Development Of Distant Metastases Research Articles

The Value of Stimulated Thyroglobulin Before the First Radioactive Iodine Treatment in Metastasis for Differentiated Thyroid Carcinoma.

To evaluate the value of preablative stimulated thyroglobulin (ps-Tg) before the first radioactive ablation iodine (RAI) treatment to predict the postoperative metastasis of DTC. A total of 235 DTC patients, who underwent total thyroidectomy and neck lymph node dissection, were enrolled. On the basis of the presence or absence of metastasis, all patients were divided into metastasis (M1) and non-metastasis (M0) groups. Besides, the patients in the M1 group were further divided into two subgroups according to sites of metastasis. These groups included cervical lymph node metastasis and distant metastasis groups. Subsequently, the level of serum ps-Tg was measured 3 - 4 days before the first RAI ablation treatment, whereas 131I whole-body imaging and SPECT/CT tomography were performed 5 - 7 days after radio ablation. Subsequently, the Mann Whitney U test was used to compare the different levels of ps-Tg between the two groups. Additionally, the relationship between ps-Tg and the metastasis of DTC was analyzed through correlation analysis, regression analysis, and the ROC curve. The ps-Tg level in the M1 group was higher than that in the M0 group. Further analysis discovered that the ps-Tg in the distant metastasis group was higher than that in the cervical lymph node metastasis and non-metastasis groups. Also, the ps-Tg level was positively correlated with distant metastasis (r = 0.599, p = 0.000). Besides, the results of multivariate logistic regression analysis outlined that the level of ps-Tg was an independent risk factor for the development of distant metastasis (OR = 1.008, p = 0.018). Subsequently, the results from the ROC analysis also showed a good diagnostic performance for ps-Tg in treating distant metastasis (AUC = 0.964, p = 0.000), and the optimal cutoff value was 61.87 ng/mL. The ps-Tg in patients with DTC before the first RAI ablation treatment is an independent risk factor and a meaningful indicator in predicting postoperative distant metastasis.

Management of Adenoid Cystic Carcinoma of the Head and Neck: Experience of the National Cancer Institute, Egypt

This study presents the experience of the National Cancer Institute, Cairo University, in diagnosis and management of ACC of the head and neck.This is a retrospective review of 57 patients with ACC managed during the period from January 2011 to January 2016. Data about the characteristics and management of the disease were recorded. All patients were followed up to detect the development of local recurrence and distant metastasis and their management.The mean age was 45.5 ± 15.1, with a femaleto-male ratio of 1.5:1. The minor salivary glands were affected in 61.4% of cases. Four patients (7%) were metastatic at presentation. The main presenting symptom was swelling, followed by pain. Surgical resection was performed in 48 patients (84.2%) followed by adjuvant radiotherapy in 36 of them. Four patients received radical radiotherapy. Treatment failed in 3 patients. Recurrences were recorded in 21 out of the 50 cured patients; 9 had locoregional recurrence, 9 had distant metastases, and 3 had both. The overall survival (OS) and disease-free survival (DFS) at three years were 79% and 57.1%, respectively. Surgical resection improved OS (p<0.001). Advanced T-stage, lymph node invasion, solid tumors, close or positive margins worsened OS. Adjuvant radiotherapy was associated with better DFS (p = 0.003), while solid tumors were associated with worse DFS.Despite aggressive management with radical surgery and adjuvant radiotherapy, recurrence affects 42% of the patients within three years. Patients with unresectable tumors have a poor prognosis. Adjuvant radiotherapy improves DFS but not OS.

Histologically confirmed distant metastatic urothelial carcinoma from the urinary bladder: a retrospective review of one institution's 20-year experience.

