities are still difficult to achieve it in one step. Here, we present a dual-scale multi-wavelength photoacoustic imaging approach cooperative with/without unique optical dyes to overcome this dilemma. Label-free photoacoustic imaging depicted the multiple heterogeneous features of neovascularization in tumor progression. In combination with classic Evans blue assay, the microelectromechanical system based photoacoustic microscopy enabled dynamic quantification of BBB dysfunction. Concurrently, using self-fabricated targeted protein probe (αCD11b-HSA@A1094) for tumor-associated myeloid cells, unparalleled imaging contrast of cells infiltration associated with tumor progression was visualized by differential photoacoustic imaging in the second near-infrared window at dual scale. Our photoacoustic imaging approach has great potential for tumor-immune microenvironment visualization to systematically reveal the tumor infiltration, heterogeneity, and metastasis in intracranial tumors.

Immune and pathologic responses in patients with localized prostate cancer who received daratumumab (anti-CD38) or edicotinib (CSF-1R inhibitor).

BACKGROUND: The prostate tumor microenvironment (TME) is immunosuppressive, with few effector T cells and enrichment of inhibitory immune populations, leading to limited responses to treatments such as immune checkpoint therapies (ICTs). The immune composition of the prostate TME differs across soft tissue and bone, the most common site of treatment-refractory metastasis. Understanding immunosuppressive mechanisms specific to prostate TMEs will enable rational immunotherapy strategies to generate effective antitumor immune responses. Daratumumab (anti-CD38 antibody) and edicotinib (colony-stimulating factor-1 receptor (CSF-1R) inhibitor) may alter the balance within the prostate TME to promote antitumor immune responses. HYPOTHESIS: Daratumumab or edicotinib will be safe and will alter the immune TME, leading to antitumor responses in localized prostate cancer. PATIENTS AND METHODS: In this presurgical study, patients with localized prostate cancer received 4 weekly doses of daratumumab or 4 weeks of daily edicotinib prior to radical prostatectomy (RP). Treated and untreated control (Gleason score ≥8 in prostate biopsy) prostatectomy specimens and patient-matched pre- and post-treatment peripheral blood mononuclear cells (PBMCs) and bone marrow samples were evaluated. The primary endpoint was incidence of adverse events (AEs). The secondary endpoint was pathologic complete remission (pCR) rate. RESULTS: Twenty-five patients were treated (daratumumab, n=15; edicotinib, n=10). All patients underwent RP without delays. Grade 3 treatment-related AEs with daratumumab occurred in 3 patients (12%), and no ≥grade 3 treatment-related AEs occurred with edicotinib. No changes in serum prostate-specific antigen (PSA) levels or pCRs were observed. Daratumumab led to a decreased frequency of CD38+ T cells, natural killer cells, and myeloid cells in prostate tumors, bone marrow, and PBMCs. There were no consistent changes in CSF-1R+ immune cells in prostate, bone marrow, or PBMCs with edicotinib. Neither treatment induced T cell infiltration into the prostate TME. CONCLUSIONS: Daratumumab and edicotinib treatment was safe and well-tolerated in patients with localized prostate cancer but did not induce pCRs. Decreases in CD38+ immune cells were observed in prostate tumors, bone marrow, and PBMCs with daratumumab, but changes in CSF-1R+ immune cells were not consistently observed with edicotinib. Neither myeloid-targeted agent alone was sufficient to generate antitumor responses in prostate cancer; thus, combinations with agents to induce T cell infiltration (eg, ICTs) will be needed to overcome the immunosuppressive prostate TME.

Thermo-pH-Sensitive Polymer Conjugated Glucose Oxidase for Tumor-Selective Starvation-Oxidation-Immune Therapy.

Protein drugs are increasingly used as therapeutics for the treatment of cancer. However, their inherent drawbacks, such as poor stability, low cell membrane and tissue permeability, lack of tumor selectivity, and severe side effects, limit their wide applications in cancer therapy. Herein, screening of a thermo-pH-sensitive polymer-glucose oxidase conjugate that can controllably self-assemble into nanoparticles with improved stability is reported. The size, surface charge, and bioactivity of the conjugate can be tuned by adjustment of the solution temperature and pH. The cellular uptake, intracellular hydrogen peroxide generation, and tumor cell spheroid penetration of the conjugate are greatly enhanced under the acidic tumor microenvironment, leading to increased cytotoxicity to tumor cells. Upon a single intratumoural injection, the conjugate penetrates into the whole tumor tissue but hardly diffuses into the normal tissues, resulting in the eradication of the tumors in mice without perceivable side effects. Simultaneously, the conjugate induces a robust antitumor immunity to efficiently inhibit the growth of distant tumors, especially in combination with an immune checkpoint inhibitor. These findings provide a novel and general strategy to make multifunctional protein-polymer conjugates with responsiveness to the acidic tumor microenvironment for selective tumor therapy.

