Non-metastatic Tumors Research Articles

Abstract PR013: Lymph node colonization promotes distant tumor metastasis through the induction of tumor-specific immune tolerance

Abstract The majority of cancer-associated deaths result from distant organ metastasis, yet the mechanisms that enable this process remain poorly understood. For most solid tumors, colonization of regional or distant lymph nodes (LNs) typically precedes the formation of distant organ metastases, yet it remains unclear whether LN metastasis plays a functional role in disease progression. LNs are major sites of anti-tumor lymphocyte education, including in the context of immunotherapy, yet LN metastasis frequently correlates with further disease progression. Here, we find that LN metastasis represents a critical step in tumor progression through the capacity of such metastases to induce tumor-specific immune tolerance in a manner that promotes further dissemination of tumors to distant organs. Using an in vivo passaging approach of a non-metastatic syngeneic melanoma, we generated 300 unique cell lines exhibiting varying degrees of LN metastatic capacity. We show that the presence of these LN metastases enables distant organ seeding of metastases in a manner that the parental tumor cannot, and this effect is eliminated in mice lacking an adaptive immune response. Furthermore, this promotion of distant seeding by LN metastases is tumor specific. Using flow cytometry and single-cell sequencing to perform comprehensive immune profiling, we identify multiple cellular mediators of tolerance. In particular, we find that LN metastases have the capacity to both resist NK cell cytotoxicity and induce regulatory T cells (Tregs). Furthermore, depletion of NK cells in vivo enables non-metastatic tumors to disseminate to LNs, and ablation of Tregs using FoxP3-DTR mice eliminates the occurrence of lymphatic metastases. Adoptive transfer of Tregs from the LNs of mice bearing LN metastasis to naïve mice facilitates metastasis in a manner that Tregs from mice without LN metastases cannot, and we find that these Tregs are induced in an antigen-specific manner. Whole exome sequencing revealed that neither the metastatic proclivity nor immunosuppression evolve through the acquisition of driver mutations, loss of neoantigens, loss of MHC class I presentation, or decreases in melanoma antigen expression. Rather, by RNA-seq and ATAC-seq, we show that a conserved interferon signaling axis is upregulated in LN metastases and is rendered stable through epigenetic reprogramming of chromatin accessibility resulting from chronic exposure to interferons in vivo. Furthermore, using CRISPR/Cas9, we find that these pathways are required for LN metastatic seeding, and validate their conserved significance in additional mouse models of pancreatic ductal adenocarcinoma and head and neck squamous cell carcinoma and humans with LN metastatic disease. Together, these findings demonstrate a critical role for LN metastasis in promoting tumor-specific immunosuppression. Citation Format: Nathan E. Reticker-Flynn, Weiruo Zhang, Julia A. Belk, Pamela A. Basto, Andrew J. Gentles, John B. Sunwoo, Ansuman K. Satpathy, Sylvia K. Plevritis, Edgar G. Engleman. Lymph node colonization promotes distant tumor metastasis through the induction of tumor-specific immune tolerance [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR013.

Profile of patients of colon cancers treated without any targeted therapies and comparison of treatment outcome between left- and right-sided tumors: A retrospective study from a tertiary cancer center in South India