BackgroundUrothelial carcinoma (UC) accounts for roughly 90% of bladder cancer, and has a high propensity for diverse differentiation. Recently, certain histologic variants of UC have been recognized to be associated with unfavorable clinical outcomes. Several UC studies have also suggested that tumor budding is a poor prognostic marker. Distant metastasis of UC after radical cystectomy is not uncommon. However, these metastatic lesions are not routinely confirmed with histology.MethodsWe investigated the histopathologic features of 13 cases of UC with biopsy-proven distant metastases, with a special emphasis on histologic variants and tumor budding.ResultsLymph nodes (6/13, 46%) were the most common metastatic sites, followed by the lung (4/13, 31%), liver (4/13, 31%), and the adrenal gland (2/13, 15%). The histologic variants including squamous (n = 1), micropapillary (n = 4), and plasmacytoid (n = 1) variants in five cases of UC. Most histologic variants (4/5, 80%) of primary UCs appeared in the metastatic lesions. In contrast, high-grade tumor budding was detected in six cases (46%), including one case of non-muscle invasive UC. Our study demonstrates that histologic variants are not uncommonly detected in distant metastatic UCs. Most histologic variants seen in primary UCs persist in the distant metastatic lesions. In addition, high-grade tumor budding, which occurs frequently in primary tumors, may contribute to the development of distant metastasis.ConclusionsTherefore, assessing the presence or absence of histologic variants and tumor budding in UCs of the urinary bladder, even in non-muscle invasive UCs, may be useful to predict distant metastasis.

Manganese Porphyrin and Radiotherapy Improves Local Tumor Response and Overall Survival in Orthotopic Murine Mammary Carcinoma Models.

Novel synthetic compounds, known as manganese porphyrins (MnPs), have been designed to shift the redox status of both normal cells and cancer cells. When MnPs are coupled with cancer therapies, such as radiation, they have been shown to sensitize tumor cells to treatment and protect normal tissues from damage through the modulation of the redox status of various tissue types. Until now, our preclinical studies have focused on local effects of MnPs and radiation; however, we recognize that successful outcomes for cancer patients involve control of tumor cells throughout the body. In this study, using murine orthotopic mammary tumor models, we investigated how MnPs and radiation influence the development of distant metastasis. We hypothesized that the combination of MnP (MnP/RT), such as MnTnBuOE-2-PyP5+ and radiation treatment (RT) would increase local tumor control via a shift in the intratumoral redox environment, leading to subsequent downregulation of HIF-1 in the primary tumor. Secondarily, we hypothesized that these primary tumor treatment effects would result in a reduction in pulmonary metastatic burden. Balb/c mice with orthotopic 4T1 mammary carcinomas were treated with saline, MnP, RT or MnP/RT. We found MnP/RT did extend local tumor growth delay and overall survival compared to controls and was associated with increased intratumoral oxidative stress. However, the primary tumor growth delay observed with MnP/RT was not associated with a reduced pulmonary metastatic burden. Future directions to investigate the effects of MnP/RT on the development of distant metastasis may include modifications to the radiation dose, the experimental timeline or using a murine mammary carcinoma cell line with a less aggressive metastatic behavior. Clinical trials are underway to investigate the clinical utility of MnTnBuOE-2-PyP5+ for patients undergoing radiotherapy for various tumor types. The promising preclinical data from this study, as well as others, provides support that MnP/RT has the potential to improve local tumor control for these patients.

Incidence and prognosis of distant metastasis in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are a type of soft tissue sarcomas (STS) with recurrence and metastatic potential. We aimed to investigate the risk factors for developing distant metastases (DM) and to identify the prognostic factors in patients with DM. Based on the Surveillance, Epidemiology, and End Result (SEER) database, MPNST patients diagnosed between 2010 and 2016 were extracted in our study. The logistic regression model was performed for predicting DM development while the Cox proportional hazard regression model was conducted for revealing the prognostic factors. Eventually, 764 patients diagnosed with MPNSTs were included with 109 cases presenting with metastases at initial diagnosis. Larger tumor size and lymph node metastases were independent risk factors for developing DM. The median overall survival (OS) for patients with metastases was 8.0 (95% CI: 6.1-9.9) months. Multiple metastatic sites and no surgical treatment were prognostic factors for worse survival. Tumors located in non-head and neck region were related with better survival. The incidence of DM was 14.3% with a dismal median OS of 8.0months for metastatic MPNSTs. More evaluation should be applied for patients with large tumor size and lymph metastases. Tumors located in head and neck region and the presence of multiple metastases predicted worse survival outcome. Surgical treatment can significantly improve the survival of MPNST patients with distant metastasis.

