Tumor Metastatic Potential Research Articles

Review of primary superficial soft tissue mesenchymal tumors of malignant or intermediate biological potential.

The majority of the sarcomas are deep in location, larger than 5cm in size, and heterogenous in imaging appearance. However, when sarcomas occur superficially, these typical features may be absent, failing to alert the radiologist to a malignancy and mimicking one of the more numerous benign superficial tumors that make up the bulk of soft tissue mass evaluations. This manuscript will discuss the current role of imaging in recognizing features concerning for superficial soft tissue sarcomas. Provided is an overview of the demographic, clinical, and imaging features of the most commonly encountered superficial soft tissue sarcomas, including undifferentiated pleomorphic, leiomyosarcoma, synovial sarcoma, liposarcoma, myxofibrosarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, and angiosarcoma. A less common but primary superficial tumor, angiomatoid fibrous histiocytoma, is also reviewed as the diagnosis may be confounding both clinically and on imaging studies.

Variant type of leiomyomas: 13 years of experience in a single institution.

Our understanding of a variant type of leiomyoma lags far behind of leiomyoma/leiomyosarcoma of the uterus. The rarity of variant type leiomyomas limits epidemiologic study, evidence-based guidance for diagnosis and treatment. We aimed to analyze clinical, pathologic and radiological features of variant type of leiomyomas in women who underwent surgical therapy for symptomatic disease in a tertiary center. We furthermore intended to put forth the recurrence patterns of variant type of leiomyoma after uterine-conserving therapies. Pathology results and inpatient files of women undergoing surgery (vaginal or abdominal hysterectomy; total abdominal hysterectomy and bilateral salphingoopherectomy; abdominal myomectomy; polipectomy) for symptomatic disease and with a histologic diagnosis of variant type of leiomyoma were assessed. Patient gravida, parity, menopausal status, patient complaint, type of initial surgical procedure, size of neoplasms, number of mitosis, presence of atypia, and necrosis, MRI evaluation, recurrence and any subsequent therapy were documented. A total of 3275 patients' medical records were evaluated between 2005-2018. The study sample comprised of 185 women with a diagnosis of variant type of leiomyoma. The patients ranged from 23 to 79 years of age. One hundred thirty-five cases were postmenopausal and 50 cases were during the reproductive period. The most common presenting symptom was menometrorrhagia (38.9%). Four point nine percent of cellular leiomyoma, 14.2% of smooth muscle tumors of uncertain malignant potential (STUMP) and 4.7% of atypical leiomyomas were recurred with clinical follow-up. Clinicians should be aware of variant type leiomyomas and their associated clinical, imaging, and pathologic issues.

Primary Giant Cell Tumor of Soft Tissue in The Female Breast

A giant cell tumor of soft tissue (GCT-ST) is a rare tumor composed of mononuclear and osteoclast-like multinucleated giant cells. It is a low-grade malignant potential tumor morphologically analog to a giant cell tumor of bone. The superficial and deep soft tissue of extremities is the most frequent site of this tumor which is cured by complete or radical resection. GCT-ST as a primary tumor in the female Breast is exceedingly rare. Presentation of osteoclast-like multinucleated giant cells in the breast tumor has been described in association with the variant of breast carcinoma. We report a case of primary GCT-ST arising in the female Breast without a relationship with the epithelial component. To the best of our knowledge, this is the fifth such case report, and only the second one occurred in a female under 50 years.

