Tumor Metastatic Potential Research Articles

Risk of Recurrence in Uterine Leiomyoma with Bizarre Nuclei: a Systematic Review and Meta-Analysis.

Objective Leiomyoma with bizarre nuclei (LBN) is a variant of uterine leiomyoma, which has replaced the previous category of “atypical leiomyoma” and must be distinguished from smooth muscle tumors of uncertain malignant potential (STUMP). However, previously published series of “atypical leiomyoma” might have included both LBN and STUMP, due to the lack of strict diagnostic criteria. Based on such hypothesis, we aimed to define the risk of recurrence in LBN. Study Design A systematic review and meta-analysis was performed by searching 4 electronic databases for all studies assessing the outcome of patients with “atypical leiomyoma” or LBN. The pooled absolute risk of recurrence was calculated. The included studies were subdivided into two subgroups based on the criteria used: “LBN + STUMP” or “LBN-only”. Results Twelve studies with 433 patients were included. The pooled risk of recurrence was 5.5% overall. The funnel plot showed two cluster of studies which superimposed to the two subgroups. In the LBN + STUMP cluster/subgroup, the pooled risk of recurrence was 7.7%. In the LBN-only cluster/subgroup, the pooled risk of recurrence was 1.9%. Statistical heterogeneity was null in all analyses. Conclusion Our results show a risk of recurrence of 1.9% for LBN; higher recurrence rates in older studies are likely due to the inclusion of STUMPs.

Scope of Artificial Intelligence in Gastrointestinal Oncology.

Simple SummaryGastrointestinal cancers cause over 2.8 million deaths annually worldwide. Currently, the diagnosis of various gastrointestinal cancer mainly relies on manual interpretation of radiographic images by radiologists and various endoscopic images by endoscopists. Artificial intelligence (AI) may be useful in screening, diagnosing, and treating various cancers by accurately analyzing diagnostic clinical images, identifying therapeutic targets, and processing large datasets. The use of AI in endoscopic procedures is a significant breakthrough in modern medicine. Although the diagnostic accuracy of AI systems has markedly increased, it still needs collaboration with physicians. In the near future, AI-assisted systems will become a vital tool for the management of these cancer patients.Gastrointestinal cancers are among the leading causes of death worldwide, with over 2.8 million deaths annually. Over the last few decades, advancements in artificial intelligence technologies have led to their application in medicine. The use of artificial intelligence in endoscopic procedures is a significant breakthrough in modern medicine. Currently, the diagnosis of various gastrointestinal cancer relies on the manual interpretation of radiographic images by radiologists and various endoscopic images by endoscopists. This can lead to diagnostic variabilities as it requires concentration and clinical experience in the field. Artificial intelligence using machine or deep learning algorithms can provide automatic and accurate image analysis and thus assist in diagnosis. In the field of gastroenterology, the application of artificial intelligence can be vast from diagnosis, predicting tumor histology, polyp characterization, metastatic potential, prognosis, and treatment response. It can also provide accurate prediction models to determine the need for intervention with computer-aided diagnosis. The number of research studies on artificial intelligence in gastrointestinal cancer has been increasing rapidly over the last decade due to immense interest in the field. This review aims to review the impact, limitations, and future potentials of artificial intelligence in screening, diagnosis, tumor staging, treatment modalities, and prediction models for the prognosis of various gastrointestinal cancers.

Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms (Review).

Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in ‘liquid’ biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors.

