Metastatic Tumor Sites Research Articles

Real-world study on the effect of nab-paclitaxel treatment on clinical outcomes and laboratory parameters in patients across metastatic tumor sites

Objectives: PacliALLTM is the first and only indigenously developed brand of nab-paclitaxel in India that has shown bioequivalence to the global reference (Abraxane®). However, real-world Evidence is scarce about the use of it in different tumor sites beyond approved indications. This study assessed the effects of nab-paclitaxel (PacliALLTM) on clinical outcomes in patients diagnosed with different metastatic cancers in a tertiary care hospital in India. Material and Methods: In this retrospective study, data on demographics, medical history, and laboratory investigations were collected from medical records of patients with metastatic cancer. Patients on nab-paclitaxel were included, and data on laboratory findings, including hematological, liver, and kidney function tests and prognostic outcomes, were evaluated. Results: The study population consisted of 73 patients with metastatic cancer (mean age- 54.6 years). Primary sites of cancer in most patients were the oral cavity (40.8%), followed by breast and ovary (15.3%, each). The Eastern Cooperative Oncology Group score was 0 in 84.3% and 1 in 14.3% of patients. Weekly analyses showed no significant differences in hemoglobin, neutrophil, creatinine, random blood glucose (RBG), and serum glutamic-oxaloacetic transaminase levels. A significant proportion of patients reported anemia and RBG >125 mg/dL at baseline (97.1% and 63.4%, respectively) and week 17 (85.1% and 88.1%, respectively). Most patients had a partial response at week 17 (76.8%), respectively. No serious adverse reactions were reported, requiring a change in treatment. Conclusion: Nab-paclitaxel showed manageable tolerability and favorable response rates in metastatic cancer patients. It is widely used beyond approved indications in a significant proportion of patients across various tumor sites.

The utility of the lineage specific immunohistochemical stains SATB2, CDX2, and villin, and the mucin glycoproteins MUC2, MUC5AC, and MUC6 to distinguish pulmonary invasive mucinous adenocarcinoma from metastatic colorectal carcinoma

ContextThe lungs are a common site of tumor metastasis. While morphology and immunophenotype can help differentiate primary from metastatic tumors, distinguishing pulmonary invasive mucinous adenocarcinoma (PIMA) from metastatic colorectal adenocarcinoma (CRC) may occasionally be challenging due to overlapping morphological and immunohistochemical features. Lineage-specific markers such as CDX2, TTF-1, and napsin A are helpful with pulmonary non-mucinous adenocarcinoma (PNMA), however they are non-specific and insensitive when applied to PIMA. SATB2 is a newer marker that distinguishes CRC from upper gastrointestinal and pancreaticobiliary tumors; its utility in distinguishing CRC from PIMA has not been fully elucidated. ObjectiveTo evaluate the performance of lineage-specific and mucin glycoprotein immunostains in distinguishing PIMA and CRC. DesignWe stained tissue microarrays comprising 34 PNMA, 31 PIMA, and 32 CRC with CK7, CK20, SATB2, CDX2, villin, TTF-1, napsin A, and gel-forming mucins MUC2, MUC5AC, and MUC6. ResultsPIMA showed significant (>50% of cells) expression of SATB2 (6%), CDX2 (6%), villin (74%), TTF-1 (13%), and napsin A (23%). However, significant CK7 expression was seen in nearly all PIMA (30/31) and none of the metastatic CRC. ConclusionOur results suggest that CK7 remains one of the most useful markers for distinguishing primary PIMA from metastatic CRC. Expression of the mucin glycoproteins MUC5AC and MUC6 and lack of expression of MUC2 favored a diagnosis of PIMA, but expression of these markers was too heterogeneous to be of clinical utility. To our knowledge this is the only study comparing the immunohistochemical profile of PIMA and metastatic CRC in lung metastasectomy specimens.

Application of Separation Surgery Combined with Radiofrequency Ablation and Bone Cement Strengthening in Thoracolumbar Metastasis.