Introduction: Left- and right-sided colon cancers differ in pathology, tumor biology, and response to therapies. In our country, most of the patients with carcinoma of colon, do not afford targeted therapies and are treated with chemotherapy only, for their metastatic diseases. Aims: The present study aimed to find out differences in terms of survival outcomes between right- and left-sided colon carcinoma patients who were treated without any targeted therapy or immunotherapy. Materials and Methods: Retrospectively, data of patients of carcinoma colon who were diagnosed and treated in between January 2010 and August 2017 were collected. The different clinicopathological and survival parameters were compared between right-sided and left-sided colon carcinoma patients using Kaplan–Meier models, unadjusted Cox regression models, and Cox models stratified by stage. Results: Mean disease-free survival (DFS) for Stage I, II, and III patients was 37.9 months, 33.7 months, and 28.9 months, respectively, and mean progression-free survival (PFS) in 1st line for metastatic disease was 8.1 months. Mean PFS for metastatic diseases in 1st line was not different significantly between left- and right-sided tumors (left vs. right: 8.1 months vs. 8.5 months, P = 0.72). For nonmetastatic disease, mean overall survival (OS) was significantly better in left-sided tumors (left vs. right: 46.2 months vs. 39.6 months, P = 0.019). Those with metastatic disease at presentation, OS did not vary with side (left vs. right: 24.5 months vs. 24.2 months, P = 0.89). Among the patients, who had undergone curative surgery, either upfront or after conversion chemotherapy, left-sided tumors were found to have higher mean DFS and OS (left vs. right, DFS: 31.2 months vs. 20.4 months, P = 0.006, hazard ratio [HR] = 0.54, 95% confidence interval [CI]: [0.38–0.77]; OS: 46.4 months vs. 39.6 months, HR = 0.51, 95% CI = [0.31–0.84], P = 0.008). Conclusion: Patients with left-sided nonmetastatic tumors or metastatic tumors that could undergo curative surgery had higher DFS and OS. Among the patients who did not undergo curative surgery, and were treated with chemotherapy alone, PFS and OS were similar for tumors of both sides. With only chemotherapy without any targeted agents for the metastatic disease, there was no difference in survival with the side.

Sodium Thiosulfate: Pediatric First Approval.

Sodium thiosulfate (Pedmark®) is a chemoprotectant/antioxidant developed by Fennec Pharmaceuticals (formerly Adherex Technologies) to reduce to risk of hearing loss associated with cisplatin. Sodium thiosulfate reduces the risk of ototoxicity by interacting directly with cisplatin to produce inactive platinum species, as well as by causing intracellular effects (such as increasing antioxidant glutathione levels and inhibition of oxidative stress) after entering the cells through the sodium sulfate cotransporter 2. In September 2022, sodium thiosulfate received its first approval in the USA for reducing the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumours. Sodium thiosulfate is under regulatory review in the EU for the prevention of ototoxicity induced by cisplatin chemotherapy in patients 1 month to < 18 years of age with localised, non-metastatic, solid tumours. This article summarizes the milestones in the development of sodium thiosulfate leading to this pediatric first approval for reducing the risk of ototoxicity associated with cisplatin in pediatric patients.

Immune signature of pheochromocytoma and paraganglioma in context of neuroendocrine neoplasms associated with prognosis.

To understand prognostic immune cell infiltration signatures in neuroendocrine neoplasms (NENs), particularly pheochromocytoma and paraganglioma (PCPG), we analyzed tumor transcriptomic data from The Cancer Genome Atlas (TCGA) and other published tumor transcriptomic data of NENs. We used CIBERSORT to infer immune cell infiltrations from bulk tumor transcriptomic data from PCPGs, in comparison to gastroenteropancreatic neuroendocrine tumors (GEPNETs) and small cell lung carcinomas (SCLCs). PCPG immune signature was validated with NanoString immune panel in an independent cohort. Unsupervised clustering of the immune infiltration scores from CIBERSORT was used to find immune clusters. A prognostic immune score model for PCPGs and the other NENs were calculated as a linear combination of the estimated infiltration of activated CD8+/CD4+ T cells, activated NK cells, and M0 and M2 macrophages. In PCPGs, we found five dominant immune clusters, associated with M2 macrophages, monocytes, activated NK cells, M0 macrophages and regulatory T cells, and CD8+/CD4+ T cells respectively. Non-metastatic tumors were associated with activated NK cells and metastatic tumors were associated with M0 macrophages and regulatory T cells. In GEPNETs and SCLCs, M0 macrophages and regulatory T cells were associated with unfavorable outcomes and features, such as metastasis and high-grade tumors. The prognostic immune score model for PCPGs and the NENs could predict non-aggressive and non-metastatic diseases. In PCPGs, the immune score was also an independent predictor of metastasis-free survival in a multivariate Cox regression analysis. The transcriptomic immune signature in PCPG correlates with clinical features like metastasis and prognosis.

