Multiple Secondary Sites Research Articles

Neo-vascularization-based therapeutic perspectives in advanced ovarian cancer.

The process of angiogenesis is well described for its potential role in the development of normal ovaries, and physiological functions as well as in the initiation, progression, and metastasis of ovarian cancer (OC). In advanced stages of OC, cancer cells spread outside the ovary to the pelvic, abdomen, lung, or multiple secondary sites. This seriously limits the efficacy of therapeutic options contributing to fatal clinical outcomes. Notably, a variety of angiogenic effectors are produced by the tumor cells to initiate angiogenic processes leading to the development of new blood vessels, which provide essential resources for tumor survival, dissemination, and dormant micro-metastasis of tumor cells. Multiple proangiogenic effectors and their signaling axis have been discovered and functionally characterized for potential clinical utility in OC. In this review, we have provided the current updates on classical and emerging proangiogenic effectors, their signaling axis, and the immune microenvironment contributing to the pathogenesis of OC. Moreover, we have comprehensively reviewed and discussed the significance of the preclinical strategies, drug repurposing, and clinical trials targeting the angiogenic processes that hold promising perspectives for the better management of patients with OC.

Exploration of drug resistance in advanced gastrointestinal stromal tumor.

662 Background: Gastrointestinal stromal tumors (GISTs) are prone to multi-drug resistance after drug treatment, but tissue samples from advanced patients with drug resistance are hard to obtain, impeding the study of the mechanism of drug resistance. In this study, plasma samples from TKI-resistant GIST patients were collected for next generation sequencing (NGS) to detect circulating tumor DNA (ctDNA), which were then used to generate mutation profiles leading to TKI resistance. Methods: A total of 82 GIST patients who acquired TKI resistance were enrolled from Apr. 2016 to Jun. 2021. Plasma ctDNA samples after drug resistance were collected for NGS analysis of 425 genes. Results: Among 82 patients, 54 received monotherapy with imatinib, 24 with 2 TKIs (21 with imatinib and subsequent sunitinib, 2 with imatinib subsequent regorafenib, and 1 with imatinib subsequent anlotinib), and 4 with 3 TKIs (imatinib subsequent sunitinib and regorafenib). Fifty patients (61%) were ctDNA-positive and their mutation profiles were further analyzed. Detection rate of ctDNA in imatinib-resistant patients was 57% (31/54). Among these 31 patients, 12 (39%) showed KIT gene mutation (8 with the known drug-resistant KIT mutations, 6 of these patients exhibited single-drug resistance while 2 showed multi-drug resistance due to KIT mutations mainly in Exon 13 V654A, Exons 17 Y823D, D820Y, N822Y, and N822K). The remaining 19/31 cases (61%) could be attributed to other gene mutations, with 47% due to cancer-associated mutations or other downstream signaling pathways (such as, cell cycle, TP53, RAS and PI3K). Among patients resistant to imatinib followed by other TKIs, ctDNA detection rate was 68% (19/28). Among these 19 patients, 10 (53%) showed KIT gene mutation (including 5 with the known drug-resistant KIT mutations, 4 of these patients exhibited single-drug resistance, while 1 showed multi-drug resistance due to mutations mainly in Exon 13 V654A, Exons 17 D820A, and D820G). The remaining 9/19 cases (47%) could be attributed to other gene mutations, with 44% due to cancer-associated mutations or other in downstream signaling pathways (such as Wnt, cell cycle, TP53, RAS and PI3K). Results indicated a growing trend of mutations leading to resistance among GIST patients treated with multiple TKIs (baseline vs. imatinib resistance vs. multiple TKIs resistance, 3.95% vs. 25.81% vs. 26.32%). Conclusions: Advanced GIST patients who received one or more TKI(s) may be resistant to single or multiple drugs due to complex mutations. NGS can be used to detect ctDNA without the need to obtain tumor tissue samples. This approach facilitates the monitoring of drug resistance in patients with advanced tumors, especially those with multiple metastases. NGS allows detection of mutations at multiple secondary sites and helps to overcome tumor heterogeneity, ctDNA-based NGS analysis will play an increasingly important role in assessment of drug resistance in GIST patients.

Interaction of Benzbromarone with Subdomains IIIA and IB/IIA on Human Serum Albumin as the Primary and Secondary Binding Regions.