The spine is a common site for metastatic tumors, with 5%-10% of patients developing epidural spinal cord compression (ESCC), which significantly reduces their quality of life and accelerates the process of death. When total en-bloc spondylectomy (TES) radical surgery does not achieve the desired tumor control, palliative care remains the primary treatment option. Traditional laminar decompression or partial tumor resection can only relieve local compression. Although the surgical trauma and complications are less, these methods cannot effectively address tumor recurrence and secondary compression. Therefore, separation surgery combined with radiofrequency ablation and bone cement strengthening was used to treat thoracolumbar metastatic tumors, aiming to achieve good clinical results. In this protocol, the steps and key points of separation surgery combined with radiofrequency ablation and bone cement reinforcement for thoracolumbar metastatic tumors are introduced in detail. Meanwhile, the clinical data of 67 cases of thoracolumbar metastatic tumors in our hospital meeting the inclusion criteria were retrospectively analyzed. Different treatment methods divided the patients into two groups: separation surgery combined with radiofrequency ablation and bone cement strengthening (group A, 33 cases) and the radiotherapy group (group B, 34 cases). All patients were evaluated using improved Tokuhashi, Tomita, SINS, and ESCC scores before treatment. VAS score, Frankel grading, and Karnofsky scores during different periods of the two treatments were compared to assess the clinical outcomes. Studies have shown that separation surgery combined with radiofrequency ablation and bone cement strengthening can significantly reduce pain, promote neurological function recovery, enhance mobility, and improve quality of life in treating thoracolumbar metastatic tumors.

Accumulation of liposomes in metastatic tumor sites is not necessary for anti-cancer drug efficacy

BackgroundThe tumor microenvironment is profoundly heterogeneous particularly when comparing sites of metastases. Establishing the extent of this heterogeneity may provide guidance on how best to design lipid-based drug delivery systems to treat metastatic disease. Building on our previous research, the current study employs a murine model of metastatic cancer to explore the distribution of ~ 100 nm liposomes. MethodsFemale NCr nude mice were inoculated with a fluorescently labeled, Her2/neu-positive, trastuzumab-resistant breast cancer cell line, JIMT-1mkate, either in the mammary fat pad to create an orthotopic tumor (OT), or via intracardiac injection (IC) to establish tumors throughout the body. Animals were dosed with fluorescent and radio-labeled liposomes. In vivo and ex vivo fluorescent imaging was used to track liposome distribution over a period of 48 h. Liposome distribution in orthotopic tumors was compared to sites of tumor growth that arose following IC injection. ResultsA significant amount of inter-vessel heterogeneity for DiR distribution was observed, with most tumor blood vessels showing little to no presence of the DiR-labelled liposomes. Further, there was limited extravascular distribution of DiR liposomes in the perivascular regions around DiR-positive vessels. While all OT tumors contained at least some DiR-positive vessels, many metastases had very little or none. Despite the apparent limited distribution of liposomes within metastases, two liposomal drug formulations, Irinophore C and Doxil, showed similar efficacy for both the OT and IC JIMT-1mkate models. ConclusionThese findings suggest that liposomal formulations achieve therapeutic benefits through mechanisms that extend beyond the enhanced permeability and retention effect.

Tracing unknown tumor origins with a biological-pathway-based transformer model

Cancer of unknown primary (CUP) represents metastatic cancer where the primary site remains unidentified despite standard diagnostic procedures. To determine the tumor origin in such cases, we developed BPformer, a deep learning method integrating the transformer model with prior knowledge of biological pathways. Trained on transcriptomes from 10,410 primary tumors across 32 cancer types, BPformer achieved remarkable accuracy rates of 94%, 92%, and 89% in primary tumors and primary and metastatic sites of metastatic tumors, respectively, surpassing existing methods. Additionally, BPformer was validated in a retrospective study, demonstrating consistency with tumor sites diagnosed through immunohistochemistry and histopathology. Furthermore, BPformer was able to rank pathways based on their contribution to tumor origin identification, which helped to classify oncogenic signaling pathways into those that are highly conservative among different cancers versus those that are highly variable depending on their origins.

