Targeted therapies: How can CT imaging improve evaluations and help understand mechanism of drug action?

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13012-e13012
Author(s):  
Hubert Beaumont ◽  
Antoine Iannessi ◽  
Emmanuel Chamorey ◽  
Nathalie Faye ◽  
Catherine Klifa ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Targeted Therapies ◽  
Metastatic Breast ◽  
Breast Tumors ◽  
Tumor Location ◽  
Tumor Burden ◽  
Trastuzumab Therapy ◽  
Differential Responses ◽  
Differential Imaging ◽  
Lung Lymph

e13012 Background: We compared the therapeutic response between Varlitinib plus Capecitabine (VC) and Lapatinib plus Capecitabine (LC) by stratifying changes in tumor’s longest diameter (LD) and volume (VOL) per tumor location in patients with HER2+ metastatic breast cancer after trastuzumab therapy. Methods: We retrospectively analyzed the ASLAN001-003 double-arm trial (NCT02338245). We first tested the intra and inter-arm equivalence in number and size of tumors at each location of the disease.Second, we compared the inter-arm average changes in 1) tumor burden according to RECIST; 2) stratified tumor burden in summing, for each patient, the target lesions from the same organ locations; 3) tumors considered independent but grouped per organ location of the disease.Third, we tested the intra-arm differential responses of pairwise groups of tumor locations: breast-lung, breast-liver, breast-lymph nodes, lung-liver, lung-lymph nodes and liver-lymph nodes. A sensitivity analysis tested the robustness of our results. Results: We followed 74 tumors in 35 patients (14 VC; 21 LC) after 12 weeks of treatment. Primary breast tumors had a larger size than metastasis (p < 0.002). Tumor proportions at each organ location of the disease were not significantly different. The inter-arm difference in changes of tumor burden yielded: p = 0.086 (LD) and p = 0.13 (VOL); in stratifying patients per breast tumors: p = 0.002 (LD) and p < 0.001 (VOL); and for independent breast tumors: p = 0.001 (LD) and p < 0.001 (VOL). We found differential responses in the LC arm for breast-liver (p = 0.007 (VOL)) and Liver-Lymph node (p = 0.06 (VOL)). After outlier’s removal, the inter-arm difference was confirmed for breast tumors (p = 0.004 (LD); p < 0.001 (VOL)) and when considering all tumors as independent (p < 0.01(LD); p = 0.04 (VOL)). The differential Breast-Liver response in the VC arm was confirmed p < 0.05 (LD or VOL). Conclusions: Differential imaging responses were found across treatment arms and tumor locations. The stratification of changes provides new insights into responses of targeted therapies and more accurate drug comparisons. The stratification is a promising approach to better understand therapy mechanisms of action behind tumor heterogeneity.

Identification of proteins promoting development of metastatic breast tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1041-1041
Author(s):  
E. Seeley ◽  
R. E. Ellsworth ◽  
D. Ellsworth ◽  
M. Sanders ◽  
J. A. Hooke ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Tumor Cells ◽  
Metastatic Disease ◽  
Metastatic Breast ◽  
Breast Tumors ◽  
Lymph Node Status ◽  
Thymosin Β4 ◽  
Treatment Regimens ◽  
Specific Subset

1041 Background: Primary breast tumors are constantly shedding tumor cells into the circulatory and lymphatic systems. Although detection of occult tumor cells is a risk factor for recurrence and progression, tumor cells remain detectable years after initial diagnosis in patients without clinical or histological detection of metastasis. Thus the question remains as to why some women with circulating tumor cells develop metastatic breast cancer while others do not. Methods: Negative lymph nodes from women with node negative (n=22) and node positive disease (n=36) were obtained from patients enrolled in the Clinical Breast Care Project. Negative lymph node status was confirmed by IHC analysis. Frozen tissues were sectioned and mounted on gold coated MALDI target plates for protein expression profiling. Hematoxylin and eosin (H&E) stained slides were prepared from serial sections for histological characterization. MALDI matrix was deposited as individual spots on the tissue sections in a histology directed manner to assay specific areas and tissue types of interest. Mass spectral data were then acquired from multiple sites across each tissue section. Results: 131 features were observed in negative nodes from patients without metastatic disease and 129 in negative nodes from patients with lymph node metastases. While the majority of features detected were similar between the two groups, 8.5% were differentially expressed. Two of the features which were expressed at significantly higher levels in nodes from patients with metastatic disease have been putatively identified as thymosin β4 and thymosin β10. Conclusions: Thymosin β4 and 10 have been associated with disease progression and metastatic capacity in a number of tumor types. The overexpression of these proteins in tumor-negative nodes from patients with metastatic disease in other regional nodes suggests lymph nodes do not play a passive role in metastasis, rather, expression of a specific subset of proteins creates an hospitable environment to facilitate colonization. These markers of metastasis may permit molecular discrimination of those patients with indolent disease from those at risk for metastasis and will thus allow for the design of customized treatment regimens to more effectively treat, or prevent, metastatic spread. No significant financial relationships to disclose.