Neoadjuvant relatlimab and nivolumab in resectable melanoma.

Relatlimab and nivolumab combination immunotherapy improves progression-free survival over nivolumab monotherapy in patients with unresectable advanced melanoma1. We investigated this regimen in patients with resectable clinical stage III or oligometastatic stage IV melanoma (NCT02519322). Patients received two neoadjuvant doses (nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks) followed by surgery, and then ten doses of adjuvant combination therapy. The primary end point was pathologic complete response (pCR) rate2. The combination resulted in 57% pCR rate and 70% overall pathologic response rate among 30 patients treated. The radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57%. No grade 3-4 immune-related adverse events were observed in the neoadjuvant setting. The 1- and 2-year recurrence-free survival rate was 100% and 92% for patients with any pathologic response, compared to 88% and 55% for patients who did not have a pathologic response (P = 0.005). Increased immune cell infiltration at baseline, and decrease in M2 macrophages during treatment, were associated with pathologic response. Our results indicate that neoadjuvant relatlimab and nivolumab induces a high pCR rate. Safety during neoadjuvant therapy is favourable compared to other combination immunotherapy regimens. These data, in combination with the results of the RELATIVITY-047 trial1, provide further confirmation of the efficacy and safety of this new immunotherapy regimen.

Thermosensitive Polymer Conjugated Prodrug-Activating Enzyme with Enhanced Tumor Retention and Antitumor Efficacy.

Enzyme-activated prodrug therapy has emerged as an effective strategy for cancer therapy. However, the inefficient delivery of prodrug-activating enzymes into tumor tissues leads to unsatisfactory antitumor efficacy and undesirable toxicity to normal tissues. Herein, we report in situ growth of a thermosensitive polymer of poly(diethylene glycol) methyl ether methacrylate (PDEGMA) from horseradish peroxidase (HRP) to yield a HRP-PDEGMA conjugate with well-retained activity as compared to HRP. The conjugate shows a sharp phase transition behavior with a lower critical solution temperature of 23 °C. The conjugate catalyzes the conversion of non-cytotoxic indole-3-acetic acid (IAA) into cytotoxic species for killing tumor cells. Notably, the PDEGMA conjugation not only increases the stability and cellular uptake of HRP but also prolongs the tumor retention time of HRP upon intratumoral injection. As a result, in mice bearing melanoma, the conjugate inhibits the growth of melanoma much more efficiently than HRP. These results demonstrate that the thermosensitive polymer conjugation of an enzyme is an effective strategy that can enhance the antitumor efficacy of an enzyme-activated prodrug.

Self-Activated Cascade Biocatalysis of Glucose Oxidase-Polycation-Iron Nanoconjugates Augments Cancer Immunotherapy.

Biocatalytic therapy by reactive-oxygen-species-generating enzymes not only kills cancer cells directly but also stimulates an anticancer immune response and inverses the immunosuppressive microenvironment of a variety of solid tumors, which is potentially beneficial to overcoming the limitations of cancer immunotherapy. Herein, we report the in situ growth of polycation chains from glucose oxidase to generate glucose oxidase-polycation conjugates, which can be used as a template for the in situ reduction of ferrous ions into iron nanoparticles to yield glucose oxidase-polycation-iron nanoconjugates. The nanoconjugates exhibit enhanced cellular uptake and cancer retention as well as self-activated cascade biocatalysis that consumes glucose and generates highly toxic hydroxyl radicals, leading to enhanced starvation-like and chemodynamic cancer therapy. The cancer treatment with the nanoconjugates efficiently triggers the program of immunogenic cell death for enhanced immune checkpoint blockade therapy. The synergy of self-activated cascade biocatalysis and immune checkpoint blockade not only eradicates primary cancers but also inhibits the progression of distant cancers, which leads to the abscopal effect on cancers. Our findings provide a method for the in situ synthesis of self-activated cascade nano-biocatalysts for cascade biocatalysis-enhanced immunotherapy of cancer.