Abstract PO1-29-04: Spatial tumor microenvironment profiling identifies immune features that correlate with response to T-DXd treatment in patients with metastatic breast cancer

Abstract Objective: It is unclear which patients with metastatic breast cancer respond to the new antibody drug conjugate T-DXd treatment. Methods: We profiled 22 pre-T-DXd treatment metastatic tissue samples from patients using Nanostring GeoMX digital spatial profiler of tumor infiltrating immune cells and stroma components. Among the 22 metastatic samples, 10 were bone metastases 7 of the patients were defined as responder (R) and 3 were defined as non-responder (NR) to T-DXd treatment; 4 brain metastases with 2 R and 2 NR; 4 lymph node metastases with 2 R and 2 NR, and 3 liver metastases with all patients were NR to T-DXd. In each metastatic tissue section, 6-8 circular regions of interest (ROI) with 300µm diameter were selected by tumor epithepial marker (pan CK) and immune cells marker (CD45) throughout different areas of the tumor. The spatial quantification of 22 immune markers and 3 stroma elements (fibronectin, fibroblast activation protein, and smooth muscle actin) in each ROI was analyzed. Results: Based on the segmented CD45-positive cell numbers, a total of 144 ROIs were classified into high tumor-infiltrating immune ROIs (high-TIL, n=47) and low-TIL ROIs (n=97). Within the high-TIL ROIs, none immune markers showed significant difference in either the R or NR group across all metastasis sites (P >0.05, Figure 1). Within the low-TIL ROIs, several immune markers, including PD-L1, PD-1, CD3, CD56, CD20, CD14, CD11c, CTLA-4, CD45, and B2M (Beta-2-microglobulin, an antigen presentation marker) showed significant elevation in the R group than those in the NR group (P < 0.05, Figure 2). Other immune markers including CD4 and CD8 were not significantly different in the R vs. NR groups in the low-TIL ROIs. High Ki-67 was correlated with R in both high and low-TIL ROIs. None of the three stroma markers was associated to treatment response to T-DXd. Conclusions: Enrichment of PD-L1, PD-1, CD3, CD56, CD20, CD14, CD11c, CTLA-4, CD45, and B2M in the metastatic tumor sites favors the treatment response to T-DXd in patients with metastatic breast cancer. Our study provides novel evidence that immune-suppression is associated with patients’ response to T-DXd treatment, which may due to the unique mechanism of action of T-DXd. Citation Format: Hong Zhao, Matthew Vasquez, Jeffrey Zhang, Glori Das, Ji-Hoon Lee, Yuan Gao, Jilun Zhang, Xiaoxian Li, Jenny Chang, Stephen Wong. Spatial tumor microenvironment profiling identifies immune features that correlate with response to T-DXd treatment in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-29-04.

Initial [18F]DCFPyL PET/CT in treatment-naïve prostate cancer: correlation with post-ADT PSA outcomes and recurrence.

Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) targeting tracers has emerged as a valuable diagnostic tool for prostate cancer (PCa), androgen deprivation therapy (ADT) stands as the cornerstone treatment for advanced PCa, yet forecasting the response to hormonal therapy poses a significant clinical hurdle. In a prospective cohort of 86 PCa patients undergoing short-term ADT, this study evaluated the prognostic potential of [18F]DCFPyL PET/CT scans. Comprehensive data encompassing clinical profiles, baseline prostate-specific antigen (PSA) levels, and imaging metrics were assessed. We developed predictive models for assessing decreases in PSA levels (PSA50 and PSA70) based on a combination of PET-related parameters and clinical factors. Kaplan-Meier survival analysis was utilized to ascertain the prognostic value of PET-based metrics. In this study, elevated [18F]DCFPyL uptake within the primary tumor, as indicated by a SUV ≥ 6.78 (p = 0.0024), and a reduction in the tumor volume (TV) of primary PSMA-avid tumor with PSMA-TV < 41.96 cm3 (p = 0.038), as well as an increased burden of metastatic PSMA-avid tumor, with PSMA-TV (PSMA-TV ≥ 71.39 cm3) (p = 0.012) were identified in association with diminished progression-free survival (PFS). PET and clinical parameters demonstrated constrained predictive capacity for PSA50 response as indicated by an area under the curve (AUC) of 0.442. Our study revealed that pretreatment [18F]DCFPyL uptake in primary or metastatic tumor sites is prognostically relevant in high-risk PCa patients undergoing ADT. Further research is needed to develop robust predictive models in this multifaceted landscape of PCa management.