Association of tumor burden characteristics with outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5043-5043
Author(s):  
A. R. Golshayan ◽  
P. Elson ◽  
L. S. Wood ◽  
J. A. Garcia ◽  
R. Dreicer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lymph Nodes ◽  
Disease Progression ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Tumor Burden ◽  
Curative Therapy ◽  
Prior Systemic Therapy ◽  
The Impact

5043 Background: An important goal of non-curative therapy for mRCC is tumor burden (TB) control. However, the impact of tumor burden characteristics on clinical outcome has not been studied in mRCC pts treated with VEGF-targeted therapy. Methods: Pts with clear-cell mRCC treated with sunitinib from June 1, 2004, to October 5, 2007, were retrospectively identified. CT scan images were re-reviewed from baseline, at the time of maximal tumor burden shrinkage (TS), at time of disease progression and at time of last assessment prior to death. TB and percent TS were measured per RECIST criteria. Results: Sixty-nine pts were identified. The majority (54%) were favorable risk based on CCF TKI risk group classification. All pts underwent prior nephrectomy and 77% had received prior systemic therapy. Sites of metastases included: lung (87%), mediastinal lymph nodes (52%), retroperitoneal lymph nodes (36%), adrenal (29%), bone (38%), liver (22%), pancreas (14%), kidney (7%), and brain (6%). There were a median of 8 metastatic deposits across all organs (range, 1–20). Median TB at start of therapy was 14.0 cm (range, 3.0–42.2 cm). Overall response rate was 52% and 87% had some degree of TS. Median progression-free survival (PFS) and overall survival (OS) were 13.5 months and 30.9 months, respectively. In multivariable analysis, disease confined to above the diaphragm (p = 0.03) and total TB <13cm (p = 0.09) prior to sunitinib were independent positive predictors of PFS. Total number of metastases <10 (p < 0.001) and tumor volume above the diaphragm <6.5 cm (p = 0.05) were independent positive predictors of OS. Increased TS while on sunitinib was also prognostic for OS (p < 0.001). Fifty-nine pts (86%) have progressed. At time of disease progression (PD), tumor location and pattern of progression were not associated with OS. However, total TB (p = 0.003) and total number of metastatic deposits (≤12 vs. >12, p < 0.001) were significant predictors of OS from PD. At the time of last assessment prior to death, median TB was 23.9 cm, significantly higher (p < 0.001) than in pts still alive (median TB 14.4 cm). Conclusions: Tumor burden shrinkage and tumor burden at time of disease progression are associated with overall survival in pts with mRCC treated with sunitinib. [Table: see text]

scholarly journals MiRNA10b-directed nanotherapy effectively targets brain metastases from breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Byunghee Yoo ◽  
Alana Ross ◽  
Pamela Pantazopoulos ◽  
Zdravka Medarova
Keyword(s):  
Breast Cancer ◽  
Rna Interference ◽  
Lymph Nodes ◽  
Therapeutic Effect ◽  
Metastatic Breast ◽  
Treatment Modalities ◽  
Transcriptional Level ◽  
Metastatic Progression ◽  
Therapeutic Modalities ◽  
Metastatic Colonization