Abstract 6253: RNA-seq based somatic variant calling and gene expression analysis reveals tumor heterogeneity and metastatic potential in colorectal cancers

Abstract Colorectal cancer (CRC) is the third common malignant tumor and the second most responsible for worldwide cancer deaths. Also, RNAseq technology has been used for two purposes: to find exonic regions on the genome and quantify the expression level of the gene. We tried to validate the pipeline for identifying somatic variants from RNA-seq data, mainly following GATK4 somatic calling pipelines with some optimizing modifications. It is intended to examine whether somatic mutations driven from RNAseq data are associated with the biological behaviors of the individual colorectal cancer cells. We found that key genes (i.e., tumor suppressor genes such as APC and p53) are mostly mutated by T to C (in the non-coding region) or C to T (in the coding region) transitions, so that causes missense and nonsense mutations. However, highly mutated genes did not show significant expressional changes compared to the normal tissue. Otherwise, genes related to the metastatic potentials were observed to have highly increased expression. Our results can substantially verify the reliability of the somatic mutation calling approach using RNAseq data to call cancer-driving mutation and confirm an increase of extracellular matrix metabolism in the CRC. Citation Format: Ji Won Choi, Kwangsung Ahn, Sangsoo Kim, Dong-Il Park, Soo-kyung Park. RNA-seq based somatic variant calling and gene expression analysis reveals tumor heterogeneity and metastatic potential in colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6253.

Abstract 2737: A mechanistic model for prediction of metastatic relapse in early-stage breast cancer using routine clinical features

Abstract Estimation of the risk of metastatic relapse is a major challenge to decide treatment options for early-stage breast cancer patients. To date, metastasis free survival (MFS) analysis mainly relies on classical - agnostic - statistical models (e.g., Cox regression). Instead, we propose to derive mechanistic models to predict MFS. The data consisted of patients who did not receive adjuvant systemic therapy from two databases: one (data 1, N = 163) with routine clinical features and the PAI-1 and uPA biomarkers and two (data 2, N = 692) with 11 routine clinical features. The mathematical models are based on a partial differential equation describing a size-structured population of metastases. They predict MFS from the size of the tumor at diagnosis and two mathematical parameters, α and μ describing respectively the tumor growth speed and metastatic dissemination potential. Using mixed-effects modeling, the population distributions of α and μ were assumed to be lognormal and to depend on routine clinical variables, whereas the observation error was assumed lognormal on the time-to-relapse. Variable selection consisted first in a univariate Wald test for all covariates with effect either on α or μ. We then used a backward elimination procedure. Significance of the covariates in the final model was assessed by a multivariable Wald test. Concordance indexes (c-index) were computed to assess the predictive power in cross-validation procedures as well as test sets. The model was implemented as an R package using optimized C++ code for the mechanistic part and enabling parallelization, resulting in a 4-fold reduction of the computing compared to a former python implementation. Nevertheless, over 4 hours are still needed to run a 100 samples bootstrap on a distributed computing cluster. The model selection procedure on data 1 revealed an association of PAI1 and age with μ, and of Estrogen receptor level with alpha, consistent with the established biological link between PAI-1 and tumor invasiveness. The resulting model achieved good prediction performances with a c-index of 0.72 in 5 folds cross-validation. Using only routine clinical markers, the algorithm on data 2 selected a model with the grade and Progesterone Receptors in α, Ki67 and node status in μ. These were able to adequately describe the data on calibration plots but performed poorly in prediction with a cross validated c-index of 0.60. Mechanistic modeling was able to unravel the biological and predictive role of PAI-1 but showed limited predictive power when using only on routine clinical features. Citation Format: Célestin Bigarré, Pascal Finetti, François Bertucci, Xavier Muracciole, Sébastien Benzekry. A mechanistic model for prediction of metastatic relapse in early-stage breast cancer using routine clinical features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2737.