Benzbromarone has been used for the treatment of gout for more than 30 years. Although it shows a high level of binding to plasma proteins (>99%), our knowledge of this binding is not sufficiently extensive to permit us to understand its pharmacokinetics and pharmacodynamics. To address this issue in more detail, we characterized the binding of benzbromarone to human serum albumin (HSA), the most abundant protein in plasma. Equilibrium dialysis and circular dichroism findings indicated that benzbromarone binds strongly to one primary as well as to multiple secondary sites on HSA and that the bromine atoms of benzbromarone play important roles in this high affinity binding. An X-ray crystallographic study revealed that benzbromarone molecules bind to hydrophobic pockets within subdomains IB, IIA, and IIIA. Inhibition experiments using site specific ligands (subdomain IB; fusidic acid, IIA; warfarin, IIIA; diazepam) indicated that the primary and secondary binding sites that benzbromarone binds to are within subdomains IIIA and IB/IIA, respectively. Lastly, a study of the effect of fatty acids on the benzbromarone-HSA interaction suggested that benzbromarone, when displaced from subdomain IIIA by sodium oleate, could transfer to subdomains IB or IIA. Thus, these data will permit more relevant assessments of the displacement interactions of benzbromarone especially in cases of co-administered drugs or endogenous compounds that also bind to subdomain IIIA. In addition, the findings presented herein will also be useful for designing drug combination therapy in which pharmacokinetic and pharmacodynamic performance need to be controlled.

Surgery at primary and metastatic sites for stage IV breast cancer (BC): A National Cancer Database (NCDB) analysis.

1099 Background: There is no clear evidence of a survival benefit of primary tumor resection in patients with stage IV breast cancer (BC). This large study evaluated factors associated with undergoing primary tumor resection, and whether resection at the primary site, or distant site resection (metastasectomy), was associated with better overall survival (OS). Methods: This retrospective analysis of stage IV BC cases used the 2004-2016 National Cancer Database (NCDB) population. To evaluate variables associated with primary tumor resection, we used univariate analyses (chi-squared and Wilcoxon rank-sum test), followed by multivariate logistic regression. Consequently, we conducted multivariate Cox regression survival analyses on the following groups: 1) all stage IV BC patients; 2) a subset of those with only 1 site of metastasis; and 3) another subset with metastasis to > 1 distant site. Results: A total of 54,871 stage IV BC patients were included in this analysis. From this, we analyzed a subset with only 1 distant site involved (n = 30,480) and another subset with multiple secondary sites (n = 17,344). In total, 15,661 patients underwent surgery at the primary site: 11,451 (73.1%) were non-Hispanic white; 2479 (15.8%) were non-Hispanic black; 981 (6.3%) were Hispanic and 484 (3.1%) were Asian. Variables associated with undergoing resection of the primary tumor were: age, race, Charlson/Deyo score, insurance and facility type, involved breast quadrant, receptor status, N-staging, extent of metastasis and year of diagnosis. Survival analysis of all stage IV patients showed that both lumpectomy (HR 0.59, 95% CI: 0.57-0.62, p < 0.0001) and mastectomy (HR 0.62, 95% CI: 0.60-0.64, p < 0.0001) were associated with better OS when compared to no surgery. The statistical effect was larger in the subgroup with metastasis to 1 site, but still significant in the subgroup with multiple metastatic sites. Distant site resection also yielded a survival benefit compared to no metastasectomy across all 3 groups. In the subgroup with metastasis to only 1 site, metastasectomy was associated with better OS when the metastatic site was liver (HR 0.60, 95% CI: 0.43-0.82, p = 0.0018), lung (HR 0.47, 95% CI: 0.37-0.61, p < 0.0001), and brain (HR 0.70, 95% CI: 0.55-0.88, p = 0.0022). Conclusions: Across all 3 patient subgroups, primary tumor resection (lumpectomy or mastectomy) and metastasectomy were associated with improved OS. Additional stratified analysis in the subgroup with only 1 metastatic site showed benefit of metastasectomy when that site was the lung, liver or brain.