The Correlation of Ten Immune Checkpoint Gene Expressions and Their Association with Gastric Cancer Development.

In the immunotherapy based on immune checkpoint inhibition (IC), additional ICs are being studied to increase its effectiveness. An almost unstudied feature is the possible co-expression of ICs, which can determine the therapeutic efficacy of their inhibition. For the selection of promising ICs, information on the association of their expression with cancer development may be essential. We have obtained data on the expression correlation of ADAM17, PVR, TDO2, CD274, CD276, CEACAM1, IDO1, LGALS3, LGALS9, and HHLA2 genes in gastric cancer (GC). All but one, TDO2, have other IC genes with co-expression at some stage. At the metastatic stage, the expression of the IDO1 does not correlate with any other gene. The correlations are positive, but the expressions of the CD276 and CEACAM1 genes are negatively correlated. The expression of TDO2 and LGALS3 is associated with GC metastasis. The expression of TDO2 four-fold higher in metastatic tumors than in non-metastatic tumors, but LGALS3 was two-fold lower. The differentiation is associated with IDO1. The revealed features of TDO2, with a significant increase in expression at the metastatic stage and the absence of other IC genes with correlated expression indicates that the prospect of inhibiting TDO2 in metastatic GC. IDO1 may be considered for inhibition in low-differentiated tumors.

GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in non-metastatic colorectal tumors and predict poor clinical outcome

CD8+ T cells are a major prognostic determinant in solid tumors, including colorectal cancer (CRC). However, understanding how the interplay between different immune cells impacts on clinical outcome is still in its infancy. Here, we describe that the interaction of tumor infiltrating neutrophils expressing high levels of CD15 with CD8+ T effector memory cells (TEM) correlates with tumor progression. Mechanistically, stromal cell-derived factor-1 (CXCL12/SDF-1) promotes the retention of neutrophils within tumors, increasing the crosstalk with CD8+ T cells. As a consequence of the contact-mediated interaction with neutrophils, CD8+ T cells are skewed to produce high levels of GZMK, which in turn decreases E-cadherin on the intestinal epithelium and favors tumor progression. Overall, our results highlight the emergence of GZMKhigh CD8+ TEM in non-metastatic CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics.

Impact of Radiation Therapy on Biological Parameters in Cancer Patients: Sub-analysis from the RIT Prospective Epidemiological Study

Scarce data investigate the impact of radiotherapy (RT) on biology markers. An analysis of ancillary study of RIT (Radiation Impact on Thromboembolic events) prospective trial was carried out. All patients with non-metastatic solid tumors and treated with radiotherapy and/or brachytherapy in curative and consenting to have blood samples were included. A significant decrease in white blood count, (i.e. lymphocytes, monocytes, neutrophils and basophils) and platelet counts was observed after RT and maintained at 6 months. Whereas, eosinophils, D-dimers and hemoglobin levels were affected respectively 3 months and 6 months after RT initiation. Conversely, red cells count and CRP level were not affected by RT. This study is an advocacy to develop an understanding of basic immune system in relation with RT.

Abstract 11728: Predictors of Secondary Pulmonary Hypertension-Related Hospitalizations and Subsequent Mortality in Adults With Obstructive Sleep Apnea