Abstract 2187: A multiplexed staining method to quantify EMT derived tumor heterogeneity presents a means of predicting patient prognosis based on EMT state

Abstract Intra-tumoral heterogeneity is a key contributor to poor prognosis and metastatic disease in breast cancer. This study seeks to detect and quantify intra-tumoral heterogeneity deriving from the Epithelial-to-Mesenchymal transition using a multi-round, multiplexed immunofluorescence staining approach to delineate EMT states at a single cell resolution in primary tumor specimens to aid in pathological patient diagnosis. Despite major advances in our understanding, the contributions of EMT research to improvements in diagnostic pathology or cancer therapy have been minimal. One reason for this gap stems from our inability to accurately detect and quantify epithelial-mesenchymal heterogeneity in primary tumor specimens. Secondly, the significance of recently identified intermediate or partial EMT states to predicting tumor prognosis and therapy response are unclear. To study the role of various states within the EMT spectrum and their regulatory networks, the heterogeneous breast cancer cell line, SUM149PT, was used to derive six single cell clones encompassing the spectrum of EMT states, from epithelial to mesenchymal. Interrogation of this model system in vivo has revealed increased tumor growth and metastatic potential in the intermediate EMT states when compared to the extreme epithelial and mesenchymal states. To further elucidate EMT states in vivo, we employ a 6-marker multi-round immunofluorescence-based staining approach to identify cells that reside in various states along the EMT spectrum. We subsequently used cell-segmented, entropy-based approach and weighted phenotype analysis on these tumors with the purpose of scoring heterogeneity and overall EMT state. Notably, this analysis segregated stromal infiltrates and their contributions to aggregate EMT scoring, which has been a major hurdle in using EMT as a scoring metric in patient samples. Overall, SUM149 clone-derived tumors held true to the relative EMT states of the starting cell populations; intermediate-derived tumors displayed high heterogeneity while epithelial and mesenchymal clone-derived tumors had lower levels of heterogeneity, despite retaining different EMT scores. Decoupling of heterogeneity and EMT state in this way provides two metrics to assess potential metastatic ability of a tumor. This staining method and analysis has been successfully applied in a preliminary set of patient tumors, showing promise for these two factors, E-M Heterogeneity and EMT score, as a tumor prognostic indicator to inform therapeutic decision-making. In the future, this staining and quantification shows promise as a means of predicting patient prognosis and informing potential treatment options based on targeting EMT states. Citation Format: Meredith S. Brown. A multiplexed staining method to quantify EMT derived tumor heterogeneity presents a means of predicting patient prognosis based on EMT state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2187.

Abstract 5270: Developing a predictive model for pancreatic neuroendocrine tumor metastatic potential: A multi-institutional analysis

Abstract Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms that arise from cells in the islets of Langerhans, with surgical resection presently recommended for tumors > 2cm. While many PNETs have the propensity to be indolent, some small tumors display aggressive features with early metastatic potential. We used machine learning to develop a predictive model of metastatic potential dependent upon the transcriptomic signature of primary PNET tissue. To build this model, RNA sequencing data was obtained from the primary tissue of 96 surgically-resected PNETs from various institutions. Two cohorts were generated with equally balanced metastatic PNET composition (15 (32.6%) vs. 13 (26.5%), p=0.52). A differential gene expression analysis identified 20 concordantly differentially expressed genes associated with metastatic status between the two cohorts. Unsupervised surrogate variable analysis estimated and adjusted for significant sources of variation not related to metastatic potential and mitigated unwanted noise and batch effects. A gene set enrichment analysis identified an additional 29 genes that most frequently contributed to the enriched biologic pathways extrapolated from the sequencing data. Log transformed, batch corrected TPM values for these 49 genes were combined with an additional 10 clinically-relevant genes, including ARX and PDX1, that are known to contribute to PNET signatures or oncogenesis. The datasets were subsequently randomized in a 1:1 ratio and informative features with respect to metastatic status were identified utilizing a Boruta algorithm, with a priori exclusion of highly-correlative genes and those that displayed near zero variance. Nine genes, including AURKA, ARX, CDCA8, CPB2, MYT1L, NDC80, PAPPA2, SFMBT1 and ZPLD1, were identified as sufficient to classify the localized or metastatic outcome. Distributed random forests (DRF), generalized linear models (GLM), gradient boosting machines (GBM) and extreme gradient boosting (XGBoost) models were trained utilizing these 9 genes. Training ROC ranged from 0.92 for DRF to 1 for XGboost. When applied to 47 independent validation samples, the testing sensitivity ranged from 75% for DRF to 94% for GBM; specificity ranged from 84% for DRF to 94% to XGboost and GLM; positive predictive value ranged from 72% for DRF to 86% for GLM; negative predictive value ranged from 88% for GLM to 97% to GBM. The degree of predictive agreement between models ranged from 64% to 91%. Taken together, we have developed a highly sensitive predictive model of the metastatic PNET phenotype that is based on expression of nine genes. Its application as a guide for management should be studied prospectively in patients with newly diagnosed PNETs. Citation Format: Jacques A. Greenberg, Nikolay A. Ivanov, Yajas Shah, Scott Kulm, Jelani Williams, Catherine G. Tran, Theresa Scognamiglio, Yeon Joo Lee, Caitlin E. Egan, Irene M. Min, Rasa Zarnegar, James Howe, Xavier Keutgen, Thomas J. Fahey, Olivier Elemento, Brendan M. Finnerty. Developing a predictive model for pancreatic neuroendocrine tumor metastatic potential: A multi-institutional analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5270.

