Purpose: Clinical trials have shown limited efficacy of anti-programmed cell death protein 1 (PD-1) treatment for glioblastoma (GBM). In this study, we examined the expression of TGFbRI in GBM-infiltrating CD8+ T cells and the characteristics of TGFbRI+CD8+ T cells. We examined the ex vivo effects of co-blockade of PD-1 and TGFb on the functions of GBM-infiltrating CD8+ T cells. Experimental Design:

A recent article presents a molecular analysis of High-Grade Gliomas in teenagers and young adults (TYAs). To maximise the benefit of this advancing knowledge we must address the basics. Here, we highlight the challenge of lengthy diagnostic intervals for TYAs, arguing that these must reduce to reap the benefits of molecular insights.

Purpose: Melanoma brain metastases (MBM) are common in advanced melanoma and linked to poor prognosis. Preventing MBM can improve survival and reduce morbidity. While dual-agent immunotherapy (dIT) improves survival, its role in MBM prevention is unclear. We compared MBM incidence, overall survival (OS), and brain metastasis-free survival (BMFS) between dIT and single-agent immunotherapies (sIT). Experimental

Nasopharyngeal carcinoma (NPC) is rare in children and adolescents. Although radiation has been an essential component of treatment for this often-curable tumor, it can lead to severe side-effects in survivors. Therefore, the reduction of radiation-related long-term effects by limiting radiation dose is a key clinical priority. Previous pediatric clinical trials by the Children’s Oncology Group (COG)

Observational studies demonstrate aspirin use after diagnosis of colorectal cancer, particularly tumors with mutated PIK3CA, improves outcomes. However, randomized controlled trial data are lacking. Here, we discuss the SAKK41/13 adjuvant aspirin randomized controlled trial results in context of other adjuvant aspirin trials and emerging data on potential mechanisms of action.

Purpose: Mutant TP53 stabilized by heat shock protein 90 (HSP90) is a novel target in oncology. The open-label randomized phase II GANNET53 trial is the first to evaluate the HSP90 inhibitor Ganetespib (G) with Paclitaxel (P) in platinum-resistant epithelial ovarian cancer (EUDRACT 2013-003868-31; EU FP7 #602602). Patients and Methods: Patients were randomized 2:1 to receive G+P or P alone until progression

In December 2021, FDA approved abatacept (Orencia; Bristol Myers Squibb) in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX) as the first drug for prophylaxis of acute graft versus host disease (aGVHD) in adults and pediatric patients 2 years and older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor (URD). Study IM101311

On August 1, 2024, the FDA granted accelerated approval to afamitresgene autoleucel, a melanoma-associated antigen-A4 (MAGE-A4)-directed genetically modified autologous T-cell immunotherapy, for the treatment of adults with unresectable or metastatic synovial sarcoma (SS) who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumors express MAGE-A4

Purpose: Hereditary colorectal cancer (CRC) syndromes remain incompletely understood, with many cases lacking defined genetic causes. This study aimed to identify pathogenic mutations associated with hereditary CRC and explore their potential for targeted therapies. Experimental Design: This observational study was conducted in Yunnan Province, China. We analyzed 43 individuals from 12 hereditary CRC

Purpose: Human papillomavirus-associated (HPV+) oropharyngeal carcinoma (OPC) is associated with excellent survival, yet treatment drives substantial toxicity. Improved biomarkers are needed to select patients for de-escalated treatment. Circulating tumor HPV-DNA (ctHPV-DNA) represents a promising non-invasive biomarker to gauge treatment response and surveil for disease recurrence. Patients and Methods:

Purpose: The Complexity Index in SARComas (CINSARC) predicts the metastatic risk in patients with soft tissue sarcoma. The aims of this study were to provide the first independent validation of CINSARC in patients with retroperitoneal sarcoma (RPS) and to evaluate whether CINSARC could enhance the performance of Sarculator. Experimental design: A retrospective cohort included patients with primary

Purpose: The mechanisms driving the progression of vocal cord leukoplakia (VCL) to laryngeal squamous cell carcinoma (LSCC) remain unclear, posing a significant barrier to the effective prevention, early diagnosis, and targeted treatment of LSCC. Therefore, it is essential to characterize the cellular microenvironmental differences between VCL and LSCC at the single-cell resolution. Experimental Design:

Purpose: BR-PDAC is treated with perioperative chemotherapy and surgical resection +/- SBRT, but long-term survival is rare. GVAX is a GM-CSF- secreting vaccine that activates T-cell immunity against tumor-associated antigens. This multi- center phase II clinical trial evaluated the safety and immune effects of GVAX/Cy/nivolumab and SBRT on the PDAC TME. Methods: Patients received neoadjuvant mFOLFIRINOX