Background: Secondary pulmonary hypertension (SPH) is a predictor of poor outcomes in obstructive sleep apnea (OSA) patients. In this study, we examined sex/racial disparities, predictors and inpatient mortality in SPH-related hospitalizations among OSA patients. Methods: We used the National Inpatient Sample (2019) and ICD-10 codes to identify OSA-related hospitalizations with SPH. The burden of SPH and disparities by sex/race were assessed. We also compared the odds and predictors of in-hospital mortality in OSA patients with vs. without SPH. Results: Of total adult OSA hospitalizations (n=2317136, median age 66[56-74] years, males: 57.2%), 9.4% (218795/2317136) had SPH. Females vs Males (11.3% vs. 8.1%) and Blacks vs. other race groups (13.5%) with OSA had a higher prevalence of SPH [Fig. 1] . The SPH cohort often consisted of females (51 vs 41.9%), blacks (20.9 vs 14.0%), patients from lowest income quartile (29.7 vs 27.6%), Medicare insured (73.4 vs 60.6%), and non-elective admissions (89.2 vs 74.4%) vs. non-SPH cohort. SPH cohort also had a higher burden of complicated HTN (52.9 vs 36.3%), DM with complications (42.7 vs 32.4%), hyperlipidemia (59.4 vs 57.6%), COPD (52.5 vs 36.9%), history of prior MI (11.4 vs 9.6%) and venous thromboembolism (10.4 vs 8.4%). However, in-hospital mortality was more likely to be in males (OR 1.12 95%CI 1.00-1.25, p=0.048) vs Females, and OSA patients with metastatic cancer (OR 2.73 95%CI 2.04-3.65), solid non-metastatic tumors (OR 1.65 95%CI 1.26-2.15) (p&lt;0.001). Our analysis also showed black ethnicity, hyperlipidemia, obesity, tobacco use, and history of venous thromboembolism and TIA were protective against inpatient mortality in SPH-OSA patients. Conclusions: The prevalence of SPH with OSA was greater in females and blacks, whereas males and whites had higher subsequent inpatient mortality. More prospective studies are needed to understand the role of co-morbidities on survival outcomes.

Controversies in upper gastrointestinal oncology: neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy in oesophageal adenocarcinoma

Recent data have presented intriguing information about the treatment of patients with oesophageal adenocarcinoma. However, the actual standard of care in the neoadjuvant treatment for nonmetastatic tumour remains one of the hottest controversial topics in upper gastrointestinal tumours.

Multiparametric MRI enables for differentiation of different degrees of malignancy in two murine models of breast cancer.

The objective of this study was to non-invasively differentiate the degree of malignancy in two murine breast cancer models based on identification of distinct tissue characteristics in a metastatic and non-metastatic tumor model using a multiparametric Magnetic Resonance Imaging (MRI) approach. The highly metastatic 4T1 breast cancer model was compared to the non-metastatic 67NR model. Imaging was conducted on a 9.4 T small animal MRI. The protocol was used to characterize tumors regarding their structural composition, including heterogeneity, intratumoral edema and hemorrhage, as well as endothelial permeability using apparent diffusion coefficient (ADC), T1/T2 mapping and dynamic contrast-enhanced (DCE) imaging. Mice were assessed on either day three, six or nine, with an i.v. injection of the albumin-binding contrast agent gadofosveset. Ex vivo validation of the results was performed with laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), histology, immunhistochemistry and electron microscopy. Significant differences in tumor composition were observed over time and between 4T1 and 67NR tumors. 4T1 tumors showed distorted blood vessels with a thin endothelial layer, resulting in a slower increase in signal intensity after injection of the contrast agent. Higher permeability was further reflected in higher Ktrans values, with consecutive retention of gadolinium in the tumor interstitium visible in MRI. 67NR tumors exhibited blood vessels with a thicker and more intact endothelial layer, resulting in higher peak enhancement, as well as higher maximum slope and area under the curve, but also a visible wash-out of the contrast agent and thus lower Ktrans values. A decreasing accumulation of gadolinium during tumor progression was also visible in both models in LA-ICP-MS. Tissue composition of 4T1 tumors was more heterogeneous, with intratumoral hemorrhage and necrosis and corresponding higher T1 and T2 relaxation times, while 67NR tumors mainly consisted of densely packed tumor cells. Histogram analysis of ADC showed higher values of mean ADC, histogram kurtosis, range and the 90th percentile (p90), as markers for the heterogenous structural composition of 4T1 tumors. Principal component analysis (PCA) discriminated well between the two tumor models. Multiparametric MRI as presented in this study enables for the estimation of malignant potential in the two studied tumor models via the assessment of certain tumor features over time.