Abstract 4978: Genomic characterization of metastatic pancreatic cancer according to tumor sample sites

Abstract Background: Our research aimed to evaluate and compare the genetic variations in the primary and metastatic sites of patients with metastatic pancreatic cancer. Methods: In this study, we selected individuals with metastatic pancreatic cancer from the data provided by the American Association for Cancer Research Project GENIE (version 14.1). The comparison of genetic mutations between primary and metastatic tumor sites was conducted using the Fisher exact test, augmented with the Benjamini-Hochberg adjustment technique. Results: In a study of 3,108 patients with metastatic pancreatic cancer, 38.9% had metastatic site tumor samples, while 61.1% had samples from the primary tumor. The most frequent mutations were KRAS (89.4%), TP53 (72.9%), SMAD4 (21.2%), and CDKN2A (17.4%). Metastatic samples showed higher rates of CDKN2A, CDKN2B, and MTAP mutations compared to primary site samples (40.1% vs. 29.1%; 20.3% vs. 10.4%; and 20.8% vs. 8.9%, respectively, all with p&amp;lt;0.001 and q&amp;lt;0.001). In patients with young-onset pancreatic cancer (younger than 50 years), there was no notable difference in gene mutations between the two sample groups. Conclusion: Our findings corroborate the notion that identifying the precise genes that contribute to the development of metastatic pancreatic cancer is vital for gaining a more comprehensive understanding of the biological mechanisms. Moreover, genomic profiling could be a key in pinpointing potential biomarkers for diagnosis and therapy. Citation Format: Suleyman Y. Goksu, Muhammet Ozer, Busra Bacik Goksu, Nina N. Sanford, Amy Jones, Nilesh Verma, Syed Kazmi. Genomic characterization of metastatic pancreatic cancer according to tumor sample sites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4978.

Abstract 2914: AI/ML-driven discovery of CTHRC1, collagen triple helix repeat-containing 1, a novel proteoglycan for stroma + tumor targeting and delivery of 4-1BB costimulation

Abstract Background: While checkpoint inhibitors have demonstrated efficacy in a number of solid tumor indications, those with high stromal presence have been difficult to treat with minimal objective responses observed. Phenomic has developed a proprietary machine learning/artificial intelligence platform to identify novel stromal targets with superior expression profiles that enable selective targeting of immune activating agents that will relieve these immunosuppressive barriers in difficult to treat indications. Methods: Using our single cell RNA Atlas, we assessed cancer-associated fibroblasts (CAFs) in several solid tumor indications for identification of novel targets, including proteoglycans. Our Atlas was also used to identify immune activating payloads whose cognate receptors were present in indications of interest. Antibodies were generated, and lead clones who demonstrated potent ligand binding and cell staining were used to generate fusion proteins to immune activating ligands. Efficacy and PD were assessed in multiple syngeneic tumor models. Results: Bioinformatic analysis identified a unique subset of pathogenic CAFs, which are TGF beta responsive, secrete several ECM proteins, and their presence tracks with poor outcome and resistance to immunotherapy in several solid tumor types. CTHRC1 was identified as a novel matrix protein highly expressed in this CAF subtype as well as tumor epithelium and is highly selective in a range of tumor types such as ovarian cancer, triple negative breast cancer, and pancreatic ductal adenocarcinoma. While secreted, CTHRC1 is complexed on the cell surface and affords the opportunity to drug this target in a variety of ways. We identified an absence of 4-1BBL expression across indications of interest, and fusion proteins were generated to deliver 4-1BBL via CTHRC1 targeting. In checkpoint-resistant tumor models, we observed significant increases in CD8 T cells and robust anti-tumor activity with anti-CTHRC1-targeted 4-1BBL. Biodistribution studies were conducted using our targeting mAb and demonstrate uptake only in sites of primary and metastatic tumors, even at doses 20-fold higher than those that achieve maximal therapeutic activity, suggesting the potential to minimize the toxicity that has been observed with other 4-1BB agonists. Conclusions: We have identified CTHRC1 as a novel proteoglycan expressed by both pathogenic CAFs and tumor cells that is highly selective for tumors, enabling the therapeutic targeting of immune activating payloads with the potential for safely delivering payloads while limiting toxicity. Given the specificity and selectivity afforded by CTHRC1 expression, ADC and CD3 engager approaches are also being pursued. These data represent novel approaches aimed at breaking down stromal barriers in tumors previously unresponsive to immunotherapies. Citation Format: Christopher Harvey, Elizabeth Koch, Amanda Hanson, Lindsey Rice, Amy Berkley, Kerry White, Reza Saberianfar, Nikolai Suslov, Sam Cooper, Michael Briskin. AI/ML-driven discovery of CTHRC1, collagen triple helix repeat-containing 1, a novel proteoglycan for stroma + tumor targeting and delivery of 4-1BB costimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2914.

