Distant Tumor Research Articles

Synergistic Effects of Metal-Organic Nanoplatform and Guanine Quadruplex-Based CpG Oligodeoxynucleotides in Therapeutic Cancer Vaccines with Different Tumor Antigens.

Oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanosine (CpG) motifs are readily recognized by Toll-like receptor 9 on immune cells, trigger an immunomodulatory cascade, induce a Th1 -biased immune milieu, and have great potential as an adjuvant in cancer vaccines. In this study, a green one-step synthesis process was adopted to prepare an amino-rich metal-organic nanoplatform (FN). The synthesized FN nanoplatform can simultaneously and effectively load model tumor antigens (OVA)/autologous tumor antigens (dLLC) and immunostimulatory CpG ODNs with an unmodified PD backbone and a guanine quadruplex structure to obtain various cancer vaccines. The FN nanoplatform and immunostimulatory CpG ODNs generate synergistic effects to enhance the immunogenicity of different antigens and inhibit the growth of established and distant tumors in both the murine E.G7-OVA lymphoma model and the murine Lewis lung carcinoma model. In the E.G7-OVA lymphoma model, vaccination efficiently increases the CD4+, CD8+, and tetramer+CD8+ T cell populations in the spleens. In the Lewis lung carcinoma model, vaccination efficiently increases the CD3+CD4+ and CD3+CD8+ T cell populations in the spleens and CD3+CD8+, CD3-CD8+, and CD11b+CD80+ cell populations in the tumors, suggesting the alteration of tumor microenvironments from cold to hot tumors.

The dynamic duo: A narrative review on the synergy between stereotactic body radiotherapy and immunotherapy in lung cancer treatment (Review).

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), is undoubtedly one of the major breakthroughs in lung cancer research. Patient survival and prognosis have all been improved as a result, although numerous patients do not respond to immunotherapy due to various immune escape mechanisms of the tumor cells. Recent preclinical and clinical evidence has shown that stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, has a prominent immune priming effect that could elicit antitumor immunity against specific tumor antigens and destroy distant tumor cells, thereby achieving the elusive abscopal effect, with the resulting immuno‑active tumor environment also being more conducive to ICIs. Some landmark trials have already demonstrated the survival benefit of the dynamic duo of SBRT plus immunotherapy in metastatic non‑small‑cell lung cancer, while others such as PEMBRO‑RT further suggest that the addition of SBRT to immunotherapy could expand the current indication to those who have historically responded poorly to ICIs. In the present review, the biological mechanisms that drive the synergistic effect of SBRT and immunotherapy were first briefly outlined; then, the current understanding from clinical trials was summarized and new insight into the evolving role of immunotherapy and SBRT synergy in lung cancer treatment was provided. Finally, novel avenues for discovery were highlighted. The innovation of the present review lies in the inclusion of non‑ICI immunotherapy in the discussion, which provides a more comprehensive view on the current development and future trend of SBRT + immunotherapy synergy.

Surgery versus thermal ablation for small-size colorectal liver metastases (COLLISION): An international, multicenter, phase III randomized controlled trial.

LBA3501 Background: The standard of care for local treatment of patients (pts) with colorectal liver metastases (CRLM) is surgical resection. However, growing evidence suggests thermal ablation to be associated with a superior safety profile, lower costs, and shorter hospital stay, while rivaling surgical resection in terms of local control and overall survival (OS). This study aimed to explore the potential non-inferiority of thermal ablation compared to surgical resection for pts with small-size (≤3cm) resectable CRLM. Methods: In this multicenter, phase 3 Dutch Colorectal Cancer Group trial, pts aged 18 years and older with previously untreated CRLM were recruited from 14 centers in the Netherlands, Belgium and Italy. Pts with ≤10 CRLM, no extrahepatic metastases and ECOG 0-2 were stratified into low, intermediate and high disease burden subgroups and randomly assigned (1:1) to undergo surgical resection or thermal ablation. Though approach was left at the discretion of the operator, laparoscopic (+/- robot) resections and percutaneous ablations were favored over open procedures. To avoid drop-outs patients undergoing open procedures were randomized intra-operatively. The primary outcome was overall survival (OS) (log-rank; power 80%, 5% type I error rate; 1-sided). Secondary outcomes include distant and local tumor progression-free survival (PFS), local control, safety, length of hospital stay, quality of life and cost-effectiveness. Results: A total of 341 patients were enrolled; 299 were randomly assigned: 147 assigned to thermal ablation, 148 to surgical resection; 4 were excluded after randomization for not having the disease assessed. The trial was stopped at halftime for having met predefined stopping rules. After a median follow-up time of 28.8 months there was no difference regarding OS (HR 1.042; 95% CI, 0.689-1.576; p = 0.846) with a conditional probability of >90% to prove the hypothesis of non-inferiority. Procedure related mortality was 2.1% (n=3) for resection vs. 0% (n=0) for thermal ablation. The total number of adverse events (p = <0.001), the length of hospital stay (median 4 days [range 1-36] vs 1 day [range 1-44], p = <0.001) and local control also favored thermal ablation (HR 0.184; 95% CI, 0.040-0.838; p = 0.029). No differences were found regarding local (HR 0.833; 95% CI, 0.473-1.469; p = 0.528) and distant PFS (HR 0.982; 95% CI, 0.739-1.303; p = 0898). Conclusions: In conclusion, transitioning from surgical resection to thermal ablation as standard of care for patients with small-size (≤3 cm) CRLM would reduce complications, shorten hospital stay and improve local control, without compromising disease-free and overall survival. COLLISION is funded by a Medtronic-Covidien Investigator Sponsored Research grant. Clinical trial information: NCT03088150 .