High Frequency of Microsatellite Instability among Non-Metastatic Gastric Cancer.

Background: Microsatellite instability (MSI) is considered a key factor in carcinogenesis and a genetic alteration pattern in many types of cancers such as gastric cancer (GC). Although the role of MSI in colorectal cancer (CRC) is well known, its prognostic impact on GC has not been clearly defined. The assessment of MSI in GC has notbeen documented in the Iranian population yet. Therefore, this study analyzed the association of MSI status with GC in Iranian patients. Materials and Methods: We compared the frequency of MSI at 5 loci from formalin-fixed paraffin-embedded (FFPE) gastrectomy specimens, between metastatic and non-metastatic cases of GC (N = 60). A panel of five quasi-monomorphic markers and a single dinucleotide marker with linker-based fluorescent primers was used. Results: MSI was observed in 46.6% of cases, including MSI-high (H) (33.3%) and MSI-Low (L) (13.3%). Moreover, the most unstable and stable markers in our study were NR-21 and BAT-26 accordingly. MSI-H and MSI were seen more frequently in non-metastatic tumors (p= 0.028 and p= 0.019, respectively). Conclusion: The current study showed MSI status more frequently in non-metastatic GC which may reflect a good prognostic factor in GC like CRC. Although, larger and more comprehensive studies are needed to confirm this statement. A panel consisting of NR-21, BAT-25, and NR-27 mononucleotide markers appears to be reliable and useful markers for detecting MSI in GC in Iranian patients.

Understanding the mechano and chemo response of retinoblastoma tumor cells

IntroductionCellular homeostasis with its environment is bidirectional and dynamic in nature. Extracellular matrix plays an important role in retinoblastoma tumor cell's response to chemotherapeutic drugs. The present study was designed to investigate the effect of mechanotransduction along with the chemotherapeutic effect on RB cells grown on three-dimensional matrices. MethodsMatrigels of varying stiffness (low and high) were prepared and characterized. Drug sensitivity of RB cells on various matrigel stiffness was measured using cytotoxicity (MTT) assay and IC50 value was found for carboplatin and etoposide. Further, the effect on the proliferation and migration of RB cells in various stiffness matrigels was investigated. FindingsThe results showed that drug sensitivity decreased with an increase in matrix stiffness when compared to RB cells grown in suspension. In higher stiffness, the drug sensitivity decreases with an increase in cell proliferation. Data from a gene expression study revealed that Vinculin was variably regulated between metastatic and non-metastatic tumor cells, and upregulated RhoA was altered in different stiffness gradient matrigel during drug treatment. InterpretationThese results enhance the understanding of the fundamental molecules responding to drug sensitivity in a stiffness-altering environment. Additionally, it provides a new avenue for understanding how RB cells respond to chemotherapeutic intervention.