The relationship between clinical and pathological findings and FDG - PET uptake in metastatic colorectal cancers.

In metastatic colorectal cancer (mCRC), the genetic structure and cell metabolism of the primary tumor lesion might be different from metastatic lesions. It is thought that cell-level glucose metabolism may differ due to the difference in RAS wild and mutant mCRC patients' prognosis. In this study, we aimed to compare 2-deoxy-2-[fluorine-18]-fluoro-D-glucose Positron Emission Tomography (18F-FDG PET/CT) uptake levels for KRAS mutation status and primary-metastatic tumor localization. Our study is a retrospective cohort analysis that included RAS mutation status study and staging-oriented 18F-FDG PET/CT conducted on mCRC patients. There was no significant relationship between metastasis and primary tumor maximum Standardized uptake value (SUVmax) values according to the KRAS mutational status (P > 0.05). Patients with liver metastasis along with mutant BRAF mutation status had significantly higher SUVmax values in PET-CT scans (P = 0.04). There was a negative correlation between SUVmax values of lung metastases and overall survival (r = -0.35, P = 0.04). Patients with high carcinoembryonic antigen (CEA) levels had significantly higher SUVmax values of lung metastasis than patients with normal CEA levels (P = 0.009). Patients with high CA19-9 levels had significantly higher SUVmax values of liver, peritoneal, and bone metastasis than patients with normal CA19-9 levels (P = 0.002, P = 0.001, P = 0.004, respectively). There was no significant correlation between SUVmax values of metastasis and Lactate dehydrogenase (LDH) values. Liver metastasis of right-sided mCRCs had significantly higher SUVmax values (P = 0.03). We could not demonstrate a significant association between KRAS mutation and SUVmax values of PET scan in primary or metastatic tumor sites in advanced CRC.

Combining Dual Checkpoint Immunotherapy with Ablative Radiation to All Sites of Oligometastatic Non-Small Cell Lung Cancer: Toxicity and Efficacy Results of a Phase 1b Trial

BackgroundAblative local treatment of all radiographically detected metastatic sites in patients with oligometastatic NSCLC increases progression free survival (PFS) and overall survival (OS). Prior studies demonstrated safety of combining stereotactic body radiation therapy (SBRT) with single agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anti-CTLA-4 and anti-PD-L1 immunotherapy for patients with oligometastatic NSCLC. MethodsWe conducted a phase Ib clinical trial in patients with oligometastatic NSCLC with up to 6 sites of extracranial metastatic disease. All sites of disease were treated with stereotactic body radiation therapy (SBRT) to a dose of 30 – 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days following completion of radiation utilizing anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) immunotherapy for a total of four cycles followed by durvalumab alone until progression or toxicity. ResultsSeventeen patients were enrolled on study, with 15 patients receiving at least one dose of combination immunotherapy per protocol. The study was closed early (17 of planned 21 patients) due to slow accrual during COVID 19 pandemic. Grade 3+ treatment related adverse events were seen in 6 patients (40%). Of these, only one was felt possibly related to the addition of SBRT to immunotherapy. Median PFS was 42 months while median OS has not yet been reached. ConclusionsDelivering ablative SBRT to all sites of metastatic disease in combination with dual checkpoint immunotherapy did not result in excessive rates of toxicity compared to historical studies of dual checkpoint immunotherapy alone. While not powered for treatment efficacy results, durable PFS and OS results suggest potential therapeutic benefit compared to immunotherapy or radiation alone in this patient population.