874 Solitary Fibrous Tumours of the Pleura: Immunohistochemistry

Abstract Aim To evaluate immunohistopathology markers of solitary fibrous tumours of the pleura (SFTP), including markers of benign and malignant variants. Method Retrospective review of immunohistopathology reports on 4 patients diagnosed with SFTP between January-October 2020 at the Golden Jubilee National Hospital. Data was collated on markers tested or detected. Benign and malignant cases were compared. A literature review was conducted to summarise the current evidence. Results Ki-67, Anti-bcl-2, CD99, STAT6, Desmin, AE1/3, Calretinin and S100 were tested in 100% (4/4) cases. CD34, EMA and CD117 were tested in 75% (3/4). Betacatenin and Vimentin were tested in 25% (1/4). Of those tested, Ki-67 was present in 100% (4/4), Anti-bcl-2 and CD99 in 75% (3/4), STAT6 in 50% (2/4), Desmin in 25% (1/4), AE1/3 in 25% (1/4), Calretinin in 25% (1/4), S100 in 0% (0/4), CD34 in 67% (2/3), EMA in 0% (0/3), CD117 in 0% (0/3), Betacatenin in 100% (1/1) and Vimentin in 100% (1/1). One out of 4 cases were malignant based on clinical presentation. Of the markers tested in all cases, Desmin was only detected in the malignant case, AE1/3 and Calretinin only in the benign cases, and the other markers in both benign and malignant cases. Anti-bcl-2 and Ki-67 intensity did not correlate with tumour diameter or malignant potential. Immunohistopathology could not confirm SFTP diagnosis in 50% (2/4) cases; it could not determine malignant potential or SFTP-subtype in 100% (4/4) cases. Conclusions A better understanding of SFTP immunohistopathology is needed for investigating SFTP, including benign and malignant tumour variants.

Genomic Biomarkers of Meningioma: A Focused Review

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

P53, p16 and ki67 as immunohistochemical prognostic markers in uterine smooth muscle tumors of uncertain malignant potential (STUMP)

The risk stratification in gynecologic smooth muscle tumors of uncertain malignant potential (STUMP) is a crucial issue, but at present there are no validated prognostic markers. We aimed to assess p53, p16 and ki67 as immunohistochemical prognostic markers in STUMP through a systematic review and meta-analysis. Electronic databases were searched from their inception to July 2020. All studies assessing p53, p16 and/or ki67 immunohistochemistry in gynecologic STUMP series were included. Immunohistochemical patterns were categorized as “abnormal” vs “wild-type” for p53, “diffuse” vs “focal/negative” for p16, ≥ 10% vs 10% for ki67. The prognostic value for recurrence was assessed through Cox regression analysis; a p-value 0.05 was considered significant. Markers that resulted significant were assessed for prognostic accuracy with calculation of area under the curve (AUC) and post-test probability of recurrence. Seven studies with 171 patients were included. Significant association with disease-free survival was found for p53 (p 0.0001) and p16 (p 0.0001), but not for ki67 (p = 0.911). p53 showed sensitivity= 83%, specificity= 86%, AUC= 0.89, and post-test recurrence probabilities of 54% and 7% in the case of abnormal and wild-type expression, respectively. p16 showed sensitivity= 84%, specificity= 88%, AUC= 0.91 and post-test recurrence probabilities of 56% and 7% in the case of diffuse and focal/negative expression, respectively. In conclusion, p53 and p16 might be useful in the risk assessment of STUMP, despite not being suitable as stand-alone prognostic markers.

Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas.

BackgroundUveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1142 European UM patients and 882 healthy controls .MethodsWe combined 2 independent datasets (Global Screening Array) with the dataset described in a previously published GWAS in UM (Omni5 array), which were imputed separately and subsequently merged. Patients were stratified according to their chromosome 3 status, and identified UM risk loci were tested for differential association with M3 or D3 subgroups. All statistical tests were 2-sided.ResultsWe recapitulated the previously identified risk locus on chromosome 5 on CLPTM1L (rs421284: odds ratio [OR] =1.58, 95% confidence interval [CI] = 1.35 to 1.86; P = 1.98 × 10-8) and identified 2 additional risk loci involved in eye pigmentation: IRF4 locus on chromosome 6 (rs12203592: OR = 1.76, 95% CI = 1.44 to 2.16; P = 3.55 × 10-8) and HERC2 locus on chromosome 15 (rs12913832: OR= 0.57, 95% CI = 0.48 to 0.67; P = 1.88 × 10-11). The IRF4 rs12203592 single-nucleotide polymorphism was found to be exclusively associated with risk for the D3 UM subtype (ORD3 = 2.73, 95% CI = 1.87 to 3.97; P = 1.78 × 10-7), and the HERC2 rs12913832 single-nucleotide polymorphism was exclusively associated with risk for the M3 UM subtype (ORM3 = 2.43, 95% CI = 1.79 to 3.29; P = 1.13 × 10-8). However, the CLPTM1L risk locus was equally statistically significant in both subgroups.ConclusionsThis work identified 2 additional UM risk loci known for their role in pigmentation. Importantly, we demonstrate that UM tumor biology and metastatic potential are influenced by patients’ genetic backgrounds.