[Serum metabolomics of chronic obstructive pulmonary disease with lung-Qi deficiency syndrome].

The present study analyzed the potential biomarkers of chronic obstructive pulmonary disease(COPD) with lung-Qi deficiency syndrome by non-targeted metabolomics and explored the biological basis of this syndrome. Blood samples of 96 COPD patients with lung-Qi deficiency syndrome(COPD with lung-Qi deficiency syndrome group) and 106 healthy people(healthy control group) were collected, and the metabolic profiles of both groups were analyzed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS). Multivariate statistical analysis and differential metabolite screening were carried out by using Progenesis QI and Simca-P. Metabolic pathways were constructed through the MetaboAnalyst. Seven potential biomarkers, such as L-cystathionine, protoporphyrinogen Ⅸ, and citalopram aldehyde, were identified. Compared with the results in the healthy control group, the content of citalopram aldehyde, N1-methyl-2-pyridone-5-carboxamide, and 11ß,17ß-dihydroxy-4-androsten-3-one was significantly up-regulated, while that of the other four compounds such as L-cystathionine, dihydrotestosterone, protoporphyrinogen Ⅸ, and D-urobilinogen was down-regulated. These potential biomarkers involved six metabolic pathways, including cysteine and methionine metabolism, porphyrin and chlorophyll metabolism, drug metabolism of cytochrome P450, steroid hormone biosynthesis, glycine, serine, and threonine metabolism, and nicotinate and nicotinamide meta-bolism. This study is expected to provide a certain scientific basis for the research on traditional Chinese medicine syndrome of COPD with lung-Qi deficiency syndrome from the molecular biology level.

A phase 1-2 trial of sitravatinib and nivolumab in clear cell renal cell carcinoma following progression on antiangiogenic therapy.

The accumulation of immune-suppressive myeloid cells is a critical determinant of resistance to anti-programmed death-1 (PD-1) therapy in advanced clear cell renal cell carcinoma (ccRCC). In preclinical models, the tyrosine kinase inhibitor sitravatinib enhanced responses to anti-PD-1 therapy by modulating immune-suppressive myeloid cells. We conducted a phase 1-2 trial to choose an optimal sitravatinib dose combined with a fixed dose of nivolumab in 42 immunotherapy-naïve patients with ccRCC refractory to prior antiangiogenic therapies. The combination demonstrated no unexpected toxicities and achieved an objective response rate of 35.7% and a median progression-free survival of 11.7 months, with 80.1% of patients alive after a median follow-up of 18.7 months. Baseline peripheral blood neutrophil-to-lymphocyte ratio correlated with response to sitravatinib and nivolumab. Patients with liver metastases showed durable responses comparable to patients without liver metastases. In addition, correlative studies demonstrated reduction of immune-suppressive myeloid cells in the periphery and tumor microenvironment following sitravatinib treatment. This study provides a rationally designed combinatorial strategy to improve outcomes of anti-PD-1 therapy in advanced ccRCC.

6-Shogaol alleviates CCl4-induced liver fibrosis by attenuating inflammatory response in mice through the NF-κB pathway.

Liver fibrosis is a global health problem caused by a number of diseases related to liver damage. 6-Shogaol is a biologically active substance derived from the rhizome of Zingiber officinale Roscoe with anti-tumor, anti-inflammatory, and antioxidant properties. To explore the effects of 6-Shogaol on liver fibrosis, we used a mouse model of the condition in which mice were injected intraperitoneally with carbon tetrachloride (CCl4) at a dose of 2 mL/kg three times per week for a period of 4 weeks. 6-Shogaol was administered orally at two different doses (5 mg/kg, 20 mg/kg) 30 min before CCl4 injection. CCl4 induced severe liver injury and fibrosis, as indicated by significant inflammatory cell infiltration, disordered liver structure, increased activities of aspartate aminotransferase and alanine aminotransferase (liver damage markers) in serum, elevated collagen deposition, and overexpressed alpha-smooth muscle actin (α-SMA, marker of hepatic stellate cells activation) in liver tissues, whereas 6-Shogaol administration rescued those alterations dose-dependently. We found that 6-Shogaol suppressed CCl4-induced inflammatory response by inhibiting macrophage recruitment, release of pro-inflammatory factors, and activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in liver tissues. Additionally, we demonstrated that 6-Shogaol blocked CCl4-induced activation of the nuclear factor-kappa B (NF-κB) pathway, which is a vital transcriptional regulator of the inflammatory response. Altogether, this study demonstrates that 6-Shogaol can prevent CCl4-induced liver fibrosis by suppressing inflammatory response through the NF-κB pathway and suggests that 6-Shogaol can be used for liver fibrosis prevention.