The Transfigured Ingot-Gastrointestinal Stromal Tumour

Gastrointestinal stromal tumour is a frequently discerned, mesenchymal neoplasm occurring within gastrointestinal tract. Predominantly incriminating gastric region, tumefaction arises from interstitial cells of Cajal which constitute myenteric plexus situated within muscularis propria. Previously designated as gastrointestinal smooth muscle tumour, gastrointestinal autonomic nerve tumour, leiomyoblastoma, smooth muscle tumour of uncertain malignant potential or gastrointestinal pacemaker cell tumour, gastrointestinal stromal tumour may exhibit malignant biological behaviour [1,2]. Of obscure aetiology, majority of neoplasms are sporadic. However, few familial neoplasms may occur. Chromosomal mutations of KIT and PDGFRA genes are singularly associated with the tumour. Neoplasm may be discovered incidentally during various imaging or endoscopic procedures of gastrointestinal tract [1,2].

Active Surveillance versus Immediate Intervention for Small Renal Masses: A Cost-Effectiveness and Clinical Decision Analysis.

Active surveillance (AS) with the possibility of delayed intervention (DI) is emerging as a safe alternative to immediate intervention for many patients with small renal masses (SRMs). However, limited comparative data exist to inform the most appropriate management strategy for SRMs. Decision analytic Markov modeling was performed to estimate the health outcomes and costs of 4 management strategies for 65-year-old patients with an incidental SRM: AS (with possible DI), immediate partial nephrectomy, radical nephrectomy, and thermal ablation. Mortality, direct medical costs, quality-adjusted life-years, and incremental cost-effectiveness ratios were evaluated over 10 years. The 10-year all-cause mortality was 22.6% for AS, 21.9% for immediate partial nephrectomy, 22.4% for immediate radical nephrectomy, and 23.7% for immediate thermal ablation. At a willingness-to-pay threshold of $100,000/quality-adjusted life-year, AS was the most cost-effective management strategy. The results were robust in univariate, multivariate, and probabilistic sensitivity analyses. Clinical decision analysis demonstrated that the tumor's metastatic potential, patient age, individual preferences, and health status were important factors influencing the optimal management strategy. Notably, if the annual probability of metastatic progression from AS was sufficiently low (under 0.35%-0.45% for most ages at baseline), consistent with the typical metastatic potential of SRMs <2 cm, AS would achieve higher health utilities than the other strategies. Compared to immediate intervention, AS with timely DI offers a safe and cost-effective approach to managing patients with SRMs. For patients harboring tumors of very low metastatic potential, AS may lead to better patient outcomes than immediate intervention.

Prognostic role of tumor stroma ratio, tumor-infiltrating lymphocytes, and tumor budding in patients with intestinal-type gastric cancer after radical resection.