Epithelioid Leiomyosarcoma of the Uterus: Modern Outcome-based Appraisal of Diagnostic Criteria in a Large Institutional Series.

Epithelioid leiomyosarcoma of the uterus is rare and poorly understood. Herein, we characterize a large institutional series of epithelioid leiomyosarcomas aiming to define outcome-determinant diagnostic pathologic features. We also retrieved epithelioid smooth muscle tumors of unknown malignant potential and evaluated a consecutive cohort of leiomyomas for epithelioid subtypes. Of a total of 1177 uterine leiomyosarcomas, 81 (7%) were categorized as epithelioid after review. Epithelioid leiomyosarcoma was strictly defined as having round to polygonal cells with visible pink cytoplasm and round to ovoid nuclei in ≥50% of the tumor volume. Average age was 55 years (range: 26 to 81 y). Median tumor size was 11 cm; tumor was >5 cm in 93% of subjects; 47% were stage 1 at presentation. An infiltrative tumor border was observed, grossly and/or microscopically, in 89% of cases; necrosis was noted in 80%, and vascular invasion in 47%. Mitotic count in 2.4 mm2 (totalling 10 high-power fields, each field 0.55 mm in diameter) ranged from 3 to 100 (median: 26). All cases had moderate, severe or highly pleomorphic atypia. All cases had 2 or 3 of the following: necrosis, at least moderate atypia and ≥4 mitoses in 2.4 mm2. Immunohistochemistry revealed frequent expression of smooth muscle markers including SMA (96%), desmin (95%), and caldesmon (81%). HMB45 and Melan-A were negative in 92% and 100% of cases, respectively. Estrogen and progesterone receptors were expressed by 65% and 54% of tumors, respectively. Follow-up information was available in 68 subjects (median: 23 mo, range: 1 to 254); cancer-related death occurred in 63%, and an additional 15% had recurrent or metastatic disease at last follow-up. Disease-specific survival was shorter in epithelioid leiomyosarcoma patients (median: 44 mo; 35% at 5-y) than in a matched cohort of nonepithelioid leiomyosarcoma (median: 55 mo; 46% at 5-y) (P=0.03). Three epithelioid smooth muscle tumors of unknown malignant potential were evaluated, all <5 cm in size and with atypia and/or irregular borders but mitotic count below the threshold for malignancy. Two of these had follow-up available, which was uneventful. Of 142 consecutive leiomyomas assessed, none had epithelioid morphology as defined. Epithelioid leiomyosarcoma is an aggressive neoplasm, sometimes with a remarkably low mitotic count. In the setting of an epithelioid smooth muscle tumor of the uterus, we postulate that the diagnosis of malignancy is made in the presence of ≥2 of the following: moderate or severe atypia, ≥4 mitoses/2.4 mm2 and tumor cell necrosis. In their absence, the finding of tumor size ≥5 cm, vascular invasion, infiltrative edges or atypical mitoses should be treated with caution, and designation as of at least uncertain malignant potential is warranted.

Uterine smooth muscle tumors of uncertain malignant potential (STUMP): A retrospective study in a single center