Extramedullary Plasmacytoma of the Sinonasal Cavity: Magnetic Resonance Imaging Characteristics With Readout-Segmented Diffusion-Weighted Imaging and Dual-Energy Computed Tomography Features.

PURPOSE: To determine magnetic resonance imaging (MRI) with readout-segmented diffusion-weighted imaging (RESOLVE-DWI) and dual-energy computed tomography (DECT) features of sinonasal extramedullary plasmacytoma (SN-EMP). METHODS: The MRI and/or DECT of 10 patients with SN-EMP confirmed by pathology were retrospectively reviewed. Apparent diffusion coefficient (ADC) values of RESOLVE-DWI were analyzed in 9 patients. The quantitative parameters derived from DECT, including the iodine concentration (IC), effective atomic number, and the slope (k) of spectral attenuation curve, were measured in 3 patients. RESULTS: On conventional MRI, typical lesions were well defined (7 of 9), and isointense to the brain on both T1WI and T2WI (9 of 9). Most lesions presented with marked enhancement on contrast-enhanced T1WI without significant necrosis (8 of 9). Notably, multiple flow-void signals were observed in all lesions (9 of 9). On RESOLVE-DWI, the average ADC value was 0.55 × 10-3 mm2/s, and the normalized ADC value was 0.66 ± 0.04. On DECT, the average values of IC, effective atomic number, and slope (k) was 2.7 mg/mL, 8.62, and 3.8, respectively. CONCLUSIONS: Some typical MRI features (well-defined mass, isointensity to the brain, marked enhancement without obvious cystic changes, multiple flow voids, and a lower ADC value) strongly suggest the diagnosis of SN-EMP. The quantitative parameters derived from RESOLVE-DWI and DECT may provide more information for the diagnosis of SN-EMP.

Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. FINDINGS: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. INTERPRETATION: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. FUNDING: Bristol Myers Squibb and the US National Institutes of Health.

Protein tyrosine phosphatase non-receptor type 12 (PTPN12), negatively regulated by miR-106a-5p, suppresses the progression of hepatocellular carcinoma.

Protein tyrosine phosphatase non-receptor type 12 (PTPN12) is abnormally expressed in many human cancers. However, its role in hepatocellular carcinoma (HCC) is indeterminate. In this study, immunohistochemistry and Western blot were adopted to detect PTPN12 protein expression in HCC tissues and cell lines. MiR-106a-5p and PTPN12 mRNA expressions were determined by quantitative real-time polymerase chain reaction (qRT-PCR). siRNA was used to knockdown PTPN12 expression in HCC cells, and the multiplication, migration, and invasion of HCC cells were determined by cell counting kit 8 (CCK-8) and Transwell assays. The interaction between PTPN12 and miR-106a-5p was verified by dual-luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay. In the present study, we demonstrated that PTPN12 expression in HCC tissues and cells was significantly decreased, which was associated with the tumor size, TNM stage, and lymph node metastasis of HCC patients. Functionally, knocking down PTPN12 significantly promoted the multiplication, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. PTPN12 was identified as the direct target of miR-106a-5p, and its expression was negatively modulated by miR-106a-5p. Besides, PTPN12 counteracted the promoting effects of miR-106a-5p on the viability, migration, invasion, and EMT of HCC cells. In conclusion, this study substantiates that PTPN12 inhibits the growth, migration, invasion, and EMT of HCC cells, and miR-106a-5p contributes to its dysregulation in HCC.

Pilot study of Tremelimumab with and without cryoablation in patients with metastatic renal cell carcinoma.