Decoding the expression pattern of MUC3A in gastric adenocarcinoma: unveiling the key to successful immunotherapy

ABSTRACT Aims Despite the promise of immunotherapy for gastric adenocarcinoma, resistance is common, necessitating the validation of new targets. Based on our previous bioinformatics analysis, the MUC3A antigen emerged as a promising candidate for immunotherapy against gastric adenocarcinoma. However, a comprehensive understanding of its expression at protein level remains elusive, despite its crucial role in determining clinical response. We also sought to establish a connection between the expression pattern and relevant clinical variables of the disease, whenever feasible. Methods Immunohistochemistry was used to determine the percentage of MUC3A-positive tumor cells in primary (PT) and metastatic tumor (MT) sites of 190 gastric adenocarcinoma patients. We also evaluated the association between MUC3A expression and variables such as Lauren classification, history of neoadjuvant chemotherapy and/or radiotherapy, and overall patient survival. Results Median MUC3A expression was 50% in PT and 70% in MT sites, exhibiting a positive correlation. MT intestinal type showed significantly higher MUC3A expression compared to other types. Neoadjuvant therapy history did not affect MUC3A expression. Higher MUC3A expression correlated with improved survival. Conclusions Based on our previous bioinformatics data and the consistently high expression of MUC3A on gastric tumor cells, we propose advancing experimental aspects of anti-MUC3A immunotherapy for gastric adenocarcinoma.

Successful Implementation of Image-Guided Pencil-Beam Scanning Proton Therapy in Medulloblastomas

Medulloblastoma is the most common malignant brain tumour in children, while much rarer in adults. Although the prognosis and outcomes have greatly improved in the era of modern multidisciplinary management, long-term treatment-induced toxicities are common. Craniospinal irradiation followed by a boost to the primary and metastatic tumour sites forms the backbone of treatment. Proton therapy has been endorsed over conventional photon-based radiotherapy due to its superior dosimetric advantages and subsequently lower incidence and severity of toxicities. We report here our experience from South-East Asia’s first proton therapy centre of treating 40 patients with medulloblastoma (38 children and adolescents, 2 adults) who received image-guided, intensity-modulated proton therapy with pencil-beam scanning between 2019 and 2023, with a focus on dosimetry, acute toxicities, and early survival outcomes. All patients could complete the planned course of proton therapy, with mostly mild acute toxicities that were manageable on an outpatient basis. Haematological toxicity was not dose-limiting and did not prolong the overall treatment time. Preliminary data on early outcomes including overall survival and disease-free survival are encouraging, although a longer follow-up and data on long-term toxicities are needed.

Neoadjuvant systemic oncolytic vesicular stomatitis virus is safe and may enhance long-term survivorship in dogs with naturally occurring osteosarcoma

Osteosarcoma is a devastating bone cancer that disproportionally afflicts children, adolescents, and young adults. Standard therapy includes surgical tumor resection combined with multiagent chemotherapy, but many patients still suffer from metastatic disease progression. Neoadjuvant systemic oncolytic virus (OV) therapy has the potential to improve clinical outcomes by targeting primary and metastatic tumor sites and inducing durable antitumor immune responses. Here we describe the first evaluation of neoadjuvant systemic therapy with a clinical-stage recombinant oncolytic vesicular stomatitis virus (VSV), VSV-IFNβ-NIS, in naturally occurring cancer, specifically appendicular osteosarcoma in companion dogs. Canine osteosarcoma has a similar natural disease history as its human counterpart. VSV-IFNβ-NIS was administered prior to standard of care surgical resection, permitting microscopic and genomic analysis of tumors. Treatment was well-tolerated and a "tail" of long-term survivors (∼35%) was apparent in the VSV-treated group, a greater proportion than observed in two contemporary control cohorts. An increase in tumor inflammation was observed in VSV-treated tumors and RNA-seq analysis showed that all the long-term responders had increased expression of a Tcell anchored immune gene cluster. We conclude that neoadjuvant VSV-IFNβ-NIS is safe and may increase long-term survivorship in dogs with naturally occurring osteosarcoma, particularly those that exhibit pre-existing antitumor immunity.

