-
Cancers Jul 2023The increasing evidence of oncocytic renal tumors positive in Tc Sestamibi Single Photon Emission Tomography/Computed Tomography (SPECT/CT) examination calls for the...
The increasing evidence of oncocytic renal tumors positive in Tc Sestamibi Single Photon Emission Tomography/Computed Tomography (SPECT/CT) examination calls for the development of diagnostic tools to differentiate these tumors from more aggressive forms. This study combined radiomics analysis with the uptake of Tc Sestamibi on SPECT/CT to differentiate benign renal oncocytic neoplasms from renal cell carcinoma. A total of 57 renal tumors were prospectively collected. Histopathological analysis and radiomics data extraction were performed. XGBoost classifiers were trained using the radiomics features alone and combined with the results from the visual evaluation of Tc Sestamibi SPECT/CT examination. The combined SPECT/radiomics model achieved higher accuracy (95%) with an area under the curve (AUC) of 98.3% (95% CI 93.7-100%) than the radiomics-only model (71.67%) with an AUC of 75% (95% CI 49.7-100%) and visual evaluation of Tc Sestamibi SPECT/CT alone (90.8%) with an AUC of 90.8% (95%CI 82.5-99.1%). The positive predictive values of SPECT/radiomics, radiomics-only, and Tc Sestamibi SPECT/CT-only models were 100%, 85.71%, and 85%, respectively, whereas the negative predictive values were 85.71%, 55.56%, and 94.6%, respectively. Feature importance analysis revealed that Tc Sestamibi uptake was the most influential attribute in the combined model. This study highlights the potential of combining radiomics analysis with Tc Sestamibi SPECT/CT to improve the preoperative characterization of benign renal oncocytic neoplasms. The proposed SPECT/radiomics classifier outperformed the visual evaluation of Tc Sestamibii SPECT/CT and the radiomics-only model, demonstrating that the integration of Tc Sestamibi SPECT/CT and radiomics data provides improved diagnostic performance, with minimal false positive and false negative results.
PubMed: 37509214
DOI: 10.3390/cancers15143553 -
Nature Communications Jul 2023This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six...
This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m, however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m. Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.
Topics: Humans; Nivolumab; Interferon-gamma; Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37500647
DOI: 10.1038/s41467-023-40028-z -
Frontiers in Endocrinology 2023Papillary Thyroid Carcinoma (PTC) is the most frequent endocrine malignancy with a variety of histological presentations. Warthin-like Papillary Thyroid Carcinoma... (Review)
Review
BACKGROUND
Papillary Thyroid Carcinoma (PTC) is the most frequent endocrine malignancy with a variety of histological presentations. Warthin-like Papillary Thyroid Carcinoma (WLPTC) is an uncommon neoplasm that is recognized as a distinct subtype of PTC in the WHO classification of thyroid tumors. In this report, we present a novel case of WLPTC in a female patient and provide an in-depth review of the available literature on its clinical, pathological, and therapeutic characteristics.
CASE PRESENTATION
A 27-year-old female patient was referred for neck swelling. Ultrasound showed two suspicious thyroid nodules leading to a thyroidectomy. She was diagnosed with intermediate-risk bifocal foci of classic PTC and WLPTC, arising from a background of chronic lymphocytic thyroiditis (CLT). This pT1b(m) N1b M0 malignancy was treated with adjuvant isotopic ablation and suppressive thyroxine therapy. The 1-year outcomes were favorable.
LITERATURE REVIEW
It covered articles published from 1995 to 2022, by searching PubMed and Google Scholar using specific terms. Out of 148 articles reviewed by two authors, 25 relevant articles were selected, including 13 case reports and 12 case series. The study included 150 cases of WLPTC. Data related to clinical presentation, imaging, histological features, management, and outcomes, were extracted. The mean age of diagnosis was 39 years, with a female predominance. The most common clinical presentation was neck swelling. Thyroid autoimmunity was positive in 71.6% of patients. Lymph node metastases were present in 28% of cases, with no reported distant metastases. Overall, the outcomes were favorable.
CONCLUSION
WLPTC shares similar clinical and radiological presentations as classic PTC. The hallmark histological features of WLPTC are papillae lined with oncocytic tumor cells with papillary nuclear changes and lymphoid stroma. WLPTC is almost constantly associated with CLT. The management of WLPTC aligns with that of classic PTC with comparable stage and risk category, often resulting in favorable outcomes.
Topics: Humans; Female; Adult; Male; Thyroid Cancer, Papillary; Carcinoma; Carcinoma, Papillary; Thyroid Neoplasms; Hashimoto Disease
PubMed: 37497347
DOI: 10.3389/fendo.2023.1210943 -
The Journal of Histochemistry and... Aug 2023Telomerase reverse transcriptase () gene aberrancies correlate to adverse prognosis in follicular thyroid carcinoma (FTC). As loss of 5-hydroxymethylcytosine (5hmC) has...