PH-responsive coacervate with adrenergic nerve blockade function inhibits triple-negative breast cancer metastasis by blocking nerve-tumor-immune loop

Chronic stress, a common comorbidity of breast cancer, is shown to promote tumor progression by affecting tumor microenvironment. Metastasis is the leading cause of death in triple-negative breast cancer (TNBC), and clarifying the specific role of chronic stress on TNBC metastasis will facilitate the development of new targets and improve its prognosis. In this study, a reciprocal nerve-tumor-immune loop is firstly depicted to promote TNBC metastasis under chronic stress and can be interrupted by propranolol (Pro), which shows rapid clinical translation potential due to “new uses for old drugs”. However, low bioavailability and insufficient efficacy of Pro when applied systemically may hinder its clinical translation in cancer patients. Based on this, an injectable and pH-responsive Pro-loaded coacervate (Pro@Coa) is further developed, which can accumulate and sustainably release Pro within the tumor. For the first time, the study demonstrates that Pro@Coa not only inhibits TNBC metastasis by interrupting the reciprocal loop but also suppresses distant tumor growth by inducing systemic immunity. Compared to traditional free Pro administration, Pro@Coa improves treatment efficiency and has no side effects on normal tissues. Overall, this work delineates a nerve-tumor-immune loop that promotes TNBC metastasis under chronic stress and provides a reference for applying Pro@Coa for safer and more effective treatment of TNBC metastasis, which is more promising for clinical translation.

Engineering an Organic Nanoplatform for Augmented Pyroeletroimmunotherapy.

Photothermal immunotherapy has shown great promise in the treatment of tumor metastasis. However, the thermal resistance of tumor cells substantially compromises the treatment effect of photothermal immunotherapy. Herein, a high-performance organic pyroelectric nanoplatform, tBu-TPAD-BF2 nanoparticles (NPs), is rationally engineered for the effective pyroelectroimmunotherapy of tumor metastasis. Biocompatible tBu-TPAD-BF2 NPs with excellent pyroelectric and photothermal conversion properties are constructed by assembling organic, low-bandgap pyroelectric molecules with amphiphilic polymers. After internalization by tumor cells, treatment with tBu-TPAD-BF2 NPs causes an apparent temperature elevation upon near-infrared (NIR) laser irradiation, inducing potent immunogenic cell death (ICD). Additionally, the temperature variations under alternating NIR laser irradiation facilitate reactive oxygen species production for pyroelectric therapy, thus promoting ICD activation and lowering thermal resistance. Importantly, in vivo assessments illustrate that tBu-TPAD-BF2 NPs in combination with NIR laser exposure notably inhibit primary and distant tumor proliferation and prominently retarded lung metastasis. RNA profiling reveals that treatment with tBu-TPAD-BF2 NPs markedly suppresses metastasis under NIR laser illumination by downregulating metastasis-related genes and upregulating immune response-associated pathways. Therefore, this study provides a strategy for designing high-performance pyroelectric nanoplatforms to effectively cure tumor metastasis, thereby overcoming the inherent shortcomings of photothermal immunotherapy.

Repurposing hemostatic drug desmopressin in AVPR2-expressing triple-negative breast cancer: Target expression analysis and preclinical antineoplastic effects on tumor growth and metastatic progression.