Theranostic imaging and multimodal photodynamic therapy and immunotherapy using the mTOR signaling pathway

Tumor metastases are considered the leading cause of cancer-associated deaths. While clinically applied drugs have demonstrated to efficiently remove the primary tumor, metastases remain poorly accessible. To overcome this limitation, herein, the development of a theranostic nanomaterial by incorporating a chromophore for imaging and a photosensitizer for treatment of metastatic tumor sites is presented. The mechanism of action reveals that the nanoparticles are able to intervene by local generation of cellular damage through photodynamic therapy as well as by systemic induction of an immune response by immunotherapy upon inhibition of the mTOR signaling pathway which is of crucial importance for tumor onset, progression and metastatic spreading. The nanomaterial is able to strongly reduce the volume of the primary tumor as well as eradicates tumor metastases in a metastatic breast cancer and a multi-drug resistant patient-derived hepatocellular carcinoma models in female mice.

A nanoparticle composed of totally hospital-available drugs and isotope for fluorescence/SPECT dual-modal imaging-guided photothermal therapy to inhibit tumor metastasis

As primary sites of tumor metastasis, sentinel lymph nodes (SLNs) require a highly biocompatible theranostic platform for precise localization and treatment to inhibit tumor metastasis. Herein, indocyanine green-human serum albumin (ICG-HSA) nanoparticles (NPs) were fabricated by ICG-induced self-assembly and radiolabeled with technetuim-99 m (99mTc). The fabricated NPs were composed of hospital-available drugs and isotopes, making them highly biocompatible for in vivo applications. In a mouse model of SLN metastasis, the prepared NPs exhibited excellent capacity for preoperative planning by single-photon emission computed tomography (SPECT) imaging-enabled SLN localization, near-infrared fluorescence (NIRF) imaging-enabled intraoperative real-time monitoring, and SLN photothermal treatment. Photothermal treatment with SLN enhanced the inhibition of lung metastasis and significantly increased the survival time of mice. The prepared NPs were highly biocompatible and exhibited efficient theranostic properties for inhibiting cancer metastasis, making them promising candidates for clinical translation.

Elbow hemiarthroplasty with a 3D-printed prosthesis for distal humeral bone defects after tumor excision: a case report

IntroductionThe distal humerus is a rare site for primary and metastatic bone tumors. Due to the scarcity of cases and lack of standardized surgical strategies, it is often difficult for surgeons to choose the right choice. The application of a 3D-printed prosthesis with hemiarthroplasty for the treatment of the distal humerus after tumor resection can be a very effective option.Case presentationWe present a clinical case of a 3D-printed distal humeral prosthesis for the treatment of bone defects caused by metastatic bone tumors. The preoperative evaluation was aggressively performed, and the decision was made to distal humeral hemiarthroplasty (DHH) after wide resection of the tumor segment bone. Processing of the Digital Imaging and Communications in Medicine (DICOM) data from CT scans performed after mirror conversion using CT data of the contralateral humerus, we designed a 3D-printed distal humeral prosthesis with hemiarthroplasty. After reconstruction of bone and surrounding soft tissue by the 3D-printed prosthesis combined with the LARS ligament and regular follow-up for 12 months, the patient had an MSTS-93 score of 29 and an MEP of 100, which reached a good level, and the patient was fully competent in normal daily activities.ConclusionsOur results show that the 3D-printed modular prosthesis with hemiarthroplasty is a very effective option for cases of large elbow bone defects due to primary bone tumors or metastatic disease. However, careful preoperative preparation is required for the best outcome. Careful preoperative preparation and long-term follow-up are essential for the best outcome.