Abstract P2-05-08: p53 deficiency enhances metastatic potential of triple negative breast cancer by promoting growth in primary and metastatic sites

Abstract TP53 is one of the most commonly mutated genes in human cancer. Mutation or loss of TP53 can occur during the early stages of oncogenesis or as a later event as tumors progress to more aggressive forms. We used a patient-derived xenograft (PDX) model of triple negative breast cancer (TNBC) to investigate how p53 deficiency contributes to metastasis. The PDX line was generated by engrafting the primary breast tumor of a patient with TP53 wild-type metastatic TNBC into the humanized mammary fat pad of NOD/SCID mice. Isogenic lines differing only in TP53 status were generated from this model by silencing p53. Here we demonstrate that the p53-proficient and -deficient tumors metastasized from the mouse mammary gland and colonized the lung, liver, bone, brain, and lymph nodes with similar frequency. p53-deficient tumors grew faster in both the primary and metastatic sites as a result of increased mitosis and decreased apoptosis. Circulating tumor cells (CTCs) are currently being evaluated in p53-proficient and –deficient PDX models. Gene expression profiling identified candidate genes with potential clinical relevance that may be responsible for increased tumor growth upon p53 loss in late stage tumors. This model is also being used to identify genes that promote breast cancer metastasis. To enrich for metastasis, metastatic subpopulations of tumor cells were isolated from lungs and serially passaged in vivo. This serial passaging enriched for metastasis to multiple secondary sites. A transcriptional signature of putative metastasis genes was generated and is being functionalized with high throughput screening in vivo. Citation Format: Powell E, Shao J, Mistry N, Yuan Y, Tieu T, Decker K, Chen H-C, Cai S, Do K-A, Heffernan TP, Edwards J, Piwnica-Worms D, Piwnica-Worms H. p53 deficiency enhances metastatic potential of triple negative breast cancer by promoting growth in primary and metastatic sites. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-08.

Distinctive Spatiotemporal Stability of Somatic Mutations in Metastasized Microsatellite-stable Colorectal Cancer.

A multistep model of disease progression and genomic landscape has been firmly established for colorectal cancer (CRC) primaries, but the genetic makeup of related metastases and the dynamics of genetic changes during metastatic progression are scarcely known. To address these issues, we used multigene high-coverage next-generation sequencing of 24 microsatellite-stable CRC primaries, matched normal tissue, and related multiple metastases to nodes, liver, lung, and brain with a CRC-specific gene panel to infer the degree of clonal evolution during metastatic progression of the disease. Somatic mutations were detected in 40% of CRC-related genes, and we observed a striking 100% genetic concordance between primary and multiple secondary sites for APC, KRAS, FBXW7, PIK3CA, BRAF, SMAD4, and ACVR2A. Except for true de novo mutations in 4 cases (affecting SYNE1, CTNNB1, TP53, and PTEN), all remaining cases (84.4%) shared the genetic lesions of the primary tumors with all investigated metastases irrespective of the site of metastasis or time lapse between primary tumor resection and the occurrence of metastatic spread. Putative biomarkers and druggable targets were identified in 25% of the cases. Our data proves that genetic alterations occurring early in CRC carcinogenesis are remarkably stable during metastatic progression, indicating (i) a very low degree of genetic heterogeneity between primary and multiple secondary sites with respect to CRC driver mutations and (ii) that genetic interrogation of archived primary tumor samples appears to be sufficient for the application of cancer precision medicine in the metastatic setting.

Métastases uvéales des carcinomes thyroïdiens. À propos de 3 cas

To study the characteristics of ocular metastases of thyroid carcinomas through three observations of patients. Three patients aged respectively 41, 55 and 66 years were followed for thyroid carcinoma. All patients were treated by surgery followed by IRA therapy. They developed ocular metastases after a mean period of 10 years after thyroidectomy. They presented in addition multiple secondary sites such as bone, lungs and cerebrum. The uveal lesion was unilateral and localized at the choroid or iris. The predominant symptomatology was decreased visual acuity. The diagnosis was based on ophthalmoscopic examination and post-IRA therapy scan and was confirmed by anatomopathological study. Treatment options were respectively IRA therapy, sectoral iridectomy and enucleation. Evolution was fatal in 2 cases and towards aggravation for one case. Uveal metastases of thyroid cancer are associated with a pejorative prognosis. Ophthalmologic follow-up is necessary when patient presents warning sign mainly with metastatic follicular carcinoma. Conversely, thyroid carcinoma should be considered in the differential diagnosis of a uveal mass of unknown origin.

Organization of antennal lobe‐associated neurons in adult Drosophila melanogaster brain

The primary olfactory centers of both vertebrates and insects are characterized by glomerular structure. Each glomerulus receives sensory input from a specific type of olfactory sensory neurons, creating a topographic map of the odor quality. The primary olfactory center is also innervated by various types of neurons such as local neurons, output projection neurons (PNs), and centrifugal neurons from higher brain regions. Although recent studies have revealed how olfactory sensory input is conveyed to each glomerulus, it still remains unclear how the information is integrated and conveyed to other brain areas. By using the GAL4 enhancer-trap system, we conducted a systematic mapping of the neurons associated with the primary olfactory center of Drosophila, the antennal lobe (AL). We identified in total 29 types of neurons, among which 13 are newly identified in the present study. Analyses of arborizations of these neurons in the AL revealed how glomeruli are linked with each other, how different PNs link these glomeruli with multiple secondary sites, and how these secondary sites are organized by the projections of the AL-associated neurons.