4055 Background: Tumor microenvironmental (TME) features including tumor stroma ratio (TSR), tumor infiltrating lymphocytes (TILs) and tumor budding (TB), may be associated with tumor metastatic potential. We sought to identify the association of these features with prognosis of patients with resectable intestinal-type gastric cancer. Methods: Radical resection of gastric carcinoma (&gt; 15 LNs removed) was performed in 493 patients (stage I, n=225; stage II, n=119; stage III, n=149) at two university hospitals between 2010 and 2016. Cutpoints were as follows: TSR (50%), TILs (median), and TB (Bd0-Bd3). TME features and their association with clinicopathological characteristics, time-to-recurrence (TTR) and overall survival (OS) were analyzed by univariate and multivariate Cox methods.. Results: Among 493 patients, high TSR, low TILs and high TB (Bd1-Bd3) were significantly associated with higher histological grade, larger tumor size, and increased T and N stages. Each of these features was significantly associated with poorer TTR and OS at 5 years. In Cox multivariable analysis, N stage and TSR were the only variables that were significantly associated with TTR and OS (Table). The relative contribution (%) of TSR to TTR ranked second (17.5%) behind N stage (49.2%) and ahead of TILs (7.2%) and TB (0.1%). Conclusions: Among TME features, TSR was the most robust and was significantly and independently associated with TTR and OS. The relative contribution of TSR to TTR was second only to nodal status. [Table: see text]

Identifying biomarkers associated with disease-free survival in stage I non–small cell lung cancer.

8543 Background: Patients with early stage, non-small cell lung cancer (NSCLC) with solitary pulmonary lesions ≤4 cm typically have favorable outcomes. However, disease recurrence impacts up to 30% of patients, leading to either additional surgical or systemic interventions. New methods to risk stratify patients based on clinical and molecular parameters may improve our ability to select cases that would benefit from more frequent surveillance or enrollment in clinical trials evaluating systemic therapy. Methods: We retrospectively analyzed data from 179 patients with early stage (T1a-2aN0M0) NSCLC from a single institution. All patients had anatomic resection, negative margins, and systematic nodal sampling. Clinical and demographic data were abstracted from patient charts and tumor samples were molecularly profiled using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage, whole exome-capture RNA-seq). Pathogenic alterations (single nucleotide variants and insertion/deletions) and RNA expression were examined. Bivariate Cox-proportional Hazards models were used to assess the association of individual clinical, demographic, and molecular variables with recurrence-free survival, defined as the time from surgery until recurrence or death. Results: Our dataset included 166 stage IA1-3 patients and 13 stage IB patients, of which 36 patients experienced a recurrence or death event after surgery. Clinical and DNA-seq data was available for all patients, and RNA expression data was available for 172 patients. Across all patients, the most common somatically mutated genes were TP53 (33% of tumors) and KRAS (16% of tumors), consistent with previous studies. Increasing log10-RNA expression for NTRK1 (HR: 5.95; 95% CI, 1.16-30.4; p = 0.027) and CD274 (PD-L1) (HR: 7.88; 95% CI, 1.61-38.6; p = 0.013) and decreasing log10-RNA expression for EGFR (HR: 0.24; 95% CI, 0.05-1.21; p = 0.071) and ERBB2 (Her2) (HR: 0.20; 95% CI, 0.04-0.97; p = 0.042) were associated with increased risk of recurrence or death. Conclusions: Increased expression of NTRK1 and CD274 (PD-L1) and decreased expression of EGFR and ERBB2 (Her2) were associated with a increased risk for recurrence following surgery. This may have mechanistic implications for heightened tumor aggressiveness and/or metastatic potential. Future work will expand our cohort and validate our findings in a broader set of early-stage NSCLC patients.

Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation

Angiogenesis inhibitors are a critical pharmacological tool for the treatment of solid tumors. Suppressing vascular permeability leads to inhibition of tumor growth, invasion, and metastatic potential by blocking the supply of oxygen and nutrients. Disruption of the vascular endothelial growth factor (VEGF) signaling pathway is a validated target for the design of antiangiogenic agents. Several VEGFR2 inhibitors have been clinically approved over the past years. Structural analysis of these clinical VEGFR2 inhibitors highlighted key functional group overlap with the benzothiadiazine core contained in a library of in-house compounds. Herein we ascribe anti-angiogenic activity to a series of chlorinated benzothiadiazines. Selected compounds show significant activity to completely ameliorate VEGF-induced endothelial cell proliferation by suppression of VEGFR2 phosphorylation. The scaffold is devoid of activity to inhibit carbonic anhydrases and generally lacks cytotoxicity across a range of cancer and non-malignant cell lines. Assay of activity at 468 kinases shows remarkable selectivity with only four kinases inhibited > 65% at 10 µM concentration, and with significant activity to inhibit TNK2/ACK1 and PKRD2 by > 90%. All four identified kinase targets are known modulators of angiogenesis, thus highlighting compound 17b as a novel angiogenesis inhibitor for further development.

Interferon‐γ Induces Bcl3 Expression in Ovarian Cancer Cells by JAK1/STAT1 Signaling

The proto‐oncogene Bcl3 is an atypical member of IkB family, which regulates expression of a number of NFkB target genes, including anti‐apoptotic genes, cytokines, and immune checkpoints. Bcl3 expression is increased in many types of human cancers and is associated with increased tumor growth and malignant potential. Interferon‐γ (IFNγ) is a pleiotropic cytokine that has been used in cancer treatment; in addition, its expression is induced in response to radiation therapy and immune checkpoint blockade during cancer treatment. We have recently shown that IFNγ induces Bcl3 expression in ovarian cancer cells, resulting in their increased proliferation, migration, and invasion. In this study, we have investigated the mechanisms of how IFNγ induces the Bcl3 expression in ovarian cancer cells. Our results demonstrate that the IFNγ‐induced Bcl3 expression is dependent on JAK1 and STAT1 signaling, as well as on p65 NFkB. In addition, we have identified a potential interferon regulatory factor 1 (IRF1) binding site in human Bcl3 promoter and found that the IFNγ‐induced Bcl3 expression in ovarian cancer cells is associated with an increased occupancy of IRF1, Ser‐727 phosphorylated STAT1 and acetylated histone H3 at the IRF1 binding site in Bcl3 promoter. These findings identify Bcl3 as a novel target of IFNγ/JAK1/STAT1 signaling and suggest that targeting the JAK1/STAT1 pathway may suppress the IFNγ‐induced Bcl3 expression in ovarian cancer.

Practical diagnostic aspects of uterine leiomyosarcoma in the context of the 2020 WHO classification

The 2020 WHO Classification defines the spindle cell, epithelioid, and myxoid variants as subtypes of uterine leiomyosarcomas (LMS). Presence of cellular atypia (size variation of polymorphic nuclei > 2-3:1), tumor cell necroses, and mitotic count (usually ≥ 10 MF/10 HPF) are still the key features for diagnostic separation from uterine leiomyomas. Preanalytic variables, staining quality, as well as intralesional geographic distribution may affect the mitotic count. Smooth muscle tumors of uncertain malignant potential (STUMP) still exist as a not yet well-characterized diagnostic entity. Immunohistochemical stains against p16, p53, Ki-67, and WT‑1 may aid differential diagnosis in selected cases. Diagnostic molecular pathology is not yet relevant for diagnosis.

Overexpression of Tetraspanin31 contributes to malignant potential and poor outcomes in gastric cancer.