The expression of stromal biomarkers in small papillary thyroid carcinomas

BackgroundThe importance of stroma for tumor progression is recognized for many cancer types. In this study, we aim to evaluate the expression of types I (Col1) and IV (Col4) collagens, alpha-smooth muscle actin (a-SMA), and matrix metallopeptidase 9 (MMP-9) in the tumor stroma of small papillary thyroid carcinoma (PTC).Material and methodsTwenty-five non-metastatic small PTCs (pT1N0) and nineteen metastatic small PTCs (pT1N1b) including corresponding metastatic lateral lymph nodes were selected and paraffinized tissue blocks retrieved. The samples were stained for Col1, COL4, a-SMA, and MMP-9 antibodies using immunohistochemistry. The expression of the stromal proteins was scored and analyzed based on the location, intensity, and distribution.ResultsCol1 and Col4 expression were significantly higher in normal thyroid tissue compared to PTC tissue. On the contrary, expression of a-SMA and MMP-9 was higher in PTC tissue compared to normal thyroid tissue. Both Col1 and Col4 were significantly more highly expressed in the non-metastatic tumors compared with metastatic tumors. The expression of a-SMA and MMP9 was slightly, but not significantly, higher in the metastasized tumors and their respective lymph nodes. There was a significant correlation between the metastasized tumors and their respective lymph nodes in Col1 and MMP-9 expression.ConclusionsCol1, Col4, a-SMA, and MMP-9 expression in PTCs differs significantly from that of normal thyroid tissue. The higher expression of Col1 and Col4 in normal thyroid tissue and in the non-metastasized tumors indicates that Col1 and 4 might have a potential protective role in tumor progression. The higher expression of a-SMA and MMP9 in PTCs indicates that these proteins might have a role in promoting PTC progression and aggressiveness.

Cystathionine β-synthase overexpression drives metastatic dissemination in pancreatic ductal adenocarcinoma via inducing epithelial-to-mesenchymal transformation of cancer cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all cancer types with a constant rise in global incidence. Therefore, better understanding of PDAC biology, in order to design more efficient diagnostic and treatment modalities, is a priority.Here we found that the expression levels of cystathionine β-synthase (CBS), a transsulfuration enzyme, is markedly elevated in metastatic PDAC cells compared to cell lines isolated from non-metastatic primary tumors. On human immunohistochemical samples from PDAC patients we also found higher CBS staining in cancerous ductal cells compared to in non-tumor tissue, which was further elevated in the lymph node metastasis of the same patients. In mice, orthotopically injected CBS-silenced T3M4 cells induced fewer liver metastases compared to control cells indicating important roles for CBS in PDAC cancer cell invasion and malignant transformation. Wound healing and colony formation assays in cell culture confirmed that CBS-deficient metastatic T3M4 and non-metastatic BxPC3 primary tumor cells migrate slower and have impaired anchorage-independent growth capacities compared to control T3M4 cells. CBS silencing in T3M4 cells lowered WNT5a and SNAI1 gene expression down to levels that were observed in BxPC3 cells as well as resulted in an increase in E-cadherin and a decrease in Vimentin signals in mouse tumors when injected orthotopically. These observations suggested a primary role for the epithelial to mesenchymal transformation of cancer cells in CBS-mediated tumor aggressiveness. Under normal conditions, STAT3, an upstream regulator of Wnt signaling pathways, was less phosphorylated and more oxidized in shCBS T3M4 and BxPC3 compared to control T3M4 cells, which is consistent with decreased transcriptional activity at lower CBS levels due to less protection against oxidation. Sulfur metabolome analyses suggested that this CBS-mediated protection against oxidative modifications is likely to be related to persulfide/sulfide producing activities of the enzyme rather than its canonical function to produce cystathionine for cysteine synthesis. Taken together, CBS overexpression through regulation of the EMT plays a significant role in PDAC cancer cell invasion and metastasis.

329 (PB109) - Tensin2 is a novel diagnostic marker in gastrointestinal stromal tumor, associated with gastric location and non-metastatic tumors

Gastrointestinal stomal tumor (GIST) is a rare soft tissue sarcoma, for which KIT and DOG1 are used as highly sensitive diagnostic markers. Other diagnostic markers include CD34, protein kinase C θ, deficiency of succinate dehydrogenase complex subunit B, carbonic anhydrase II, and type I insulin-like growth factor receptor. However, most of these markers are expressed in other similar malignancies relevant for the differential diagnosis of GIST, such as leiomyomas, leiomyosarcomas or schwannomas.