Sequential triage of transmembrane segments by Sec61α during biogenesis of a native multispanning membrane protein

During polytopic protein biogenesis, the Sec61 translocon must rapidly orient and integrate multiple transmembrane segments (TMs) into the endoplasmic reticulum membrane. To understand this process, we examined interactions between Sec61alpha and all six TMs of the aquaporin-4 (AQP4) water channel at defined stages of synthesis using incorporated photo-cross-linking probes. Each TM interacted with and moved through the translocon in a highly ordered and sequential fashion. Strong asymmetric Sec61alpha cross-linking was observed for only one helix at a time, suggesting the presence of a single primary binding site. However, up to four TMs simultaneously contacted Sec61alpha from different molecular environments. Thus, AQP4 integration by Sec61alpha involves sequential triage of TMs from their initial portal of entry into multiple secondary sites within the translocon. This mechanism provides a means to facilitate early folding events before release into the lipid bilayer.

The melanocyte differentiation program predisposes to metastasis after neoplastic transformation

The aggressive clinical behavior of melanoma suggests that the developmental origins of melanocytes in the neural crest might be relevant to their metastatic propensity. Here we show that primary human melanocytes, transformed using a specific set of introduced genes, form melanomas that frequently metastasize to multiple secondary sites, whereas human fibroblasts and epithelial cells transformed using an identical set of genes generate primary tumors that rarely do so. Notably, these melanomas have a metastasis spectrum similar to that observed in humans with melanoma. These observations indicate that part of the metastatic proclivity of melanoma is attributable to lineage-specific factors expressed in melanocytes and not in other cell types analyzed. Analysis of microarray data from human nevi shows that the expression pattern of Slug, a master regulator of neural crest cell specification and migration, correlates with those of other genes that are important for neural crest cell migrations during development. Moreover, Slug is required for the metastasis of the transformed melanoma cells. These findings indicate that melanocyte-specific factors present before neoplastic transformation can have a pivotal role in governing melanoma progression.

CHROMOSOME PAIRING IN MAIZE

This report summarizes our observations at pachytene on opposite-arms intercrosses between stocks of interchanges that involve chromosomes 1 and 5 in maize.-Pairing does not begin at the centromeres in these intercrosses.-We propose a model which assumes different probability values along each chromosome arm for the initial or primary site of pairing. Observations on the frequencies of the different types of configurations at pachytene were used to estimate probability values which satisfactorily fit the data.-There is a relatively low probability (of the order of.1 to.3) for the initial pairing to be in a short terminal segment (about.1 of the arm length). Initial pairing in the one or two short segments adjacent to the tip segment is much higher. Initial pairing is much lower in segments successively closer to the middles of the chromosome arms, and then zero or nearly zero in the proximal half of the arm. This means that the initial pairing may fail occasionally even in a relatively long interchanged segment and produce a T-shaped (3-armed) configuration.-After the initial pairing has occurred, the average probability that a secondary site of pairing is adjacent to the centromere in a segment.3 to.4 the length of an arm is low (.13, ranging from.02 to.29).-We can predict that in an intercross in which both breakpoints in both parental interchanges are far out on the chromosomes, "pairs" will be formed with nonhomologous ends (homologous differential segments paired). In these pairing could have begun at any point in the interstitial segments, but not likely in segments close to the centromeres.-Multiple secondary sites which vary in time or in order of pairing will explain the variation in position of the cross-shaped pachytene configuration in interchange heterozygotes.-The observed configuration in any one cell is the result of a particular combination of pairing events at the various sites. This is a very different concept of pairing from previous interpretations which described it as a result of zipper-like action, and the variation in position of the pachytene cross-configuration as the result of "shifts" in position.-Our cytogenetic results and their interpretation are in close agreement with reports on chromosome ultrastructure and molecular events in the early stages of meiosis, i.e. the attachment of chromosome ends to the nuclear membrane, the manner in which synaptonemal complexes develop, and the regions of DNA whose replication is delayed until zygonema.