e15087 Background: Desmopressin (dDAVP) is a hemostatic drug that acts as an agonist of the arginine vasopressin receptor 2 (AVPR2) that is present in vascular and malignant cells. Preclinical data show that dDAVP triggers cytostatic mechanisms, blocking angiogenesis and reducing metastases by limiting the survival of circulating tumor cells. Triple-negative breast cancer (TNBC) is associated with poor prognosis due to limited response to therapy and frequent early metastatic recurrence. Considering the unsatisfied clinical need for novel therapeutic options in TNBC, we evaluated the antitumoral activity of dDAVP on experimental models of TNBC, alone or in addition to chemotherapy. We also assessed the expression and clinical impact of AVPR2 in breast cancer samples. Methods: Human and murine TNBC cell lines were used for in vitro experiments. Target expression was assessed by qPCR and immunohistochemistry (IHC), in experimental or clinical tumors (NCT01606072). Effects of dDAVP were evaluated by proliferation, clonogenic, 3D growth and chemotaxis assays, qPCR arrays, and confocal microscopy. Local and distant tumor progression were assessed in vivo in nude or BALB/c mice. TIMER2.0 and UCSC Xena platforms (BRCA TCGA /n = 1260) were used for bioinformatic studies. Results: dDAVP significantly reduced growth and chemotaxis of AVPR2-expressing TNBC cells. Cytostatic effects of dDAVP were associated with altered actin cytoskeleton dynamics and differential expression of angiogenesis and metastasis-related genes. Cooperative effects were observed in vitro and in vivo after combining dDAVP with taxane or alkylating therapy. Tumor-bearing mice were treated with intravenous injections of dDAVP (0.3 µg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.) or carmustine (25 mg/kg i.p.). Combination regimens resulted in greater survival and tumor growth and metastasis inhibition. Bioinformatic analysis of the TCGA database showed that AVPR2 had a positive prognostic impact on overall survival in breast cancer patients, especially in the basal-like molecular subtype. AVPR2 also correlated with different immune cell infiltrates such as NK and dendritic cells, and CD4+ and CD8+ T cells. Moreover, AVPR2 expression was detected by IHC in 6/18 breast cancer clinical samples using a small cohort of surgical specimens. Conclusions: AVPR2 expression is associated with improved outcomes in patients with TNBC. Agonist activation of AVPR2 using dDAVP leads to cancer cell growth inhibition in TNBC cell lines and mouse models. We propose dDAVP as a potential novel therapeutic option for treating TNBC either as monotherapy or in combination with chemotherapy. The therapeutic impact of its addition to immune checkpoint inhibitors remains to be explored.

Effect of NIR-II on cancer nanocomposite vaccines for lymph node targeted delivery and enhanced immunotherapy.

e20506 Background: Cancervaccines have become one of the hot areas of research in recent years. However, different types of tumors and the tumor tissue itself are heterogeneous. Some cancervaccines contain a single epitope and have weak immunogenicity. The antigen-presenting cells cannot adequately absorb and present the antigen peptide contained in the vaccine. As a result, the body fails to elicit an effective immune response, which greatly limits the therapeutic effect of the cancervaccine. In situ cancervaccines composed of antigens and adjuvants are a promising cancer treatment modality; however, convenient manufacturing of vaccines in vivo and their efficient delivery to lymph nodes (LNs) remain a significant challenge. In this study, we outline a facile approach to simultaneously achieve in situ programming of vaccines via two synergistic nanomedicines to generate robust immune responses. Methods: We first prepared two synergistic nanocomposite systems: Gold nanorods, amphiphilic polymer polyphosphate mPEG- b-PHEP encapsulating the immune adjuvant R848, and nanoparticles doped with cationic liposomes DOTAP. Two nanomedicines were characterized and the efficacy of the nanovaccine was verified at the Cellular Experiments. At the animal level, the lymph node targeting of the nanoparticles was demonstrated through IVIS. We also constructed distant model and lung metastasis model to verify the nanovaccine's effect on enhancing systemic immunotherapy. Results: We used amphiphilic polymer polyphosphate mPEG- b-PHEP to encapsulate TLR7/8 agonist R848 to obtain VNPR848 nanoparticles. Gold nanorods (~ 100nm) can produce a strong photothermal effect mediated by NIR-II, killing tumor cells and releasing abundant antigens at the same time. The small size of VNPR848 (~ 30nm) is beneficial to the enrichment of lymph nodes. After capturing the antigens produced by photothermal, nanoparticles will be targeted and delivered to the tumor draining lymph nodes together with R848, and will be effectively absorbed by DC cells. This in situ tumor vaccine with the ability of targeted delivery of lymph nodes can trigger a strong anti-tumor immune response. This therapy can completely inhibit distant tumors in some mice and produce a long-term immune memory effect on NSCLC metastasis. Conclusions: We propose a simple personalized in situ cancervaccine strategy, which uses nanotechnology to remove tumors in situ and release antigens. Antigens and immune adjuvants are simultaneously delivered to the draining lymph nodes to initiate the antigen presentation function of DC cells, resulting in an anti-tumor immune response to inhibit tumor recurrence and metastasis. The nano-vaccine based on powerful therapeutic effect provides an attractive technology for in situ programming of personalized cancervaccine and an effective strategy for the development of cancervaccine.

Analysis of long-lasting tumor-specific antibodies from murine tumors treated with Aliya pulsed electric fields.