Purpose: Given the limited data on the effectiveness of Atezolizumab plus Bevacizumab (Ate/Bev) in HCC patients with a Child-Pugh score (CPS) of 7, this study aims to evaluate the treatment’s efficacy in this population and identify specific CPS 7 subgroups that may benefit from it. Experimental Design: This study included patients with advanced HCC who received Ate/Bev as first-line therapy between

Outcomes from advanced melanoma, the deadliest of the skin cancers arising from melanocytes and capable of widely metastasizing, have greatly improved with death rates decreasing for AJCC stage 4 melanoma patients by 3-5 percent annually over the past 10 years (1,2). This improvement is a result of advances in both targeted therapy and immunotherapy (Fig 1). BRAF and MEK inhibitors for advanced melanoma

Purpose: Myelodysplastic syndrome and acute myeloid leukemia with complex and monosomy karyotypes show a high prevalence of TP53 mutations (TP53m), poor response to induction chemotherapy, and adverse outcomes. These diseases may respond to decitabine, but the mechanisms are presently unclear. Experimental Design: Patients with myelodysplastic syndrome and acute myeloid leukemia were treated with decitabine

Background: To address financial barriers that limit access to genomic profiling and precision medicine, philanthropy supported clinical genomic testing was offered worldwide at no cost to patients with select rare cancers via the Make-an-IMPACT program. Herein, we report our findings in pediatric patients with solid or central nervous system (CNS) tumors. Methods: Tumor DNA or CSF-derived circulating

Purpose. Pet dogs spontaneously develop many of the same tumor types as humans including osteosarcoma. Recent advances in spatial transcriptomics have improved our ability to utilize formalin-fixed paraffin-embedded tissues collected at canine autopsy. These techniques allow the canine model to be investigated alongside murine models to inform human cancer research. Herein we present the first application

Purpose: Ipilimumab (IPI) improved outcomes for high-risk melanoma patients compared to interferon-α2b (IFN) in E1609, a phase III adjuvant trial. We hypothesized that combining candidate immune biomarkers in both tumor and circulating blood could generate a superior predictive biomarker signature. Patients and Methods: We conducted gene expression profiling on baseline tumors of patients treated with

Purpose: Although ctDNA is a promising biomarker for minimal residual disease (MRD) detection in head and neck squamous cell carcinoma (HNSCC), more sensitive assays are needed for accurate MRD detection at clinically relevant time points. Ultrasensitive MRD detection early after surgery could guide adjuvant therapy decisions, but early ctDNA dynamics are poorly understood. Experimental Design: We

Purpose: The incidence of human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HPV + HNSCC) is increasing in the United States. Currently, there are no early detection approaches for HPV + HNSCC. Two blood-based analytes for early detection and diagnosis of HPV + HNSCC, circulating tumor HPV DNA (ctHPVDNA) and HPV early protein antibodies (HPV Ab), show promise, yet current

Purpose: Patients with residual nasopharyngeal carcinoma after receiving standard-of-care treatment have poor prognoses. In this trial, we aimed to assess the efficacy and safety of capecitabine maintenance therapy in patients with residual nasopharyngeal carcinoma. Patients and Methods: This open-label, single-arm, phase 2 trial was conducted at Sun Yat-sen University Cancer Center. We recruited patients

Purpose: Combined inhibition of lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) improves outcomes in patients with melanoma. Increased LAG-3 expression in colorectal cancer (CRC) correlates with reduced survival. Higher mucin and PD-L1 expression in the mismatch repair proficient (pMMR) CRC tumor microenvironment (TME) was associated with increased LAG-3 and retrospectively

Purpose: Immune checkpoints inhibitors (ICIs) combined with chemotherapy have provided successful results in patients with gastric and gastroesophageal junction (G/GEJ) cancers in the metastatic setting. Similar strategies have been explored in earlier stages. Here, we present final results of the phase II MONEO trial, which evaluated the addition of avelumab to neoadjuvant chemotherapy. Patients and

Purpose: Liquid biopsies with circulating tumor DNA (ctDNA) analysis are increasingly being utilized as a non-invasive approach to identify actionable genomic alterations in advanced/metastatic cancers. Herein, we report the correlation between ctDNA analysis of plasma samples collected from patients enrolled in the NCI-MATCH trial and tumor tissue-based sequencing. Patients and Methods: We analyzed

Purpose: In a multicenter prospective cohort-study we assessed the diagnostic yield of the Nordic guidelines for germline investigation in myeloid neoplasms (MN) and mapped the spectrum of inherited and somatic variants. Experimental Design: Eighty-five patients (acute myeloid leukemia (AML): n=38; myelodysplastic syndromes (MDS): n=26; thrombocytopenia: n=14; other: n=7) fulfilling the Nordic criteria