ObjectiveUterine smooth muscle tumors of uncertain malignant potential (STUMP) is a heterogeneous group of tumors with histological and biological diversity that cannot be defined as a benign leiomyoma or malignant leiomyosarcoma. The study aims to investigate the diagnostic methods, treatment management and prognosis of STUMP patients in a 13-year period. Study designWe retrospectively reviewed the clinicopathologic information of 31 STUMP patients in Peking University People’s Hospital. Statistical analyses were conducted to compare the difference of clinical characteristics between the women in myomectomy group and those in hysterectomy group. ResultsThe most common clinical presentation was menstrual disorder. The tumors were mainly manifested as hypoechoic, non-cystic nodules with low blood flow signal by pelvic doppler ultrasonography. Most tumors carried Ki-67 index ranging from 10% to 30%. Immunohistochemical markers such as ER, PR, p16 and Desmin was positively expressed in tumors. At the first operation, 21 cases underwent myomectomy and 10 cases underwent hysterectomy. The patients in myomectomy group were younger than those in hysterectomy group. In the follow-up period, two cases experienced a relapse in the form of STUMP within 36 months. One case died of cardiovascular accident while the other cases were alive. Six of 21 women in myomectomy group desired pregnancy and two healthy live births were recorded. ConclusionThe diagnosis of STUMP primarily depends on histopathologic features. Fertility-sparing surgery may be a treatment selection for patients with fertility desire. Patients with STUMP, especially in the case of myomectomy, should be informed of recurrence risk and monitored closely.

Latest Advances in Imaging Oxidative Stress in Cancer.

Oxidative stress is the imbalance of harmful reactive oxygen species (ROS) and the action of neutralizing antioxidant mechanisms. If left unchecked, the deleterious effects of oxidative stress result in damage to DNA, proteins, and membranes, ultimately leading to cell death. Tumors are highly proliferative and consequently generate high levels of mitochondrial ROS. To compensate for this and maintain redox homeostasis, cancer cells upregulate protective antioxidant pathways, which are further amplified in drug-resistant tumors. This review provides an overview of the latest molecular imaging techniques designed to image oxidative stress in cancer. New probes can now assess heterogeneous ROS and antioxidant production within tumors and across lesions. Together, the noninvasive imaging of these dynamic processes holds great promise for monitoring response to treatment and predicting drug resistance and may provide insight into the metastatic potential of tumors.

Digital quantification of Ki-67 and PHH3 in the classification of uterine smooth muscle tumors

<h3>Objectives:</h3> The aims of this study were to evaluate if digital quantification of proliferation marker Ki-67 and mitotic marker phosphohistone H3 (PHH3) can reliably distinguish leiomyosarcoma (LMS) from smooth muscle tumors of uncertain malignant potential (STUMP), leiomyoma with bizarre nuclei (LMBN), and leiomyoma (LM), and if digital quantification of these markers correlates with clinical outcomes. <h3>Methods:</h3> Cases of LMS, STUMP, LMBN, and LM for which paraffin-embedded tissue was available were identified from a single institution. Manual evaluation of mitotic count was performed using hematoxylin and eosin (H&E) evaluation on 50 high powered fields (5 mm²). Immunohistochemical staining for Ki-67 and PHH3 was performed on one section from each case, and a high throughput digital quantification system was used to calculate an average percent stain. Receiver operating characteristic (ROC) curves for the ability of Ki-67 and PHH3 to predict LMS versus the other diagnostic groups were generated. Univariate Cox regression assessed for associations between each marker and progression-free survival (PFS) among patients with available follow-up. <h3>Results:</h3> A total of 39 cases (17 LMS, 5 STUMP, 10 LMBN, and 7 LM) were included. Mitotic count, Ki-67, and PHH3 were significantly correlated. When comparing the LMS group to the STUMP, LMBN, and LM groups combined, LMS showed a significantly greater digital quantification of Ki-67 (median 10.6% versus 0.4%, p<0.001), and PHH3 (median 0.5% versus 0.14%, p=0.022). Area under the receiver operating characteristic curve (AUC) tests suggested Ki-67 was a better predictor of LMS than PHH3 (AUC 0.92 vs 0.73, p=0.017) (Figure 1). Above a threshold Ki-67 value of 3.8%, the sensitivity was 82% and specificity was 91%. Among 10 LMS/STUMP patients with available follow-up (8 LMS, 2 STUMP), inferior progression-free survival was noted for patients with higher values of Ki-67 (hazard ratio [HR] 1.099, p=0.039) and PHH3 (HR 2.43, p=0.035). <h3>Conclusions:</h3> This study provides preliminary evidence that digital quantification of Ki-67, and possibly PHH3, can aid in a fast and reliable diagnosis of LMS versus other uterine smooth muscle tumors.