AbstractRNA interference represents one of the most appealing therapeutic modalities for cancer because of its potency, versatility, and modularity. Because the mechanism is catalytic and affects the expression of disease-causing antigens at the post-transcriptional level, only small amounts of therapeutic need to be delivered to the target in order to exert a robust therapeutic effect. RNA interference is also advantageous over other treatment modalities, such as monoclonal antibodies or small molecules, because it has a much broader array of druggable targets. Finally, the complementarity of the genetic code gives us the opportunity to design RNAi therapeutics using computational, rational approaches. Previously, we developed and tested an RNAi-targeted therapeutic, termed MN-anti-miR10b, which was designed to inhibit the critical driver of metastasis and metastatic colonization, miRNA-10b. We showed in animal models of metastatic breast cancer that MN-anti-miR10b accumulated into tumors and metastases in the lymph nodes, lungs, and bone, following simple intravenous injection. We also found that treatment incorporating MN-anti-miR10b was effective at inhibiting the emergence of metastases and could regress already established metastases in the lymph nodes, lungs, and bone. In the present study, we extend the application of MN-anti-miR10b to a model of breast cancer metastatic to the brain. We demonstrate delivery to the metastatic lesions and obtain evidence of a therapeutic effect manifested as inhibition of metastatic progression. This investigation represents an additional step towards translating similar RNAi-targeted therapeutics for the systemic treatment of metastatic disease.

scholarly journals Paired-Agent Fluorescence Molecular Imaging of Sentinel Lymph Nodes Using Indocyanine Green as a Control Agent for Antibody-Based Targeted Agents

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Chengyue Li ◽  
Xiaochun Xu ◽  
Nathan McMahon ◽  
Omar Alhaj Ibrahim ◽  
Husain A. Sattar ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Lymph Nodes ◽  
Indocyanine Green ◽  
Metastatic Breast ◽  
Control Agent ◽  
Sentinel Lymph Nodes ◽  
Imaging Agent ◽  
Binding Potential ◽  
Cancer Spread ◽  
Kinetics Of

Purpose. Paired-agent molecular imaging methods, which employ coadministration of an untargeted, “control” imaging agent with a targeted agent to correct for nonspecific uptake, have been demonstrated to detect 200 cancer cells in a mouse model of metastatic breast cancer. This study demonstrates that indocyanine green (ICG), which is approved for human use, is an ideal control agent for future paired-agent studies to facilitate eventual clinical translation. Methods. The kinetics of ICG were compared with a known ideal control imaging agent, IRDye-700DX-labeled antibody in both healthy and metastatic rat popliteal lymph nodes after coadministration, intradermally in the footpad. Results. The kinetics of ICG and antibody-based imaging agent in tumor-free rat lymph nodes demonstrated a strong correlation with each other (r = 0.98, p<0.001) with a measured binding potential of −0.102 ± 0.03 at 20 min postagent injection, while the kinetics of ICG and targeted imaging agent shows significant separation in the metastatic lymph nodes. Conclusion. This study indicated a potential for microscopic sensitivity to cancer spread in sentinel lymph nodes using ICG as a control agent for antibody-based molecular imaging assays.

scholarly journals COL16A1 is differentially expressed in lymph node metastasis in human breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Lymph Node Metastases ◽  
Metastatic Breast ◽  
Lymphoid Organ ◽  
Primary Tumors ◽  
Node Metastases ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that collagen type XVI alpha 1 chain, COL16A1, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. COL16A1 mRNA was present at decreased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of COL16A1 in primary tumors of the breast was correlated with patient overall survival, in lymph node negative patients but not in lymph node positive patients. Modulation of COL16A1 expression may be relevant to the biology by which tumor cells metastasize from the breast to the lymph nodes and the brain in humans with metastatic breast cancer.

scholarly journals COL6A1 is differentially expressed in lymph node metastasis in human breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Lymph Node Metastases ◽  
Metastatic Breast ◽  
Lymphoid Organ ◽  
Primary Tumors ◽  
Node Metastases ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that collagen type VI alpha 1 chain, COL6A1, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. COL6A1 mRNA was present at decreased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of COL6A1 in primary tumors of the breast was correlated with patient post-progression survival, in lymph node negative patients but not in lymph node positive patients. Modulation of COL6A1 expression may be relevant to the biology by which tumor cells metastasize from the breast to the lymph nodes and the brain in humans with metastatic breast cancer.

scholarly journals TSHZ3 is differentially expressed in lymph node metastasis in human breast cancer.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Lymph Node Metastases ◽  
Metastatic Breast ◽  
Differentially Expressed ◽  
Primary Tumors ◽  
Node Metastases ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that teashirt zinc finger homeobox 3, TSHZ3, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. Analysis of a separate microarray dataset revealed that TSHZ3 was also differentially expressed in brain metastatic tissues. TSHZ3 mRNA was present at decreased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of TSHZ3 in primary tumors of the breast was correlated with patient post-progression survival, in lymph node positive patients but not in lymph node negative patients. Modulation of TSHZ3 expression may be relevant to the biology by which tumor cells metastasize from the breast to the lymph nodes and the brain in humans with metastatic breast cancer.