The CD27-CD70 interaction is recognized as a positive costimulatory pathway for T cell priming and expansion. However, recent studies showed that chronic CD27-CD70 interaction in cancer can lead to apoptosis of T cells, rendering them dysfunctional. CD70 is expressed not only by hematological tumors but also by solid tumor cells. This expression is regulated by hypoxia-induced factor (HIF), Epstein-Barr

Background: Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC to non-IBC cases. Patients and Methods: We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors, 72 metastatic

Purpose: To describe PD-L1 expression across tissue types and its associated tumor microenvironment (TME) and to investigate how it impacts its predictive value for response to pembrolizumab in treatment-naïve ovarian cancer (OC) patients included in the NeoPembrOV phase II trial (NCT03275506). Methods: PD-L1 expression was assessed for 85 patients (56 on metastasis, 29 on tubo-ovary) using tumor proportion

Purpose: Doxorubicin is standard chemotherapy for metastatic soft tissue sarcomas (STSs) but also enhances innate/adaptive immune responses by inducing immunogenic cell death. Most STSs are immune “cold” tumors that do not respond to immune checkpoint inhibitors (ICIs) blocking PD-1 and CTLA-4. We hypothesized that concurrent doxorubicin would improve tumor immunogenicity and boost efficacy of ICIs

Recent discoveries concerning the network architecture of glioblastoma, including tumor microtubules (TMs) and neuron-glioma synapses, have underscored critical pathways that sustain tumor growth, enhance resistance, and integrate glioblastoma with the surrounding neural environment. This review explores emerging therapeutic strategies targeting these pathways, including inhibitors of gap junctions

Purpose: Tifcemalimab is a recombinant humanized IgG4k monoclonal antibody targeting B and T-lymphocyte attenuator (BTLA). Co-blockade of BTLA and programmed death-1 pathways improved outcomes in non-clinical models. This phase I/II trial evaluated the safety and preliminary efficacy of tifcemalimab plus toripalimab in advanced lung cancer. Patients and Methods: Eligible patients with pathologically

Purpose: To evaluate porustobart (HBM4003), a novel anti-CTLA-4 monoclonal antibody, combined with toripalimab as second-line therapy in advanced HCC. Patients and Methods: This phase I study included two cohorts of patients with advanced HCC: cohort 1 included patients who were anti-PD-1/PD-L1 naïve and had received first-line anti-VEGFR- tyrosine kinase inhibitor; cohort 2 included patients who had

Purpose: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and early detection significantly improves treatment outcomes, but existing blood-based tests often have limited sensitivity in early-stage disease. We developed a blood-based test combining oncRNAs, a group of small cell-free RNAs (cfRNAs), with generative AI to detect CRC. Experimental Design: We leveraged

Radiopharmaceuticals, which emit either alpha or beta particles, have changed the landscape of prostate cancer imaging and treatment. Each particle type has unique physical properties that can be exploited to optimize treatment effect. Using murine models of disseminated prostate cancer and a CD46-targeted alpha-particle emitting radioimmunoconjugate, a recent study shows superior efficacy in mice

Purpose: Soft tissue sarcoma (STS) are rare malignancies with poor prognosis and limited systemic treatment options. We conducted a phase II study to assess the efficacy and safety of trabectedin and olaparib in patients with advanced disease. Patients and Methods: Patients with STS who received ≥ 1 prior therapy were recruited into two cohorts. Cohort 1 included leiomyosarcoma and liposarcoma; Cohort

Introduction: Endometrial cancer is a common gynecologic malignancy lacks effective non-invasive screening tools, as traditional approaches rely on invasive biopsies. In this large prospective study, we evaluated a novel approach combining vaginal swab DNA and plasma-based circulating tumor DNA (ctDNA) for genomic profiling to provide a comprehensive framework for diagnosis, prognosis, and disease

Purpose: The purpose was to investigate combined PARP and androgen inhibition in primary prostate cancer and understand the biological mechanisms underlying clinical efficacy, especially in the absence of mutations in homologous recombination (HR) repair pathways. Patients and Methods: The primary objective was to measure PARP inhibition, and the secondary objectives were to assess safety and feasibility

Tumor mutational burden (TMB) is considered a prototypic feature of tumor foreignness and has been established as a tumor-agnostic FDA-approved biomarker at a threshold of 10 mut/Mb for immune checkpoint inhibitors (ICI). Despite its clinical utility as a companion diagnostic for ICI across cancers, high TMB does not consistently predict response due to technical and biological limitations. Tumor heterogeneity

Purpose: Tolinapant is an inhibitor of apoptosis (IAP) antagonist that enhances apoptotic pathways. In preclinical studies, tolinapant + radiotherapy (RT) enhances anti-tumor immunity. We conducted an open-label, single-arm trial to evaluate safety and feasibility of concurrent tolinapant and RT in cisplatin-ineligible patients with head and neck squamous cell carcinoma (HNSCC). Patients and Methods:

Purpose: Tyrosine kinase inhibitors (TKIs) combined with immune checkpoint blockades (ICBs) produce enhanced anti-tumor activity in the treatment of advanced hepatocellular carcinoma (HCC). Sitravatinib is a novel multi-target TKI that targets TYRO3, AXL, MERTK (TAM) receptors, c-MET, etc. This study aimed to investigate the anti-tumor efficacy and immunomodulatory activity of sitravatinib in HCC.