Cryoablation in combination with immune checkpoint therapy was previously reported to improve anti-tumor immune responses in pre-clinical studies. Here we report a pilot study of anti-CTLA-4 (tremelimumab) with (n = 15) or without (n = 14) cryoablation in patients with metastatic renal cell carcinoma (NCT02626130), 18 patients with clear cell and 11 patients with non-clear cell histologies. The primary endpoint is safety, secondary endpoints include objective response rate, progression-free survival, and immune monitoring studies. Safety data indicate ≥ grade 3 treatment-related adverse events in 16 of 29 patients (55%) including 6 diarrhea/colitis, 3 hepatitis, 1 pneumonitis, and 1 glomerulonephritis. Toxicity leading to treatment discontinuation occurs in 5 patients in each arm. 3 patients with clear cell histology experience durable responses. One patient in the tremelimumab arm experiences an objective response, the median progression-free survival for all patients is 3.3 months (95% CI: 2.0, 5.3 months). Exploratory immune monitoring analysis of baseline and post-treatment tumor tissue samples shows that treatment increases immune cell infiltration and tertiary lymphoid structures in clear cell but not in non-clear cell. In clear cell, cryoablation plus tremelimumab leads to a significant increase in immune cell infiltration. These data highlight that treatment with tremelimumab plus cryotherapy is feasible and modulates the immune microenvironment in patients with metastatic clear cell histology.

Polymorphisms in METTL3 gene and hepatoblastoma risk in Chinese children: A seven-center case-control study.

Hepatoblastoma is the most common malignant liver cancer in childhood, yet its etiology remains unclear. As an m6A methylation modifier, methyltransferase like 3 (METTL3) has an active methyltransferase domain that functionally participates in various tumor occurrence and development. However, little is known about how METTL3 polymorphisms affect the occurrence of hepatoblastoma. Here, we attempted to investigate the associations between METTL3 gene polymorphisms and hepatoblastoma risk in a seven-center case-control study. We genotyped four METTL3 polymorphisms (rs1061026 T > G, rs1061027 C > A, rs1139130 A > G, rs1263801 G > C) by TaqMan technique in 313 cases and 1446 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the contributions of these four single nucleotide polymorphisms (SNPs) to hepatoblastoma susceptibility. In single genotype analysis, we detected no significant correlation between these four polymorphisms in METTL3 and hepatoblastoma risk. However, in the combined analysis, the presence of 2-4 risk genotypes of METTL3 was associated with an increased risk of hepatoblastoma compared with that of 0-1 risk genotypes (adjusted OR = 1.48, 95% CI = 1.03-2.12, P = 0.035). The stratified analysis further revealed that carriers of 2-4 risk genotypes are more susceptible to hepatoblastoma in the subgroups of subjects aged under 17 months (adjusted OR = 1.88, 95% CI = 1.12-3.16, P = 0.016) and females (adjusted OR = 1.79, 95% CI = 1.06-3.05, P = 0.031). Overall, our results revealed that none of these four SNPs could increase susceptibility to hepatoblastoma individually. Carriers with 2-4 risk genotypes in the combined analysis tend to increase the risk of hepatoblastoma.

Perineural Invasion as a Prognostic Factor in Laryngeal Squamous Cell Cancer: A Matched-Pair Survival Analysis.

BACKGROUND: The purpose of this study was to compare survival outcomes in patients with perineural invasion (PNI)-positive laryngeal squamous cell carcinoma (LSCC) and patients with PNI-negative LSCC. METHODS: A total of 1,272 patients with LSCC, diagnosed between 2008 and 2017, were included in this study. LSCC Patients with and without PNI were matched based on possible confounding factors. Survival analysis was performed using Kaplan-Meier estimates and the Cox proportional hazards model. RESULTS: Of the 1,272 LSCC patients, 118 (9.28%) were positive for PNI. Compared to PNI-negative patients, PNI-positive LSCC patients had significantly worse overall survival (OS) (p = 0.017), disease-specific survival (DSS) (p = 0.034) and recurrence-free survival (RFS) (p = 0.002). After pair matching, cohorts consisted of 118 patients in the PNI-positive group and 118 in the PNI-negative group. Significantly increased risk of OS (HR, 2.17; 95% confidence interval [CI], 1.29-3.61, p = 0.003), DSS (HR, 2.07; 95% CI, 1.32-3.24, p = 0.004) and RFS (HR, 2.65; 95% CI, 1.59-4.40, p < 0.001) was observed after adjustment for prognostic variables. CONCLUSIONS: Patients with PNI-positive LSCC have significantly worse survival outcomes compared to patients with PNI-negative LSCC.