Publications by authors named "Nicolas Llosa"

Background: Brain metastases in pediatric osteosarcoma are infrequent but associated with a dire prognosis.

Methods: This retrospective study examined six pediatric patients at Johns Hopkins Hospital who developed brain metastases from osteosarcoma between April 2015 and November 2023.

Results: Median survival post-brain metastasis was 2.

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Background: The large-scale proteomic platform known as the SomaScan® assay is capable of simultaneously measuring thousands of proteins in patient specimens through next-generation aptamer-based multiplexed technology. While previous studies have utilized patient peripheral blood to suggest serum biomarkers of prognostic or diagnostic value in osteosarcoma (OSA), the most common primary pediatric bone cancer, they have ultimately been limited in the robustness of their analyses. We propose utilizing this aptamer-based technology to describe the systemic proteomic milieu in patients diagnosed with this disease.

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Patients diagnosed with advanced osteosarcoma, often in the form of lung metastases, have abysmal five-year overall survival rates. The complexity of the osteosarcoma immune tumor microenvironment has been implicated in clinical trial failures of various immunotherapies. The purpose of this exploratory study was to spatially characterize the immune tumor microenvironment of metastatic osteosarcoma lung specimens.

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Article Synopsis
  • Malignant peripheral nerve sheath tumors (MPNST) pose a significant risk to patients with neurofibromatosis type 1 (NF1), with current treatments failing to improve outcomes, highlighting the need for new therapies that target the tumor's immune environment.
  • Researchers examined the immune microenvironment in NF1-associated tumors, using various techniques to analyze how immune cells infiltrate and respond to these tumors.
  • Results showed that malignant progression involved increased infiltration of specific immune cells, particularly tumor-associated macrophages, linked to worse patient outcomes, indicating a potential for therapies that can enhance anti-tumor immune responses.
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  • CIC-rearranged sarcomas are aggressive tumors that lead to poor survival rates, quick development of drug resistance, and high metastasis, prompting a need for better understanding of their management and outcomes.
  • A study at Johns Hopkins Hospital analyzed the cases of ten patients aged 10 to 67, revealing varied clinical courses, with some undergoing intensive treatments while others had prolonged disease-free survival without systemic therapy.
  • Overall survival averaged 22.1 months and progression-free survival averaged 16.7 months, highlighting diverse outcomes and emphasizing the importance of understanding individual tumor biology for better patient care.
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Activins, members of the TGF-beta superfamily, have been isolated and identified in the endocrine system, but have not been substantially investigated in the context of the immune system and endocrine-unrelated cancers. Here, we demonstrated that tumor-bearing mice had elevated systemic activin levels, which correlated directly with tumor burden. Likewise, cancer patients have elevated plasma activin levels compared to healthy controls.

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Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy.

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Purpose: To determine the association between consolidative radiation (RT) and survival in children, adolescents, and young adults with metastatic sarcoma.

Methods And Materials: Eligibility criteria included patients aged ≤39 years with newly diagnosed metastatic bone or soft tissue sarcoma who completed local control of the primary tumor without disease progression. Consolidative RT was defined as RT to all known sites of metastatic disease.

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Ewing sarcomas (ES) are rare small round cell sarcomas often affecting children and characterized by gene fusions involving one member of the FET family of genes (usually and a member of the ETS family of transcription factors (usually or ). The detection of rearrangements has important diagnostic value. Here, we conducted a retrospective review of 218 consecutive pediatric ES at diagnosis and found eight patients having data from chromosome analysis, FISH/microarray, and gene-fusion assay.

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Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas with limited treatment options, and novel effective therapeutic strategies are desperately needed. We observe anti-proliferative efficacy of genetic depletion or pharmacological inhibition using the clinically available SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy.