Cost-analysis comparison of initial clinical risk assessment and ROMA score for the triage of women with pelvic masses

<h3>Objectives:</h3> In recent years, the Risk of Ovarian Malignancy Algorithm (ROMA) score has emerged as a useful tool in the triage of women with pelvic masses. Previously, triage of women with pelvic masses to management by either benign gynecology or gynecologic oncology was performed with an initial clinical risk assessment (ICRA) alone, involving a detailed history, exam, basic laboratory tests, and imaging. We sought to determine whether use of ROMA, which is calculated using CA125, HE4, and menopausal status for triage of women with pelvic masses, provides cost savings compared to triage based on ICRA alone. <h3>Methods:</h3> A health-economic decision model was developed to assess clinical and cost differences associated with referrals for patients presenting to their gynecologist or primary care physician with an adnexal mass. In our study, we modeled the differences of two clinical pathways that included 1) use of ICRA alone and 2) use of ROMA as a determining factor in referral to a gynecologic oncologist. Using previously reported accuracy rates and patient characteristics from a prospective, multicenter, blinded clinical trial (ClinicalTrial. gov identifier NCT00987649), we assessed triage of women with a pelvic mass using ICRA alone or ROMA and modeled the related lab testing, imaging, surgical procedures, and associated costs. Costs were estimated using current Medicare reimbursement rates. <h3>Results:</h3> A total of 423 patients with pelvic masses were included. Total healthcare costs for patients triaged for epithelial ovarian cancer (EOC) using ICRA alone were higher than when triaged by ROMA ($2,461,301 vs $2,428,628), a cost savings of 1.3%. While lab costs increased 55% when using ROMA ($16,006 vs $24,809), all other costs decreased, including total laparoscopy ($1,931,568 vs $1,896,314, -1.8% difference), total laparotomy ($436,910 vs $430,689, -1.4% difference), and total surgery ($2,368,479 vs $2,327,003, -1.8% difference) (Table 1). Repeat surgeries resulting from false negative ICRA were also reduced when using ROMA (8 vs 3), a 64% decrease. Notably, total healthcare costs were further reduced when including patients with low malignant potential (LMP) tumors ($2,646,738 vs $2,558,834, -3.3% difference) and analysis of all cancers ($2,847,829 vs $2,728,247, -4.2% difference). A similar reduction in repeat surgeries was noted in patients with LMP tumors (19 for ICRA, 7 for ROMA, -61% difference) and in all cancers (29 for ICRA, 14 for ROMA, -53% difference). <h3>Conclusions:</h3> Triage of women with a pelvic mass using the more sensitive ROMA score compared to ICRA alone lowers overall healthcare costs. With fewer false negatives than ICRA alone, the ROMA score improves initial detection of malignancy and reduces second surgical treatments in women with pelvic masses.

Lamin-A interacting protein Hsp90 is required for DNA damage repair and chemoresistance of ovarian cancer cells

Ovarian cancer is the most malignant gynecologic cancer. Previous studies found that lamin-A was associated with DNA damage repair proteins but the underlying mechanism remains unclear. We speculate that this may be related to its interacting proteins, such as Hsp90. The aim of this study is to investigate the effects of Hsp90 on DNA damage repair and chemoresistance of ovarian cancer cells. In our research, co-immunoprecipitation (co-IP) and mass spectrometry (MS) were used to identify proteins interacting with lamin-A and the interaction domain. Next, the relationship between lamin-A and Hsp90 was explored by Western blotting (WB) and immunofluorescence staining. Then, effect of Hsp90 inhibition on DNA damage repair was assessed through detecting Rad50 and Ku80 by WB. Furthermore, to test the roles of 17-AAG on cell chemosensitivity, CCK-8 and colony formation assay were carried out. Meanwhile, IC50 of cells were calculated, followed by immunofluorescence to detect DNA damage. At last, the mouse xenograft model was used in determining the capacity of 17-AAG and DDP to suppress tumor growth and metastatic potential. The results showed that lamin-A could interact with Hsp90 via the domain of lamin-A1-430. Besides, the distribution of Hsp90 could be affected by lamin-A. After lamin-A knockdown, Hsp90 decreased in the cytoplasm and increased in the nucleus, suggesting that the interaction between lamin-A and Hsp90 may be related to the nucleocytoplasmic transport of Hsp90. Moreover, inhibition of Hsp90 led to an obvious decrease in the expression of DSBs (DNA double-strand break) repair proteins, as well as cell proliferation ability upon DDP treatment and IC50 of DDP, causing more serious DNA damage. In addition, the combination of 17-AAG and DDP restrained the growth of ovarian cancer efficiently in vivo and prolonged the survival time of tumor-bearing mice.