Tetraspanin has important functions in many cancers by aggregating with various proteins that interact with intracellular signaling proteins. The molecular function of Tetraspanin31 (TSPAN31), located in the 12q14 amplified region in various cancers, remains unclear in gastric cancer (GC). We tested whether TSPAN31 acts as a cancer‐promoting gene through its activation or overexpression in GC. We analyzed seven GC cell lines and 189 primary tumors, which were curatively resected in our hospital between 2011 and 2013. Overexpression of the TSPAN31 protein was frequently detected in three GC cell lines (42.9%) and 62 primary GC specimens (32.8%). Overexpression of TSPAN31 was significantly correlated with lymphatic invasion, venous invasion, more advanced pT and pN stages, and a higher recurrence rate. Moreover, TSPAN31 positivity was an independent factor predicting worse patient outcomes (p = 0.0283, hazard ratio 3.97). Ectopic overexpression of TSPAN31 facilitated cell proliferation of GC cells, and knockdown of TSPAN31 inhibited cell proliferation, migration, invasion, and epithelial–mesenchymal transition of GC cells through the PI3K‐Akt pathway and increased cell apoptosis in a TP53 mutation‐independent manner. In vivo analysis also revealed knockdown of TSPAN31 suppressed tumor progression. In addition, knockdown of TSPAN31 improved chemosensitivity to cisplatin through the suppression of ABCC2. These findings suggest that TSPAN31 plays a crucial role in tumor‐malignant potential through overexpression, highlighting its utility as a prognostic factor and a potential therapeutic target in GC.

Uterine PEComas: correlation between melanocytic marker expression and TSC alterations/TFE3 fusions

Uterine PEComas often present a diagnostic challenge as they share morphological and immunohistochemical features with smooth muscle tumors. Herein we evaluated a series of 19 uterine PEComas to compare the degree of melanocytic marker expression with their molecular profile. Patients ranged from 32–77 (median 48) years, with six tumors classified as malignant based on the modified gynecologic-specific prognostic algorithm. All patients with malignant PEComas were alive with disease or dead of disease at last follow-up, while all those of uncertain malignant potential were alive and well (median follow-up, 47 months).Seventeen of 19 (89%) PEComas harbored either a TSC1 or TSC2 alteration. One of the two remaining tumors showed a TFE3 rearrangement, but the other lacked alterations in all genes evaluated. All showed at least focal (usually strong) positivity for HMB-45, with 15/19 (79%) having >50% expression, while the tumor lacking TSC or TFE3 alterations was strongly positive in 10% of cells. Melan-A and MiTF were each positive in 15/19 (79%) tumors, but staining extent and intensity were much more variable than HMB-45. Five of six (83%) malignant PEComas also harbored alterations in TP53, ATRX, or RB1, findings not identified in any tumors of uncertain malignant potential. One malignant PEComa was microsatellite-unstable/mismatch repair protein-deficient.In summary, TSC alterations/TFE3 fusions and diffuse (>50%) HMB-45 expression are characteristic of uterine PEComas. In morphologically ambiguous mesenchymal neoplasms with myomelanocytic differentiation, especially those with metastatic or recurrent disease, next-generation sequencing is recommended to evaluate for TSC alterations; as such, patients can be eligible for targeted therapy.

Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma.

Macrophages constitute a major immune component in tumor tissues, but how these cells adapt to and survive in the nutrient-depleted and lactic acid–induced acidic tumor microenvironments is not yet fully understood. Here, we found that levels of carbonic anhydrase XII (CA12) expression were significantly and selectively upregulated on macrophages in human hepatocellular carcinoma (HCC). Transient glycolytic activation of peritumoral monocytes induced sustained expression of CA12 on tumor-infiltrating macrophages via autocrine cytokines and HIF1α pathways. On the one hand, CA12 mediated the survival of macrophages in relatively acidic tumor microenvironments, while on the other hand, it induced macrophage production of large amounts of C-C motif chemokine ligand 8 (CCL8), which enhanced cancer cell epithelial-mesenchymal transition (EMT) and facilitated tumor metastasis. Consistently, the accumulation of CA12+ macrophages in tumor tissues was associated with increased tumor metastatic potential and reduced survival of patients with HCC. Selective targeting of tumor-infiltrating macrophages with a CA12 inhibitor reduced tumor growth in mice and was sufficient to synergistically enhance the therapeutic efficacy of immune-checkpoint blockade. We suggest that CA12 activity is a previously unappreciated mechanism regulating the accumulation and functions of macrophages in tumor microenvironments and therefore represents a selective vulnerability that could be exploited in future designs for antitumor immunotherapeutic strategies.