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We present an 18-year-old male patient who presented with a 16 cm testicular tumor alongside multiple lesions in the lungs, right pelvis with involvement of the ischio/pubic bone, and enlarged pelvic lymph nodes on imaging, suspicious for metastatic disease. Histologic and immunohistochemical examinations revealed an embryonic type neuroectodermal tumor (somatic-type malignancy, 10%) arising in a malignant mixed germ cell tumor composed of teratoma (50%), embryonal carcinoma (10%) and yolk sac tumor (30%). After treatment with chemotherapy and radiation, repeat imaging demonstrated a right pelvic sidewall mass that decreased in size from 40 mm at 11 months after the initial diagnosis to 18 mm at 22 months after the initial diagnosis.

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DNA methyltransferase 3a (DNMT3a) is an important part of the epigenetic machinery that stabilizes patterns of activated T cell responses. We hypothesized that donor T cell DNMT3a regulates alloreactivity after allogeneic blood and marrow transplantation (allo-BMT). T cell conditional Dnmt3a KO mice were used as donors in allo-BMT models.

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With the modern success of immunotherapy from chimeric antigen receptor T-cell therapy to checkpoint blockade, an understanding of the tumor microenvironment has been more essential than ever. Knowing the key immune players in the tumor can provide the basis for studying cancer host immunity and interactions governing tumor tolerance. This endeavor can be approached in a step like manner-from a broad overview with immunohistochemistry to genomic expression analysis, followed by detailed functional analysis of each cell with multiparameter flow cytometry.

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Article Synopsis
  • * Our findings reveal significant variations in tumor-infiltrating lymphocytes and T cell receptor (TCR) counts that correlate with survival rates, particularly in osteosarcoma patients.
  • * We identified key immunotherapeutic targets for cancer treatments and validated multiple potential targets, including PRAME, contributing to a framework for immune-targeting strategies in pediatric extracranial solid tumors.
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Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade.

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Background: Current therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy.

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Background: The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma.

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Promising results have been reported for patients with high-risk hematologic malignancies undergoing HLA-haploidentical bone marrow transplantation (haploBMT) with posttransplantation cyclophosphamide (PTCy), but there are few data on outcomes with myeloablative conditioning in this context. We report the results of a single-institution, prospective phase 2 trial of myeloablative haploBMT using busulfan-based or total body irradiation-based conditioning in 96 children or adults (median age, 42 years; range, 1-65 years) with high-risk hematologic malignancies. Recovery of neutrophils and platelets occurred at a median of 24 and 29 days.

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Purpose: Clinical trials with immune checkpoint inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft-tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated pleomorphic sarcomas (UPS), with differing genetic underpinnings and responses to immune checkpoint inhibition to understand the mechanisms that lead to response.

Experimental Design: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with UPS and rhabdomyosarcomas, we dissected the TME by using IHC, flow cytometry, and comparative transcriptomic studies.

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Mismatch-repair deficiency in solid tumors predicts their response to PD-1 blockade. Based on this principle, pembrolizumab is approved as standard of care for patients with unresectable or metastatic microsatellite instability-high (MSI-H) cancer. Despite this success, a large majority of metastatic colorectal cancer patients are not MSI-H and do not benefit from checkpoint blockade treatment.

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Purpose: Approximately 10% of patients with mismatch repair-proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer.

Experimental Design: We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded ( = 13) versus those who did not ( = 6) to anti-PD-1 therapy (NCT01876511).

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Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that affects adolescents and young adults. The most effective treatment for FLC is surgical resection, but no standardized systemic therapy exists for patients with recurrent or unresectable FLC. As a first step to understand the immune microenvironment of FLC, we investigated targetable immune-checkpoint pathways, PD-1, PD-L1, B7-H3, IDO-1, and LAG3, in relation to CD8 cytotoxic T-lymphocyte density.

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Background: Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently.

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Clinical tissues are prepared for histological analysis and long-term storage via formalin fixation and paraffin embedding (FFPE). The FFPE process results in fragmentation and chemical modification of RNA, rendering it less suitable for analysis by techniques that rely on reverse transcription (RT) such as RT-qPCR and RNA-Seq. Here we describe a broadly applicable technique called 'Ligation in situ Hybridization' ('LISH'), which is an alternative methodology for the analysis of FFPE RNA.

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