Efficacy of local ablative therapies in patients with solid tumors treated with immune checkpoint inhibitors and oligoprogression: a single-center analysis.

The concept of oligoprogression reflects a situation where a limited number of metastatic tumor sites have progressed and other metastatic sites are under control with current systemic therapy. The optimal management of oligoprogression remains unclear. In this retrospective study, we evaluated the contribution of local ablative treatment approaches after oligoprogression to progression-free survival and response rates (RRs) in patients with renal cell carcinoma ( N : 5), nonsmall cell lung cancer ( N : 1) and melanoma ( N : 21) who received immunotherapy. We found that patients received local ablative therapies after oligoprogression had longer progression-free survival and higher RR compared to those who did not. Specifically, patients who received concurrent radiotherapy had a median survival time of 24.7 months compared to 14.5 months in those who did not. Our results suggest that local ablative therapies may have a beneficial impact on progression-free survival and RR in patients with oligoprogression who are being treated with immune checkpoint inhibitors. Further studies are needed to confirm these findings and determine the optimal use of local ablative therapies in this setting.

Nominating molecular/immunologic drivers of central nervous system (CNS) metastases in squamous cell carcinoma of the head/neck (SCCHN).

e18002 Background: In the ~1% of patients with SCCHN who experience CNS metastases, median overall survival (mOS) is &lt;1 year. We investigated whether molecular/immunologic features distinguish SCCHN cases that metastasize to the CNS. Methods: We performed a case-control study on a convenience sample of individuals with SCCHN treated at two academic institutions. Next generation targeted sequencing and/or immunoprofiling of primary and metastatic tumor sites were performed. Results: We identified 39 patients with SCCHN (21 with CNS metastases (cases), 18 without (controls)). Median age at diagnosis 60, 79% male, 46% current/former smokers, 51% oropharyngeal primary, 51% HPV+/31% HPV-/18% not tested (NT) across all cases, and 69% stage III or IV disease at diagnosis. HPV+ frequency trended higher among cases (52%+, 14%-, 33% NT) vs. controls (50%+, 50%-, 0% NT) (p=0.08). mOS from diagnosis was 34.4 months (95% CI 14.5-41.0) in cases and 44.4 months (95% CI 19.0-82.3) in controls. Genomic data was available for 18 (86%) cases and 12 (67%) controls. Most common mutations in cases were KMT2D (39%) and NOTCH1 (39%). There were no genes for which alteration frequency differed significantly between groups. Tumors of 18 (86%) cases and 18 (100%) controls underwent immunoprofiling. Mean PD-1 density at the tumor-stroma interface (TSI), CPS, and TPS were higher in controls (Table). In cases, TSI PD-1 density tended to be higher at primary sites than at sites of CNS metastases. No significant difference was seen in CD8 or FOXP3 staining. Conclusions: SCCHN with CNS metastases shows markers of lower immunogenicity at both the primary site and site of CNS metastasis vs. other SCCHN tumors, regardless of HPV status. This suggests that localized tumors with low immune infiltration and poor responsiveness to immunotherapy may be at higher risk of CNS metastasis and could imply reduced benefit from immunotherapy for patients with CNS metastases. [Table: see text]

TLR Agonist Therapy of Metastatic Breast Cancer in Mice.

Toll-like receptor (TLR) 7/8 and 9 agonists stimulate an innate immune response that supports the development of tumor-specific immunity. Previous studies showed that either agonist individually could cure mice of small tumors and that when used in combination, they could prevent the progression of larger tumors (>300mm 3 ). To examine whether these agents combined could control metastatic disease, syngeneic mice were challenged with the highly aggressive 66cl4 triple-negative breast tumor cell line. Treatment was not initiated until pulmonary metastases were established, as verified by bioluminescent imaging of luciferase-tagged tumor cells. Results show that combined therapy with TLR7/8 and TLR9 agonists delivered to both primary and metastatic tumor sites significantly reduced tumor burden and extended survival. The inclusion of cyclophosphamide and anti-PD-L1 resulted in optimal tumor control, characterized by a 5-fold increase in the average duration of survival.