e14543 Background: Pulsed electric field (PEF) tissue destruction has demonstrated meaningful systemic immune responses in mice that are superior to thermal ablation, and synergize effectively with systemic chemotherapy and checkpoint blockade (CPB) immunotherapy. Immune cell populations are increased by PEF, including tumor specific activated CD8 T-cells and plasma B-cells. Antitumor immunity can include the presence of circulating anti-cancer antibodies. However, the presence and role of circulating tumor specific antibodies induced by PEF have not been explored. Serological antibodies are often detected with the ELISA assay, where tumor-associated antigens are coated to a microtiter plate to attract the corresponding serum antibodies. Here, we quantify IgG tumor specific antibodies after PEF using an in-house ELISA. Methods: Mice bearing immune-warm (EMT6) and immune-cold (4T1) orthotopic murine breast tumors were treated with a biphasic PEF dose comparable to Aliya titrated for mouse tumors. To detect tumor specific circulating IgG1 immunoglobulin in serum, an ELISA plate was coated with EMT6 and 4T1 protein lysate, as well as with a known 4T1-expressed tumor-specific antigen (gp70). Serum draws from the treated, untreated, and naïve mice were exposed to the coated wells for 1 hour. Bound IgG were detected by anti-mouse IgG (HRP tagged) antibody added to the wells and incubated 1 hour. A TMB substrate was added and color development was allowed for 15 minutes. The optical density was quantified using a microtiter plate reader. Results: ELISA quantification of serum IgG at multiple timepoints show that 4T1 tumor-specific IgG antibodies were increased 14.3- and 2.6-fold by day 20 in the PEF-treated and untreated group survivors relative to Naïve mice, respectively, (OD=0.86 and 0.15 v. 0.06). Furthermore, IgG antibodies specific to the gp70 antigen of the 4T1 cell line were increased by 44.9- and 2.7-fold in the PEF-treated and untreated groups relative to naïve mice (OD=3.14 and 0.19 v. 0.07). In the EMT6 model, at 3 months post-treatment, only the PEF-ablated group mice survived, and showed 15.5-fold higher antibodies against EMT6 tumor antigens compared to naive mice (OD=0.62 v. 0.04). Conclusions: The specific form of PEF in this study generated tumor-specific IgG long-lived antibodies in mice for immune-warm and immune-cold tumor models, corroborating previous findings of increased murine B-cell and plasma cell populations. This effect has not been well-reported for other ablation technologies. Increases were evident by Day 20 post-PEF and persisted at least 3 months. These murine data suggest the PEF used may invoke potent, long-lived immune responses and anti-tumor immune surveillance, offering a potential approach for in situ tumor vaccination to improve metastatic disease outcomes. Future studies should determine response durability and its role in attaining distant tumor clearance.

A phase 1 trial in progress for in situ immunomodulation with CDX-301, radiation therapy, poly-ICLC, and CDX-1140 in patients with unresectable and metastatic solid tumors.

TPS2697 Background: The prognosis for patients with unresectable and metastatic solid tumors that progress on standard of care therapy remains poor due to limited treatment options. Compelling evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1) is critical to elicit anti-tumor immunity. Recently, we have demonstrated that a combinatorial regimen comprised of in situ delivery of Fms-like tyrosine kinase 3 ligand (Flt3L), radiation therapy (9Gy), and dual TLR3/CD40 stimulation 1) mobilizes cDC1 to the tumor microenvironment; 2) induces maturation of cDC1; 3) facilitates trafficking of cDC1 carrying tumor antigens to tumor-draining lymph nodes; 4) elicits de novo adaptive T cell immunity; 5) triggers regression of primary tumors, as well as non-irradiated distant tumors; and 6) develops tumor-specific systemic immunological memory using multiple syngeneic orthotopic murine models (1-4). Based on results from preclinical studies, we have initiated a phase 1 study as below. Methods: This is a phase 1 study of in situ immunomodulation with CDX-301 (Flt3L), radiation therapy, CDX-1140 and Poly-ICLC (dual CD40/TLR3 stimulation) in patients with unresectable and metastatic solid tumors. Eligibility for this study includes patients ≥ 18 yrs who have clinically or pathologically confirmed diagnosis of unresectable and metastatic melanoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or HER2/neu (-) breast cancer with no curative treatment options, and progressed on at least one line of standard systemic therapy. The unresectable disease to be irradiated and injected with medications must be located in breast, dermal, subcutaneous, or soft tissue, or lymph nodes with the longest axis of the tumor 2-7 cm, and should be considered safe for injection by the investigator. The metastatic disease must be measurable per irRECIST criteria. Patients will be treated with daily intratumoral injection of CDX-301 for 5 days (Day 1-5), radiation therapy (9Gy, Day 8) followed by administration of CDX-1140 and Poly-ICLC (Day 9). Up to 4 cycles of this combination therapy can be given every 3 weeks. The primary endpoints are safety/tolerability and to evaluate the MTD of for injection (intratumoral in the cohort A and intratumoral and intravenous in the cohort B) of CDX-1140. A standard 3+3 design, allowing for dose de-escalation, will be used within each cohort. Secondary endpoints are to evaluate immune signatures in blood and the tumor. This phase 1 trial opened to enrollment at the University of Southern California Norris Comprehensive Cancer Center in January 2023 (recruitment is currently 4 on February 6, 2024). 1. Nature Communications 2020. 2. J. Immunology 2021. 3. Cancer Research 2021. 4. Scientific Reports 2022. Clinical trial information: NCT04616248 .