scholarly journals Rare incidence of non-secretory myeloma with talaromycosis: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Haiting Qin ◽  
Ye Qiu ◽  
Yanmei Huang ◽  
Mianluan Pan ◽  
Dong Lan ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Bone Marrow ◽  
Differential Diagnosis ◽  
Lymph Nodes ◽  
Clinical Symptoms ◽  
Subcutaneous Tissue ◽  
Community Acquired Pneumonia ◽  
Pathological Examination ◽  
Subcutaneous Nodules ◽  
Lung Lymph

Abstract Background Talaromyces marneffei (TM) primarily infects patients with co-morbidities that cause immunodeficiency, but non-secretory myeloma (NSMM) is rare. TSM and NSMM are associated with fever, osteolysis, and swollen lymph nodes, thereby making it difficult for clinicians to make differential diagnosis. In this case, we describe TM infection coexisting with NSMM. Case presentation We retrospectively reviewed the case of a male (without human immunodeficiency virus infection) with fever, thoracalgia, swollen lymph nodes, and subcutaneous nodules who presented to the First Affiliated Hospital of Guangxi Medical University in February 2014. Chest computed tomography revealed patchy infiltration and positron emission tomography/computed tomography showed increased metabolic activity in the lower-right lung, lymph nodes, left ninth rib, and right ilium. Pathological examination of the lung, lymph nodes, subcutaneous nodules, and bone marrow showed no malignancy, he was diagnosed with community-acquired pneumonia. His clinical symptoms did not improve after anti-bacterial, anti-Mycobacterium tuberculosis, and anti-non-M. tuberculosis treatment. Later, etiological culture and pathological examination of the subcutaneous nodule proved TM infection, and the patient was re-diagnosed with disseminated TSM, which involved the lungs, lymph nodes, skin, bone, and subcutaneous tissue. After antifungal treatment, the patient showed significant improvement, except for the pain in his bones. Imaging showed aggravated osteolysis, and bone marrow biopsy and immunohistochemistry indicated NSMM. Thus, we conclusively diagnosed the case as NSMM with TSM (involving the lungs, lymph nodes, skin, and subcutaneous tissue). His condition improved after chemotherapy, and he was symptom-free for 7 years. Conclusion TM infection is rare in individual with NSMM. Since they have clinical manifestation in common, easily causing misdiagnosis and missed diagnosis, multiple pathological examinations and tissue cultures are essential to provide a differential diagnosis.

scholarly journals Genomic Biomarkers of Meningioma: A Focused Review

2021 ◽  
Vol 22 (19) ◽  
pp. 10222
Author(s):  
Jacob A. Pawloski ◽  
Hassan A. Fadel ◽  
Yi-Wen Huang ◽  
Ian Y. Lee
Keyword(s):  
Targeted Therapies ◽  
Recurrence Risk ◽  
Tumor Location ◽  
Genetic Mutations ◽  
Low Grade ◽  
Diverse Group ◽  
The Future ◽  
Genetic Landscape ◽  
The Impact ◽  
The Way

Meningiomas represent a phenotypically and genetically diverse group of tumors which often behave in ways that are not simply explained by their pathologic grade. The genetic landscape of meningiomas has become a target of investigation as tumor genomics have been found to impact tumor location, recurrence risk, and malignant potential. Additionally, targeted therapies are being developed that in the future may provide patients with personalized chemotherapy based on the genetic aberrations within their tumor. This review focuses on the most common genetic mutations found in meningiomas of all grades, with an emphasis on the impact on tumor location and clinically relevant tumor characteristics. NF-2 and the non-NF-2 family of genetic mutations are summarized in the context of low-grade and high-grade tumors, followed by a comprehensive discussion regarding the genetic and embryologic basis for meningioma location and phenotypic heterogeneity. Finally, targeted therapies based on tumor genomics currently in use and under investigation are reviewed and future avenues for research are suggested. The field of meningioma genomics has broad implications on the way meningiomas will be treated in the future, and is gradually shifting the way clinicians approach this diverse group of tumors.

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