S2125 Short Time Recurrence of Retroperitoneal Desmoid Tumor in Patient With Familial Adenomatous Polyposis

Introduction: A Desmoid Tumor (DT) is a locally invasive, non-metastatic mesenchymal stem cell tumor that typically manifests as a soft tissue mass occurring in muscles, fasciae and aponeuroses. We present a case of a patient with recurrence of a retroperitoneal DT shortly after resection. Case Description/Methods: A 34-year-old male presented with abdominal pain found to have a large (11 × 14.4 * 14 cm) intrabdominal mass. IR transcatheter biopsy of the mass confirmed DT. He underwent bidirectional endoscopy and found to have more than hundred adenomatous colon polyps. Genetic testing confirmed APC mutation. Patient was diagnosed with DT associate with Familial Adenomatous Polyposis (FAP). He underwent radical resection of mesenteric mass and small bowel (20 cm of terminal ileum), omentectomy as well as total colectomy with ileorectal anastomosis. There was no evidence of lymphoid involvement. About 3 months later, he was re-admitted for increased abdominal girth with abdominal pain. MRI scans demonstrated a new, extensive, lobulated soft tissue mass occupying the entire abdominal cavity measuring 23.4 × 12.5 × 24.2 cm. Biopsy of the mass confirmed recurrent DT. Given the large size and proximity to the superior mesenteric artery, the mass was deemed to be unresectable. Patient was initially started on palliative systemic treatment with liposomal Doxorubicin. Due to lack of response, he was then switched to weekly methotrexate and Vinblastine (Figure). Discussion: DTs are rare neoplasms, making up only 0.03% of all neoplasms and 3% of soft tissue tumors. They typically include the abdominal wall, extremities, and mesentery. Although the etiology of DTs is not well known, there are several risk factors that are associated with their occurrence. Genetic syndromes such as FAP and Gardner syndrome have a well-known association with DTs. Other associations include antecedent trauma to the site of the lesion, pregnancy, and female sex. Numerous studies have been done assessing the efficacy of surgery, radiotherapy, and chemotherapy in managing DTs. However, none have shown conclusive benefit. The recurrence rate, particularly following surgical management, has been found to be as high as 77%. Given the lack of definitive management and high recurrence rates, treatment options should likely include combination of both surgical intervention and systemic treatment after discussing options and adverse effects of treatment with the patient.Figure 1.: A, Contrast enhanced CT axial through the lower abdomen demonstrating recurrence of large mass now occupying the majority of the abdominal cavity (black star); B, Spindle cell lesion, with fascicular and loose storiform growth patterns (H&E, 40×) prior to resection; C, Recurrent tumor with pathology demonstrating spindle cell lesion with more edema and/or myxoid stroma.

MiR-92a-3p encapsulated in bone metastatic mammary tumor cell-derived extracellular vesicles modulates mature osteoclast longevity.

Aberrant osteoclast formation and activation are the hallmarks of osteolytic metastasis. Extracellular vesicles (EVs), released from bone metastatic tumor cells, play a pivotal role in the progression of osteolytic lesions. However, the mechanisms through which tumor cell-derived EVs regulate osteoclast differentiation and function have not been fully elucidated. In this study, we found that 4T1 bone metastatic mouse mammary tumor cell-derived EVs (4T1-EVs) are taken up by mouse bone marrow macrophages to facilitate osteoclastogenesis. Furthermore, treatment of mature osteoclasts with 4T1-EVs promoted bone resorption, which was accompanied by enhanced survival of mature osteoclasts through the negative regulation of caspase-3. By comparing the miRNA content in 4T1-EVs with that in 67NR nonmetastatic mouse mammary tumor cell-derived EVs (67NR-EVs), miR-92a-3p was identified as one of the most enriched miRNAs in 4T1-EVs, and its transfer into mature osteoclasts significantly reduced apoptosis. Bioinformatic and Western blot analyses revealed that miR-92a-3p directly targeted phosphatase and tensin homolog (PTEN) in mature osteoclasts, resulting in increased levels of phospho-Akt. Our findings provide novel insights into the EV-mediated regulation of osteoclast survival through the transfer of miR-92a-3p, which enhances mature osteoclast survival via the Akt survival signaling pathway, thus promoting bone resorption.