Interaction between histology and staging on survival outcomes of patients diagnosed with esophageal cancer over the past decade.

e16054 Background: Esophageal cancer (EC) ranks sixth globally in cancer-related deaths , continuing to be a significant public health concern . The purpose of this study is to assess the impact of staging and histopathology of EC on associated mortality. The study also aims to further investigate clinical characteristics, prognostic factors, and survival outcomes in patients diagnosed with EC between 2010 and 2017. Methods: A total of 22,979 patients diagnosed with EC between 2010 and 2017 in the United States were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database. Demographic parameters, tumor stage and histologic subtypes were analyzed and associated mortality was measured across all subgroups. Covariates reaching the level of statistical significance, demonstrable by a p-value equal to or < 0.01 were incorporated into a multivariate Cox proportional hazards model. The primary outcome of this study was discernment of clinicopathologic variables associated with mortality, with a primary focus on delineation of the association between the latter, and tumor stage and histologic subtype respectively. A hazard ratio > 1 was indicative of increased risk for mortality in presence of the variable under discussion. Results: 22,979 patients: Male (79.78%), age 60-79 (59.78%), non-Hispanic whites (77.44%). Distant metastases in 41.27%, adenocarcinoma prevalent (66.72%). Crude analysis revealed higher EC-related mortality in males (HR: 1.06, 95% CI: 1.02-1.11), non-Hispanic blacks (HR: 1.32, 95% CI: 1.25-1.39), and Hispanics (HR: 1.12, 95% CI: 1.05-1.18). Multivariate analyses showed higher overall mortality in males (HR = 1.13, 95% CI 1.08-1.18, p < 0.01), distant tumor stage (HR = 2.93, 95% CI 1.56-5.52, p < 0.01), and advanced age. Stand-alone surgical therapy (HR = 0.29, 95% CI 0.28-0.31, p < 0.01) and adenocarcinoma histology (HR = 0.49, 95% CI 0.27-0.89, p < 0.01) correlated with lower mortality. Notable interaction: Gastrointestinal Stromal Tumor (GIST) histology, especially with local structure invasion, increased overall mortality (HR = 7.25, 95% CI 1.17-45.11, p < 0.05) and GIST-related mortality (HR = 46.09, 95% CI 3.42-620.37, p < 0.01). Conclusions: Adenocarcinoma histology and distant metastases at diagnosis elevate all-cause and EC-associated mortality in EC patients. Demographics matter; males, non-Hispanic blacks, and advanced age associate with increased mortality. GIST histology, particularly with local invasion, significantly raises mortality. Further research can unravel histopathology and staging's impact on overall and cancer-specific mortality, aiding targeted therapy. This study aims to assist physicians in identifying at-risk populations and encourages more research to address racial disparities, ultimately enhancing aggressive therapies and improving mortality outcome.

Catalytic Dual-Mode Immunotherapy: Anisotropic AuPt Heterostructure Decorated with Starry Pt Nanoclusters for Robust Cancer Photometalloimmunotherapy.

To overcome current limitations in photoimmunotherapy, such as insufficient tumor antigen generation and a subdued immune response, a novel photo-/metallo dual-mode immunotherapeutic agent (PMIA) is introduced for potent near-infrared (NIR) light-triggered cancer therapy. PMIA features a dumbbell-like AuPt heterostructure decorated with starry Pt nanoclusters, meticulously engineered for enhancing plasmonic catalysis through multi-dimensional regulation of Pt growth on Au nanorods. Under NIR laser exposure, end-tipped Pt nanoclusters induce efficient electron-hole spatial separation along the longitudinal axis, resulting in radial and axial electron distribution polarization, conferring unique anisotropic properties to PMIA. Additionally, starry Pt nanoclusters on the sides of Au nanorods augment the local electron enrichment field. Validated through finite-difference time-domain analysis and Raman scattering, this configuration fosters local electron enrichment, facilitating robust reactive oxygen species generation for potent photoimmunotherapy. Moreover, Pt nanoclusters facilitate Pt2+ ion release, instigating intranuclear DNA damage and inducing synergistic immunogenic cell death (ICD) for metalloimmunotherapy. Consequently, PMIA elicits abundant danger-associated molecular patterns, promotes T cell infiltration, and triggers systemic immune responses, effectively treating primary and distant tumors, inhibiting metastasis in vivo. This study unveils a pioneering dual-mode ICD amplification strategy driven by NIR light, synergistically integrating photoimmunotherapy and metalloimmunotherapy, culminating in potent cancer photometalloimmunotherapy.

The National Landscapes of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma: Stable Trends in Black Populations and Late-Stage Tumors.