Purpose: Doxorubicin is first-line treatment for metastatic soft tissue sarcomas (STS). Ribociclib, a CDK 4/6 inhibitor, targets the retinoblastoma pathway to induce cell cycle arrest at the G1/S cell cycle checkpoint. We hypothesized that administering ribociclib prior to doxorubicin to synchronize cell cycle progression among tumor cells may enhance the efficacy of doxorubicin. Patients and Methods:

Background: This study developed 68Ga-NK224, a novel peptide-based radiotracer targeting human PD-L1, to evaluate the feasibility of 68Ga-NK224 PET/CT for assessing PD-L1 expression and tumor heterogeneity in a prospective investigator-initiated trial. Methods: In preclinical studies, NK224 was labeled with 68Ga. Small-animal PET, biodistribution, and blocking studies were performed using tumor models

Purpose: Recent advances have seen the development of targeted therapeutics against the RTK/RAS/MAPK pathway which, when aberrantly activated, drives malignant transformation of many cancer indications. However, efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (Sitneprotafib), a

Purpose: Melanoma patients progressing despite immune checkpoint blockade (ICB) may benefit from adoptive transfer of tumor infiltrating lymphocytes (TIL). Patients and Methods: We investigated the impact of a pegylated interferon-alpha (IFNa) conditioning and support regimen on the safety and efficacy of TIL plus Nivolumab (NCT03638375). ICB-resistant stage III/IV melanoma patients were treated with

An increasing number of studies suggest that a significant proportion of children with cancer harbor an underlying predisposition to malignancy, and it is likely that this proportion will only increase. Targeted surveillance for these individuals would likely improve outcome. Historically however, for most predisposition syndromes, there were no standardized surveillance protocols for early detection

Conducting phase I trials is particularly challenging when dealing with late-onset dose-limiting toxicity (DLT) or when patient accrual is rapid relative to the DLT assessment window. In such cases, a new cohort may be ready for enrollment before the DLT assessments are complete for the current cohort, complicating dose assignment decisions. The Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design

Purpose: To characterize the clinicopathologic features, molecular genetic landscape, and clinical behavior of ovarian low-grade serous tumors with histologic transformation (LGS-HT) to indeterminate/high-grade carcinoma. Experimental Design: LGS-HTs were retrospectively identified from an institutional cohort of ovarian cancer patients and underwent central pathology re-review. Data on clinicopathologic

Purpose: Acute myeloid leukemia (AML) is characterized by frequent mutation of fms-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. Here, we investigated the antileukemia efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3-internal

Despite survival gains for many pediatric cancers since the 1970s, cancer remains the leading cause of death by disease for children and adolescents in the United States. Survivors of pediatric cancer often experience acute and long-term toxicities resulting in diminished quality of life and reduced life expectancy. Thus, development of new therapies that offer a better balance between efficacy and

Purpose: To compare outcomes and molecular characteristics of patients who had surgery after neoadjuvant chemotherapy, with and without ablative radiotherapy (SAbR) for pancreas cancer. Insight could clarify the benefits of SAbR and provide molecular guidance for future therapeutic regimens. Experimental Design: This single-institution, tertiary care academic center cohort study included all patients

Purpose: Although the association between neural invasion and poor survival in oral cavity squamous cell carcinoma (OSCC) is known, innervating nerve types have not been definitively established; this has confounded mechanistic and translational studies. Therefore, we investigated innervation in human OSCC and further explored these findings in mice. Experimental Design: Sensory, sympathetic, and parasympathetic

PURPOSE: The VISION trial of tepotinib, a selective MET inhibitor, enrolled patients with NSCLC and prospectively detected MET exon 14 skipping (METex14) in liquid biopsies (LBx) and/or tissue biopsies (TBx). We evaluated patient characteristics and outcomes according to METex14 positivity in LBx (LBx-positive) or TBx (TBx-positive). METHODS: METex14 was centrally assessed by next-generation sequencing

The anti-EGFR agents, cetuximab and panitumumab, were the first targeted agents to be licensed in colorectal cancer and marked a significant advancement in personalized care. Initial biomarkers provided poor discrimination between responders and non-responders. Through hypothesis-led translational studies, tumor genomic negative predictive markers were identified, and treatment is now limited to patients