CDK 4/6 inhibitors for the treatment of meningioma.

Meningiomas are the most common non-metastatic brain tumors, and although the majority are relatively slow-growing and histologically benign, a subset of meningiomas are aggressive and remain challenging to treat. Despite a standard of care that includes surgical resection and radiotherapy, and recent advances in meningioma molecular grouping, there are no systemic medical options for patients with meningiomas that are resistant to standard interventions. Misactivation of the cell cycle at the level of CDK4/6 is common in high-grade or molecularly aggressive meningiomas, and CDK4/6 has emerged as a potential target for systemic meningioma treatments. In this review, we describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents. Further, we highlight upcoming clinical trials for patients meningiomas, and discuss future directions aimed at optimizing the efficacy of these therapies and selecting patients most likely to benefit from their use.

Predicted vs Observed Metastasis-Free Survival in Individuals With Uveal Melanoma

Accuracy of the predicted metastasis-free survival (MFS) by a commercially available gene expression profiling (GEP) test is not known. To compare the predicted MFS with the observed MFS in patients in this cohort and with those in published studies (published MFS, meta-analysis). This cohort study included consecutive patients from the University of Iowa and Cleveland Clinic who were diagnosed with uveal melanoma who underwent prognostic fine-needle aspiration biopsy at the time of primary treatment. Patients were recruited from December 2012 to December 2020. The predicted MFS for patients was extracted from the GEP report. The observed MFS was defined as time to metastasis. Cox proportional hazards models were fit to identify tumor variables impacting MFS in patients with class 2 tumors. The overall estimate of the published MFS was obtained by performing meta-analysis of data from published series. Analysis took place in August 2021. MFS. There were 92 patients from the University of Iowa and 255 patients from the Cleveland Clinic. The mean (SD) age at diagnosis was 59.4 (13.0) years. The median (IQR) follow-up interval was 38.0 (19.0-57.0) months. The observed MFS for patients with class 2 tumor in this cohort (3 years: 67% [95% CI, 59%-77%]; 5 years: 47% [95% CI, 37%-61%]) and in published studies (3 years: 62% [95% CI, 57%-66%]; 5 years: 40% [95% CI, 34%-46%]) were better than those predicted (50% and 28% for 3 and 5 years, respectively). Within patients with class 2 tumor, those with metastasis had larger tumors compared with nonmetastatic tumors (mean largest basal diameter difference, 1.7 [95% CI, 0.5-3.0] mm; P = .01; mean thickness ratio, 1.3 [95% CI, 1.04-1.5]; P = .01, respectively). An increasing tumor size was significantly associated with increased hazard ratio (1.16 [95% CI, 1.06-1.27]; P < .001) of metastasis. These findings suggest the predicted MFS for metastatic tumors (class 2) appears to be worse than that observed here and reported by others. Incorporation of tumor size in the prediction model may enhance its accuracy. Adjuvant therapy trials may not be able to rely on predicted MFS to calculate efficacy with a high degree of confidence.

Multimodality Imaging Assessment of Desmoid Tumors: The Great Mime in the Era of Multidisciplinary Teams.

Desmoid tumors (DTs), also known as desmoid fibromatosis or aggressive fibromatosis, are rare, locally invasive, non-metastatic soft tissue tumors. Although histological results represent the gold standard diagnosis, imaging represents the fundamental tool for the diagnosis of these tumors. Although histological analysis represents the gold standard for diagnosis, imaging represents the fundamental tool for the diagnosis of these tumors. DTs represent a challenge for the radiologist, being able to mimic different pathological conditions. A proper diagnosis is required to establish an adequate therapeutic approach. Multimodality imaging, including ultrasound (US), computed tomography (CT) and Magnetic Resonance Imaging (MRI), should be preferred. Different imaging techniques can also guide minimally invasive treatments and monitor their effectiveness. The purpose of this review is to describe the state-of-the-art multidisciplinary imaging of DTs; and its role in patient management.