Helicobacter pylori (H. Pylori) eradication has been the mainstream for preventing and treating gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Prior data showed disparities in eradication rates of H. Pylori between different populations. This can potentially impact the occurrence of gastric MALT lymphoma. There are limited data on the incidence and mortality rates and trends of gastric MALT lymphoma in the US. Therefore, the aim of the current study was to conduct a time-trend analysis of gastric MALT lymphoma incidence and mortality rates in different populations. The incidence rates of gastric MALT lymphoma were calculated from the United States Cancer Statistics (USCS) database (which covers nearly 98% of the US population) between 2001-2020 and were age-adjusted to the standard 2000 US population using SEER*Stat software (version 8.4.3, national cancer institute "NCI"). Incidence-based mortality (IBM) rates, also age-adjusted to the standard 2000 US population, were calculated from the Surveillance Epidemiology and End Results (SEER) database. Tumor location was specified using ICD-O-3 codes C 160-C 169 with malignant behavior. Histopathology was specified using the ICD-O-3 code 9699. The rates were categorized by sex, age, race/ethnicity, and tumor stage at diagnosis. Age groups were older adults (aged 55 years or older) and younger adults (aged younger than 55 years). Race/ethnic groups included Non-Hispanic White (White), Non-Hispanic Black (Black), Hispanic, Non-Hispanic Asian/Pacific Islander (API), and Non-Hispanic American Indian/Alaska Native (AI/AN), as reported in the database. Stage at diagnosis included early stage (in situ and localized tumors) and late stage (regional and distant site tumors). Joinpoint Regression Software (version 5.0.2, NCI) using the weighted Bayesian Information Criteria method was used to generate time trends. Trends were reported as annual percentage change (APC) and average APC (AAPC). Parametric estimations were used with a two-sided t-test to evaluate the trends with a p-value cutoff at 0.05. There were 21,625 patients diagnosed with gastric MALT lymphoma in the US between 2001 and 2020. Overall, incidence rates were significantly decreasing over the study period (AAPC = -1.93). This decrease was seen in males (AAPC = -1.67) and in females (AAPC = -1.66) (Figure). When categorized by age groups, older adults also experienced a significant decrease in gastric MALT lymphoma incidence rates (AAPC = -1.66). While this was also seen in younger adults, the rates were decreasing at a slower pace (AAPC = -1.38). When categorizing the trends by race/ethnicity, incidence rates were significantly decreasing in White (AAPC = -2.09), Hispanic (AAPC = -1.61), and API (AAPC = -3.92) populations. However, the rates were stable among Blacks. While early-stage tumors experienced a significant decrease (AAPC = -1.10), the rates were stable for late-stage tumors. When evaluating mortality, there were 11,036 patients whose death was attributed to gastric MALT lymphoma between 2000 and 2020. IBM rates were decreasing in males (AAPC = -1.47), older adults (AAPC = -1.55), Whites (AAPC = -1.23), Hispanics (AAPC = -1.73), APIs (AAPC = -2.30), and early-stage tumors (AAPC = -1.08). On the other hand, IBM rates were stable in females, younger adults, Blacks, and late-stage tumors. An extensive nationwide data analysis encompassing nearly 98% of patients diagnosed with gastric MALT lymphoma in the US unveils a declining trend in the incidence of cancer overall over the past two decades. This decline is observed in both sexes and various age groups. When stratifying by race and ethnicity, this incidence has been decreasing in all populations except among Black individuals. While early-stage tumors have also demonstrated a significant decrease in incidence rates, late-stage tumors have shown no parallel decline. Mortality evaluation also revealed an improvement in most of the US population except among females, younger adults, Black individuals, and late-stage tumors. While the cause of our findings is unclear, it could be driven by disproportionate exposure to risk factors, including H. Pylori, and disparities in screening, management, and outcomes. Future studies are warranted to investigate factors contributing to worse outcomes of gastric MALT lymphoma, especially in the Black population.

Fluorescence tracking demonstrates T cell recirculation is transiently impaired by radiation therapy to the tumor

T cells recirculate through tissues and lymphatic organs to scan for their cognate antigen. Radiation therapy provides site-specific cytotoxicity to kill cancer cells but also has the potential to eliminate the tumor-specific T cells in field. To dynamically study the effect of radiation on CD8 T cell recirculation, we used the Kaede mouse model to photoconvert tumor-infiltrating cells and monitor their movement out of the field of radiation. We demonstrate that radiation results in loss of CD8 T cell recirculation from the tumor to the lymph node and to distant sites. Using scRNASeq, we see decreased proliferating CD8 T cells in the tumor following radiation therapy resulting in a proportional enrichment in exhausted phenotypes. By contrast, 5 days following radiation increased recirculation of T cells from the tumor to the tumor draining lymph node corresponds with increased immunosurveillance of the treated tumor. These data demonstrate that tumor radiation therapy transiently impairs systemic T cell recirculation from the treatment site to the draining lymph node and distant untreated tumors. This may inform timing therapies to improve systemic T cell-mediated tumor immunity.