Telomerase reverse transcriptase () gene aberrancies correlate to adverse prognosis in follicular thyroid carcinoma (FTC). As loss of 5-hydroxymethylcytosine (5hmC) has been associated with promoter mutations in papillary thyroid carcinoma, this study sought to analyze the levels of 5hmC in a cohort of follicular thyroid tumors with available data. A total of 29 tumors (26 FTCs, 2 follicular thyroid tumors of uncertain malignant potential, and 1 oncocytic thyroid carcinoma) with known promoter mutational status and gene expression were assessed for 5hmC immunoreactivity using two antibodies (clones RM236 and 4D9.) Slides were analyzed using a semiquantitative scoring system. Of the 10 tumor cases with aberrant , only 1 scored negative with both antibodies (1/10; 10%), whereas the remaining 9 cases (9/10; 90%) exhibited some positivity for at least one antibody. Of the 19 wild-type tumors, no case was scored negative using RM236, and 2 cases (2/19; 11%) using 4D9. The differences between promoter mutated and wild-type groups were non-significant. The sensitivity and specificity for 5hmC immunohistochemistry (IHC) to detect mutated cases were 10% and 100% (RM236) and 20% and 89% (4D9). Therefore, 5hmC IHC is not a sensitive marker for detecting promoter mutations in follicular thyroid tumors.
Topics: Humans; Immunohistochemistry; Thyroid Neoplasms; Adenocarcinoma, Follicular; Mutation; Thyroid Cancer, Papillary; Telomerase
PubMed: 37486076
DOI: 10.1369/00221554231190437 -
Frontiers in Immunology 2023Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). In the current...
BACKGROUND
Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor microenvironment (TME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokines/cytokines (TLS-kines) expression levels in melanoma patients by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with patients clinicopathological and TME characteristics.
METHODS
Levels of TLS-kines in patients' sera were quantitated using a custom Luminex Multiplex Assay. The Cancer Genomic Atlas melanoma cohort (TCGA-SKCM) and a Moffitt Melanoma cohort were used for tissue transcriptomic analyses. Associations between target analytes and survival outcomes, clinicopathological variables, and correlations between TLS-kines were statistically analyzed.
RESULTS
Serum of 95 patients with melanoma were evaluated; 48 (50%) female, median age of 63, IQR 51-70 years. Serum levels of APRIL/TNFSF13 were positively correlated with levels of both CXCL10 and CXCL13. In multivariate analyses, high levels of serum APRIL/TNFSF13 were associated with improved event-free survival after adjusting for age and stage (HR = 0.64, 95% CI 0.43-0.95; p = 0.03). High expression of tumor transcripts was significantly associated with improved OS in TCGA-SKCM (HR = 0.69, 95% CI 0.52-0.93; p = 0.01) and in Moffitt Melanoma patients (HR = 0.51, 95% CI: 0.32-0.82; p = 0.006). Further incorporation of tumor transcript levels in a 3-gene index revealed that high expression was associated with improved OS in the TCGA SKCM cohort (HR = 0.42, 95% CI 0.19-0.94; p = 0.035). Melanoma differentially expressed genes positively associated with high tumor expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types.
CONCLUSION
Serum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. Patients exhibiting high coordinate expression of transcripts in their tumors displayed superior OS. Further investigation of TLS-kine expression profiles related to clinical outcomes in larger cohort studies is warranted.
Topics: Humans; Female; Middle Aged; Aged; Male; Prognosis; Melanoma; Cytokines; Gene Expression Profiling; Genomics; Tumor Microenvironment
PubMed: 37435077
DOI: 10.3389/fimmu.2023.1171978 -
Journal of Clinical Oncology : Official... Sep 2023The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant...
PURPOSE
The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points.
METHODS
The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated.
RESULTS
The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial.
CONCLUSION
End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.
Topics: Humans; Female; Breast Neoplasms; Neoadjuvant Therapy; Research Design; Progression-Free Survival
PubMed: 37433103
DOI: 10.1200/JCO.23.00435 -
The Oncologist Dec 2023Racial and ethnic minority populations are consistently under-represented in oncology clinical trials despite comprising a disproportionate share of a cancer burden....