Predictors of long-term survivorship after neoadjuvant chemotherapy in advanced ovarian cancer patients

Objectives: Although non-inferior overall survival and reduced surgical morbidity with neoadjuvant therapy (NAC) compared to primary debulking surgery, upfront debulking surgery remains the treatment of choice for newly diagnosed advanced stage ovarian cancer (OC) in the US. This can be partially attributed to the association of aggressive surgical treatment with long term survival (LTS) demonstrated in high grade serous OC (HGSOC). On the contrary, NAC has been shown to lower the odds for LTS. We aimed to identify clinico-pathologic factors associated with LTS in advanced epithelial OC (EOC) treated with NAC. Methods: This is a retrospective case-control study. Women with FIGO stage III-IV high grade epithelial cancer of the ovary, fallopian tube or peritoneum diagnosed and treated with NAC prior to 2013 were extracted from consecutive patient records of the Tel-Aviv Sourasky Medical Center. Women surviving longer than 7 years from diagnosis (defined as long-term survivors, LTS) were compared to women surviving 6-24 months from diagnosis (defined as short-term survivors, STS). Patients with low grade or low malignant potential tumors were excluded. Results: We identified 190 women with stage III/IV epithelial OC. Seventy-eight patients (41%) survived longer than 5 years from diagnosis and 47 (24%) survived longer than 7 years from diagnosis, significantly higher proportions compared to previous reports. Thirty-nine patients (20%) survived 6-24 months, similar to previous reports. Clinicopathologic and treatment characteristics of both groups are displayed in Table 1. CA125 pre-treatment or after 4 courses of chemotherapy and the number of adjuvant and total chemotherapy courses administered were similar between the groups. LTS were significantly younger than STS at diagnosis, with a mean age of 60.05 years vs 65.95 years, respectively (p=0.008). The majority of LTS received 3 courses of NAC or less compared to STS (59.6% vs 33.4%), implying a smaller disease burden or better response to NAC. LTS had a significantly longer disease-free interval (80.49 months vs 3.65 months, p Download : Download high-res image (404KB) Download : Download full-size image Conclusions: Our analysis, to the best of our knowledge, is the first to demonstrate that NAC does not compromise the odds of long-term survivorship in women with advanced EOC, further strengthening NAC as an equivalent alternative to primary debulking surgery. In addition, we identified basic clinicpathologic and treatment-related factors associated with long term survival of epithelial OC patients treated with NAC. Further investigation is needed to determine which factors should be integrated into treatment-related decisions.

Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit

Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

MicroRNA-490-3p and -490-5p in carcinogenesis: Separate or the same goal?

MicroRNA (miR)-490-3p and miR-490-5p, located on chromosome 7q33, are two independent mature products of miR-490 exerting distinct effects on tumor progression. miR-490-3p and miR-490-5p possess antitumor properties. miR-490-3p dysfunction has been associated with malignancies including colorectal cancer, while the abnormal function of miR-490-5p has been more considerably associated with bladder cancer (for example). At present, there are 30 and 11 target genes of miR-490-3p and miR-490-5p, respectively, that have been experimentally verified, of which the cyclin D1 (CCND1) gene is a common target. Through these target genes, miR-490-3p and miR-490-5p are involved in 7 and 3 signaling pathways, respectively, of which only 2 are shared regulatory signaling pathways. The present review introduces two competing endogenous RNA (ceRNA) regulatory networks centered on miR-490-3p and miR-490-5p. These networks may be important promoters of tumor cell proliferation, invasiveness, metastatic potential and apoptosis. Unlike miR-490-5p, miR-490-3p plays a unique role in promoting cancer. However, both are promising molecular markers for early cancer diagnosis and prognosis. In addition, miR-490-3p was also found to be associated with the chemical resistance of cisplatin and paclitaxel. The present review focuses on the abnormal expression of miR-490-3p and miR-490-5p in different tumor types, and their complex ceRNA regulatory networks. The clinical value of miR-490-3p and miR-490-5p in cancer diagnosis, prognosis and treatment is also clarified, and an explanation for the opposing effects of miR-490-3p in tumor research is provided.