Uterine fibroid-like tumors: spectrum of MR imaging findings and their differential diagnosis.

Uterine leiomyoma, also known as uterine fibroid, is the most common gynecological tumor, affecting almost 80% of women at some point during their lives. In the same time, other fibroid-like tumors have similar clinical presentations and about 0.5% of resected tumors of which were presumed benign fibroids in the preoperative diagnosis revealed as malignant sarcomas in the final histopathological examination. Amid the emergence of nonsurgical or minimally invasive procedures for symptomatic benign uterine fibroids, such as uterine artery embolization, high-intensity-focused ultrasound, or laparoscopic myomectomy, the preoperative diagnosis of uterine tumors through imaging becomes all the more relevant. Preoperative tissue sampling is challenging because of the variable location of the myometrial mass; thus, the preoperative evaluation of size and location is increasingly performed through magnetic resonance imaging. Features in images might also be useful for examining the full spectrum of such growths, from benign fibroids to neoplasms of uncertain behavior and malignant sarcomas. Benign fibroids include usual-type leiomyomas, myomas with degeneration, and mitotically active leiomyomas. Neoplasms of uncertain behavior include smooth muscle tumors of uncertain malignant potential, leiomyomas with bizarre nuclei, and cellular leiomyomas. Malignant sarcomas comprise leiomyosarcomas, endometrial stromal sarcomas, adenosarcomas, and carcinosarcomas. The purpose of this article is to review the spectrum of MRI findings of uterine fibroid-like tumors, from benign variants, uncertain behavior to malignant sarcomas, and update the advanced imaging modalities, including diffusion-weighted imaging, positron emission tomography/computed tomography, combining texture analysis and radiomics, to tackle this important issue.

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy.

The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.

Prognostic Utility of the Ki-67 Labeling Index in Follicular Thyroid Tumors: a 20-Year Experience from a Tertiary Thyroid Center

Follicular thyroid tumors pose a diagnostic challenge on the preoperative level, as the discrimination between follicular thyroid carcinoma (FTC) and adenoma (FTA) demands careful histopathological investigation. Moreover, prognostication of FTCs is mostly based on tumor size and extent of invasive properties, while immunohistochemical markers pinpointing high-risk cases are lacking. We have routinely established a Ki-67 labeling index for follicular thyroid tumors since 1999. To assess the potential value of Ki-67 as an adjunct tool to (1) correctly separate FTCs from FTAs and (2) help identify poor-prognosis FTCs, we collected histopathological and clinical data from 818 follicular thyroid tumors with a histological Ki-67 labeling index established in clinical routine practice (516 FTAs, 252 FTCs, and 50 follicular thyroid tumors of uncertain malignant potential (FT-UMPs)). The Ki-67 labeling index was higher in FTCs (mean 5.8%) than in FTAs (mean 2.6%) (P < 0.001), and a receiver operating characteristic curve analysis revealed a cut-off value of 4% to separate FTC from FTA with a sensitivity and specificity of 65% and 83%, respectively. Similarly, a Ki-67 labeling index above 4% was found to identify FTCs that later metastasized from clinically indolent FTCs with a sensitivity and specificity of 80% and 48%, respectively. Ki-67 constituted an independent predictor of future FTC metastases/recurrence and death of disease, and a value > 4% was a reliable prognostic marker within individual pT staging groups. We conclude that Ki-67 is a potentially valuable marker for the prognostication of FTCs, and future implementation in the histopathological assessments of follicular thyroid tumors could be beneficial if reproduced in international series.