A Carbon‐Caged Rhodamine Generating Nitrosoperoxycarbonate for Photoimmunotherapy

AbstractPhotoimmunotherapy is a promising cancer treatment modality. While potent 1‐e− oxidative species are known to induce immunogenic cell death (ICD), they are also associated with unspecific oxidation and collateral tissue damage. This difficulty may be addressed by post‐generation radical reinforcement. Namely, non‐oxidative radicals are first generated and subsequently activated into powerful oxidative radicals to induce ICD. Here, we developed a photo‐triggered molecular donor (NPCD565) of nitrosoperoxycarbonate (ONOOCO2−), the first of its class to our knowledge, and further evaluated its feasibility for immunotherapy. Upon irradiation of NPCD565 by light within a broad spectral region from ultraviolet to red, ONOOCO2− is released along with a bright rhodamine dye (RD565), whose fluorescence is a reliable and convenient build‐in reporter for the localization, kinetics, and dose of ONOOCO2− generation. Upon photolysis of NPCD565 in 4T1 cells, damage‐associated molecular patterns (DAMPs) indicative of ICD were observed and confirmed to exhibit immunogenicity by induced maturation of dendritic cells. In vivo studies with a bilateral tumor‐bearing mouse model showcased the potent tumor‐killing capability of NPCD565 of the primary tumors and growth suppression of the distant tumors. This work unveils the potent immunogenicity of ONOOCO2−, and its donor (NPCD565) has broad potential for photo‐immunotherapy of cancer.

A Carbon-Caged Rhodamine Generating Nitrosoperoxycarbonate for Photoimmunotherapy.

Photoimmunotherapy is a promising cancer treatment modality. While potent 1-e- oxidative species are known to induce immunogenic cell death (ICD), they are also associated with unspecific oxidation and collateral tissue damage. This difficulty may be addressed by post-generation radical reinforcement. Namely, non-oxidative radicals are first generated and subsequently activated into powerful oxidative radicals to induce ICD. Here, we developed a photo-triggered molecular donor (NPCD565) of nitrosoperoxycarbonate (ONOOCO2 -), the first of its class to our knowledge, and further evaluated its feasibility for immunotherapy. Upon irradiation of NPCD565 by light within a broad spectral region from ultraviolet to red, ONOOCO2 - is released along with a bright rhodamine dye (RD565), whose fluorescence is a reliable and convenient build-in reporter for the localization, kinetics, and dose of ONOOCO2 - generation. Upon photolysis of NPCD565 in 4T1 cells, damage-associated molecular patterns (DAMPs) indicative of ICD were observed and confirmed to exhibit immunogenicity by induced maturation of dendritic cells. In vivo studies with a bilateral tumor-bearing mouse model showcased the potent tumor-killing capability of NPCD565 of the primary tumors and growth suppression of the distant tumors. This work unveils the potent immunogenicity of ONOOCO2 -, and its donor (NPCD565) has broad potential for photo-immunotherapy of cancer.

Effectiveness and safety of computed tomography-guided high-dose-rate brachytherapy in treating recurrent hepatocellular carcinoma not amenable to repeated resection or radiofrequency ablation

PurposeTo assess the efficacy and safety of computed tomography (CT)-guided high-dose-rate HDR) brachytherapy in treating recurrent hepatocellular carcinoma (HCC) not amenable to repeated resection or radiofrequency ablation. Materials and methodsFrom January 2010 to January 2022, 38 patients (mean age, 70.1 years; SD ± 9.0 years) with 79 nodular and four diffuse intrahepatic HCC recurrences not amenable to repeated resection or radiofrequency ablation underwent CT-guided HDR brachytheapy in our department. Tumor response was evaluated by cross-sectional imaging 6 weeks after CT-guided HDR brachytherapy and every 3 months thereafter. Local tumor control (LTC), progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier curves (KPCs). Severity of procedure-related complications (PRCs) was classified as recommended by the Society of Interventional Radiology (SIR). ResultsPatients were available for MRI evaluation for a mean follow-up of 33.1 months (SD, ±21.6 mm, range 4–86 months; median 29 months). Patients had a mean of 2.3 (SD, ±1.4) intrahepatic tumors. Mean tumor diameter was 43.2 mm (SD, ±19.6 mm). 13 of 38 (34.2%) patients showed local tumor progression after CT-guided HDR brachytherapy. Mean LTC was 29.3 months (SD, ±22.1). Distant tumor progression was seen in 12 patients (31.6%). The mean PFS was 20.8 months (SD, ±22.1). Estimated 1-, 3-, and 5-year PFS rates were 65.1%, 35.1% and 22.5%, respectively. 13 patients died during the follow-up period. Mean OS was 35.4 months (SD, ±21.7). Estimated 1-, 3-, and 5-year OS rates were 91.5%, 77.4% and 58.0%, respectively. SIR grade 1 complications were recorded in 8.6% (5/38) and SIR grade 2 complications in 3.4% (2/58) of interventions. ConclusionCT-guided HDR brachytherapy is a safe and efficient therapeutic option for managing large or critically located HCC recurrences in the remaining liver after prior hepatic resection.

Chlorin e6 and BLZ945 Based Self-Assembly for Photodynamic Immunotherapy Through Immunogenic Tumor Induction and Tumor-Associated Macrophage Depletion.