Tumor-Associated Protrusion Fluctuations as a Signature of Cancer Invasiveness.

The generation of invasive fluctuating protrusions is a distinctive feature of tumor dissemination. During the invasion, individual cancer cells modulate the morphodynamics of protrusions to optimize their migration efficiency. However, it remains unclear how protrusion fluctuations govern the invasion of more complex multi-cellular structures, such as tumors, and their correlation with the tumor metastatic potential. Herein, a reductionist approach based on 3D tumor cell micro-spheroids with different invasion capabilities is used as a model to decipher the role of tumor-associated fluctuating protrusions in cancer progression. To quantify fluctuations, a set of key biophysical parameters that precisely correlate with the invasive potential of tumors is defined. It is shown that different pharmacological drugs and cytokines are capable of modulating protrusion activity, significantly altering protrusion fluctuations, and tumor invasiveness. This correlation is used to define a novel quantitative invasion index encoding the key biophysical parameters of fluctuations and the relative levels of cell-cell/matrix interactions, which is capable of assessing the tumor's metastatic capability solely based on its magnitude. Overall, this study provides new insights into how protrusion fluctuations regulate tumor cell invasion, suggesting that they may be employed as a novel early indicator, or biophysical signature, of the metastatic potential of tumors.

Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer

BackgroundThe heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in their biological features, invasiveness, and response to chemotherapy, but the transcriptional regulators causing their differences remain nebulous.MethodsIn this study, we compared high-grade serous ovarian cancers (HGSOCs) to low malignant potential or serous borderline tumors (SBTs). Our aim was to discover new regulatory factors causing distinct biological properties of HGSOCs and SBTs.ResultsIn a discovery dataset, we identified 11 differentially expressed genes (DEGs) between SBTs and HGSOCs. Their expression correctly classified 95% of 267 validation samples. Two of the DEGs, TMEM30B and TSPAN1, were significantly associated with worse overall survival in patients with HGSOC. We also identified 17 DEGs that distinguished stage II vs. III HGSOC. In these two DEG promoter sets, we identified significant enrichment of predicted transcription factor binding sites, including those of RARA, FOXF1, BHLHE41, and PITX1. Using published ChIP-seq data acquired from multiple non-ovarian cell types, we showed additional regulatory factors, including AP2-gamma/TFAP2C, FOXA1, and BHLHE40, bound at the majority of DEG promoters. Several of the factors are known to cooperate with and predict the presence of nuclear hormone receptor estrogen receptor alpha (ER-alpha). We experimentally confirmed ER-alpha and PITX1 presence at the DEGs by performing ChIP-seq analysis using the ovarian cancer cell line PEO4. Finally, RNA-seq analysis identified recurrent gene fusion events in our EOC tumor set. Some of these fusions were significantly associated with survival in HGSOC patients; however, the fusion genes are not regulated by the transcription factors identified for the DEGs.ConclusionsThese data implicate an estrogen-responsive regulatory network in the differential gene expression between ovarian cancer subtypes and stages, which includes PITX1. Importantly, the transcription factors associated with our DEG promoters are known to form the MegaTrans complex in breast cancer. This is the first study to implicate the MegaTrans complex in contributing to the distinct biological trajectories of malignant and indolent ovarian cancer subtypes.