Racial and ethnic minority populations are consistently under-represented in oncology clinical trials despite comprising a disproportionate share of a cancer burden. Phase I oncology clinical trials pose a unique challenge and opportunity for minority inclusion. Here we compared the sociodemographic characteristics of patients participating in phase 1 clinical trials a National Cancer Institute ( NCI)-designated comprehensive center to all patients at the center, patients with new cancer diagnosis in metropolitan Atlanta and patients with new cancer diagnoses in the state of Georgia. From 2015 to 2020, 2325 patients (43.4% female, 56.6% male) consented to participate in a phase I trial. Grouped self-reported race distribution was 70.3% White, 26.2% Black, and 3.5% other. Of new patient registrations at Winship Cancer Institute (N = 107 497) (50% F, 50% M), grouped race distribution was 63.3% White, 32.0% Black, and 4.7% other. Patients with new cancer diagnoses in metro Atlanta from 2015 to 2016 (N = 31101) were 58.4% White, 37.2% Black, and 4.3% other. Race and sex distribution of phase I patients was significantly different than Winship patients (P < .001). Over time, percent of White patients decreased in both phase I and Winship groups (P = .009 and P < .001, respectively); percentage of females did not change in either group (P = .54 phase I, P = .063 Winship). Although phase I patients were more likely to be White, male, and privately ensured than the Winship cohort, from 2015 to 2020 the percentage of White patients in phase I trials and among all new patients treated at Winship decreased. The intent of characterizing existing disparities is to improve the representation of patients from racial and ethnic minority backgrounds in phase I clinical trials.
Topics: United States; Humans; Male; Female; Ethnicity; Minority Groups; National Cancer Institute (U.S.); Neoplasms; Georgia
PubMed: 37418599
DOI: 10.1093/oncolo/oyad181 -
Cancer Medicine Aug 2023Mutations in kinases are the most frequent genetic alterations in cancer; however, experimental evidence establishing their cancerous nature is available only for a...
BACKGROUND
Mutations in kinases are the most frequent genetic alterations in cancer; however, experimental evidence establishing their cancerous nature is available only for a small fraction of these mutants.
AIMS
Predicition analysis of kinome mutations is the primary aim of this study. Further objective is to compare the performance of various softwares in pathogenicity prediction of kinase mutations.
MATERIALS AND METHODS
We employed a set of computational tools to predict the pathogenicity of over forty-two thousand mutations and deposited the kinase-wise data in Mendeley database (Estimated Pathogenicity of Kinase Mutants [EPKiMu]).
RESULTS
Mutations are more likely to be drivers when being present in the kinase domain (vs. non-kinase domain) and belonging to hotspot residues (vs. non-hotspot residues). We identified that, while predictive tools have low specificity in general, PolyPhen-2 had the best accuracy. Further efforts to combine all four tools by consensus, voting, or other simple methods did not significantly improve accuracy.
DISCUSSION
The study provides a large dataset of kinase mutations along with their predicted pathogenicity that can be used as a training set for future studies. Furthermore, a comparative sensitivity and selectivity of commonly used computational tools is presented.
CONCLUSION
Primary-structure-based in silico tools identified more cancerous/deleterious mutations in the kinase domains and at the hot spot residues while having higher sensitivity than specificity in detecting deleterious mutations.
Topics: Humans; Virulence; Mutation; Software; Sensitivity and Specificity; Neoplasms; Computational Biology
PubMed: 37409618
DOI: 10.1002/cam4.6324 -
Endocrine-related Cancer Sep 2023Whole chromosome instability with near-whole genome haploidization (GH) and subsequent endoreduplication is considered a main genomic driver in the tumorigenesis of...
Whole chromosome instability with near-whole genome haploidization (GH) and subsequent endoreduplication is considered a main genomic driver in the tumorigenesis of oncocytic cell thyroid neoplasms (OCN). These copy number alterations (CNA) occur less frequently in oncocytic thyroid adenoma (OA) than in oncocytic carcinoma (OCA), suggesting a continuous process. The current study described the CNA patterns in a cohort of 30 benign and malignant OCN, observed using a next-generation sequencing (NGS) panel that assesses genome-wide loss of heterozygosity (LOH) and chromosomal imbalances using 1500 single-nucleotide polymorphisms (SNPs) across all autosomes and the X chromosome in DNA derived from cytological and histological samples. Observed CNA patterns were verified using multiparameter DNA flow cytometry with or without whole-genome SNP array analysis and lesser-allele intensity-ratio (LAIR) analysis. On CNA-LOH analysis using the NGS panel, GH-type CNA were observed in 4 of 11 (36%) OA and in 14 of 16 OCA (88%). Endoreduplication was suspected in 8 of 16 (50%) OCA, all with more extensive GH-type CNA (P < 0.001). Reciprocal chromosomal imbalance type CNA, characterized by (imbalanced) chromosomal copy number gains and associated with benign disease, were observed in 6 of 11 (55%) OA and one equivocal case of OCA. CNA patterns were different between the histopathological subgroups (P < 0.001). By applying the structured interpretation and considerations provided by the current study, CNA-LOH analysis using an NGS panel that is feasible for daily practice may be of great added value to the widespread application of molecular diagnostics in the diagnosis and risk stratification of OCN.
Topics: Humans; Thyroid Nodule; DNA Copy Number Variations; Loss of Heterozygosity; Thyroid Neoplasms; Genome
PubMed: 37399519
DOI: 10.1530/ERC-23-0047