Immunotherapeutic effect is restricted by the nonimmunogenic tumor phenotype and immunosuppression behaviors of tumor-associated macrophages (TAMs). In this work, a drug self-assembly (designated as CeBLZ) is fabricated based on chlorin e6 (Ce6) and BLZ945 to activate photodynamic immunotherapy through tumor immunogenic induction and tumor-associated macrophage depletion. It is found that Ce6 tends to assemble with BLZ945 without any drug excipients, which can enhance the cellular uptake, tumor penetration, and blood circulation behaviors. The robust photodynamic therapy effect of CeBLZ efficiently suppresses the primary tumor growth and also triggers immunogenic cell death to reverse the nonimmunogenic tumor phenotype. Moreover, CeBLZ can deplete TAMs in tumor tissues to reverse the immunosuppression microenvironment, activating abscopal effect for distant tumor inhibition. In vitro and in vivo results confirm the superior antitumor effect of CeBLZ with negligible side effect, which might promote the development of sophisticated drug combinations for systematic tumor management.

Cascade loop of ferroptosis induction and immunotherapy based on metal‐phenolic networks for combined therapy of colorectal cancer

AbstractCancer immunotherapy is the most promising method for tumor therapy, while ferroptosis could activate the immunogenicity of cancer and strengthen the cellular immune response. However, limited by the complex tumor microenvironment, the abundant glutathione (GSH) and low reactive oxygen species (ROS) seriously weaken ferroptosis and the immune response. Herein, the authors report photothermal metal‐phenolic networks (MPNs) supplied with buthionine sulfoximine (BSO) by reducing levels of GSH and then trapping the tumor cells in the ferroptosis and immunotherapy cascade loop to eliminate colorectal cancer (CRC). The MPNs coated with the model antigen ovalbumin can accumulate at the tumor site, mediate immunogenic cell death (ICD) under NIR irradiation, and initiate tumoricidal immunity. Then the activated CD8+ T cells would release IFN‐γ to inhibit GPX4 and promote the immunogenic ferroptosis induced by Fe3+ and BSO. Finally, the tumor cells at intertumoral and intratumoral levels would be involved in the ferroptosis‐dominated cancer‐immunity circle for CRC eradication, resulting in outstanding therapeutic outcomes in both primary and distant tumor models. Overall, this strategy employs a photothermal nanoplatform to rapidly stimulate ICD and restrain the oxidation defense system, which provides a promising approach to significantly amplify the “cascade loop” of ferroptosis induction and immunotherapy for treatment of CRC.

Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases

Tumor-promoting niche after incomplete surgery resection (SR) can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment (TME). Herein, elevated neutrophil extracellular traps (NETs) and cancer-associated neurotransmitters (CANTs, e.g., catecholamines) are firstly identified as two of the dominant inducements. Further, an injectable fibrin-alginate hydrogel with high tissue adhesion has been constructed to specifically co-deliver NETs inhibitor (DNase I)-encapsulated PLGA nanoparticles and an unselective β-adrenergic receptor blocker (propranolol). The two components (i.e., fibrin and alginate) can respond to two triggers (thrombin and Ca2+, respectively) in postoperative bleeding to gelate, shaping into an interpenetrating network (IPN) featuring high strength. The continuous release of DNase I and PR can wreck NETs and antagonize catecholamines to decrease microvessel density, blockade myeloid-derived suppressor cells, secrete various proinflammatory cytokines, potentiate natural killer cell function and hamper cytotoxic T cell exhaustion. The reprogrammed TME significantly suppress locally residual and distant tumors, induce strong immune memory effects and thus inhibit lung metastasis. Thus, targetedly degrading NETs and blocking CANTs enabled by this in-situ IPN-based hydrogel drug depot provides a simple and efficient approach against SR-induced cancer recurrence and metastasis.

Prognostic relevance of radiological findings on early postoperative MRI for 187 consecutive glioblastoma patients receiving standard therapy

Several prognostic factors are known to influence survival for patients treated with IDH-wildtype glioblastoma, but unknown factors may remain. We aimed to investigate the prognostic implications of early postoperative MRI findings. A total of 187 glioblastoma patients treated with standard therapy were consecutively included. Patients either underwent a biopsy or surgery followed by an early postoperative MRI. Progression-free survival (PFS) and overall survival (OS) were analysed for known prognostic factors and MRI-derived candidate factors: resection status as defined by the response assessment in neuro-oncology (RANO)-working group (no contrast-enhancing residual tumour, non-measurable contrast-enhancing residual tumour, or measurable contrast-enhancing residual tumour) with biopsy as reference, contrast enhancement patterns (no enhancement, thin linear, thick linear, diffuse, nodular), and the presence of distant tumours. In the multivariate analysis, patients with no contrast-enhancing residual tumour or non-measurable contrast-enhancing residual tumour on the early postoperative MRI displayed a significantly improved progression-free survival compared with patients receiving only a biopsy. Only patients with non-measurable contrast-enhancing residual tumour showed improved overall survival in the multivariate analysis. Contrast enhancement patterns were not associated with survival. The presence of distant tumours was significantly associated with both poor progression-free survival and overall survival and should be considered incorporated into prognostic models.