Abstract CT260: The FLEX real-world data platform explores new gene expression profiles and investigator initiated protocols in early stage breast cancer

Abstract Background: Genomic expression profiling has significantly improved the personalized treatment of breast cancer, by providing prognostic information about the metastatic potential of tumors and enabling the classification of breast cancers into molecular subtypes, beyond clinical and pathological factors. When combined with comprehensive clinical data, full genome expression data can precisely stratify tumors into clinically actionable subgroups. The FLEX Study is aggregating a large, real-world dataset, which will enable the discovery of novel genomic profiles to improve precision in the management of breast cancer, particularly in patient subsets that are underrepresented in traditional clinical trials. Methods: The FLEX Study (NCT03053193) is a multicenter network, prospective, observational trial for patients with stage I-III breast cancer whose primary tumor is analyzed by MammaPrint, with or without BluePrint. The primary objective of FLEX is to create a large scale, population-based registry that links comprehensive clinical data with full genome expression data to elucidate new prognostic and/or predictive gene associations in a real-world setting. The FLEX Study employs a shared study infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials based on genomic data. The adaptable protocol is designed to be amended to include additional targeted sub-studies, allowing participating investigators to leverage data within the FLEX network to investigate research questions. Patients enrolled in the initial study are eligible for inclusion in sub-studies for which they meet all eligibility criteria and additional consent is not required. Data is collected on patients from diagnosis through 10 years of follow-up and any necessary additional clinical data will be collected as specified in the appendix protocols. The target enrollment of FLEX is a minimum of 10,000 patients; over 6,500 patients have enrolled since April 2017 at more than 85 sites, including eight National Cancer Institute-designated comprehensive cancer centers. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Scientific Review Committee. Sub-study research categories include: Age and Breast Cancer, Optimizing Therapy Strategies, Breast Cancer and Metabolic Syndrome, ctDNA and Liquid Biopsy, Genomics and Subtypes, Social and Ancestry, and Neoadjuvant Therapy and Surgery. To date, 29 investigator-initiated sub-studies have been approved. Trial contact information: NCT03053193 FLEX@agendia.com Citation Format: Adam Brufsky, Jennifer A. Crozier, Nina D'Abreo, Mehran Habibi, Sami Diab, Joyce O'Shaughnessy, Douglas K. Marks, VK Gadi, Amy M. Truitt, Lisa Blumencranz, Erin Yoder, William Audeh, Sarah Untch, Bastiaan van der Baan, FLEX Investigators' Group. The FLEX real-world data platform explores new gene expression profiles and investigator initiated protocols in early stage breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT260.

Uterine Sarcomas: Are There MRI Signs Predictive of Histopathological Diagnosis? A 50-Patient Case Series with Pathological Correlation.

Purpose To make clear distinction between two radiological types of uterine sarcomas. Methods 50 preoperative MRI were analyzed retrospectively, blinded to histopathology: 11 endometrial stromal sarcomas (ESS), 19 leiomyosarcomas (LMS), 18 carcinosarcomas/malignant mixed Mullerian tumors (MMMT), and 2 smooth muscle tumors of uncertain malignant potential (STUMP). Results According to their locations, two radiological types of sarcomas were identified: type 1: intracavitary (ESS, MMMT) and type 2: intramyometrial (LMS, STUMP). In both types, all tumors displayed intermediate T2-weighted signal (p < 0.001) and high diffusion-weighted imaging (DWI) b1000 signal (p < 0.001). Dynamic contrast-enhanced (DCE) MRI showed intratumoral pathologic vessels (98%) and heterogeneity at venous phase (p < 0.001). In the type 1 subgroup, all tumors displayed local spread: invasion of junctional zone on T2-weighted imaging (T2WI), irregular margins on DWI, and disruption of arcuate arteries subendometrial ring on DCE-MRI. In the type 2 subgroup, all tumors displayed irregular margins on T2WI, DWI, and DCE-MRI. Tumor heterogeneity was due to necrosis (p < 0.001). Most commonly the tumor was single (61%). In both types, apparent diffusion coefficient (ADC) lesser than or equal to 0.86 × 10−3 mm2/s (sensitivity = 73%, specificity = 92%) was suggestive of malignancy. Conclusion It may be feasible to get close to histological type of a uterine sarcoma based on our topographic classification into two radiological subgroups, corresponding to two kinds of diagnostic difficulties. Advances in knowledge. MRI signs suggestive of histopathological malignancy are identifiable, considering the triad T2WI/DWI/DCE-MRI, easily for type 1 but less easily for type 2; the threshold value for ADC is 0.86 × 10−3 mm2/s.