Nucleolar protein 10 (NOP10) predicts poor prognosis in invasive breast cancer

PurposeNucleolar protein 10 (NOP10) is required for ribosome biogenesis and telomere maintenance and plays a key role in carcinogenesis. This study aims to evaluate the clinical and prognostic significance of NOP10 in breast cancer (BC).MethodsNOP10 expression was assessed at mRNA level employing the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1980) and Cancer Genome Atlas (TCGA) BC cohorts (n = 854). Protein expression was evaluated on tissue microarray of a large BC cohort (n = 1081) using immunohistochemistry. The correlation between NOP10 expression, clinicopathological parameters and patient outcome was assessed.ResultsNOP10 expression was detected in the nucleus and nucleolus of the tumour cells. At the transcriptomic and proteomic levels, NOP10 was significantly associated with aggressive BC features including high tumour grade, high nucleolar score and poor Nottingham Prognostic Index. High NOP10 protein expression was an independent predictor of poor outcome in the whole cohort and in triple-negative BC (TNBC) class (p = 0.002 & p = 0.014, respectively). In chemotherapy- treated patients, high NOP10 protein expression was significantly associated with shorter survival (p = 0.03) and was predictive of higher risk of death (p = 0.028) and development of distant metastasis (p = 0.02) independent of tumour size, nodal stage and tumour grade.ConclusionHigh NOP10 expression is a poor prognostic biomarker in BC and its expression can help in predicting chemotherapy resistance. Functional assessments are necessary to decipher the underlying mechanisms and to reveal its potential therapeutic values in various BC subtypes especially in the aggressive TNBC class.

66P The TILs near solid structures is a potential prognostic factor of distant metastases in the luminal HER2-negative breast cancer

The phenomenon of intratumoral morphological heterogeneity is associated with both the progression of the disease and chemosensitivity and chemoresistance. However, there are very few data about the microenvironment heterogeneity near morphological structures in breast cancer patients of various molecular subtypes. This phenomenon may underlie the failure of tumor-infiltration lymphocytes as a prognostic factor in luminal forms of breast cancer. 152 patients with IC NST (T1–3N0–2M0) aged 29 to 75 years were enrolled in the study. The molecular subtype was determined using immunohistochemical analysis of the expression of estrogen and progesterone receptors, Ki-67 and Her2/neu. TILs were assessed in accordance with the recommendations of the International TILs Working Group It was shown that TILs near the various morphological structures is heterogeneous only in luminal Her2-negative patients. In addition, was found that the development of distant metastases and worse metastatic-free survival in this cohort of patients is associated with a high (more than 5%) TILs near solid structures and also depended on Ki-67 level. TILs near solid structures is a potential prognostic factor for the development of distant metastasis in the luminal Her2-negative and Ki-67 level less 20% subtype of IC NST. The study was supported by the Russian Science Foundation (grant #20-75-10033).

Ephrin Receptors (Eph): EphA1, EphA5, and EphA7 Expression in Uveal Melanoma-Associations with Clinical Parameters and Patient Survival.

Uveal melanoma is the most common primary intraocular malignancy in adults. The development of distant metastases is associated with a poor prognosis. Ephrine receptors (Eph) are the largest subpopulation of tyrosine kinase receptors. They play an important role in processes related to the formation and progression of cancer. The aim of the study was to evaluate the expression of ephrin receptors EphA1, EphA5, and EphA7 in uveal melanoma and its associations with clinicopathological parameters, overall survival, and disease-free survival. The study included 94 previously untreated patients who underwent enucleation due to uveal melanoma. High expression of EphA1 was positively correlated with a smaller tumor size, less frequent extra-scleral extension, lower mitotic activity, and more frequent vitreous hemorrhage. High expression of EphA5 was associated with less frequent chromosome 3 loss, absence of distant metastases, and more frequent vitreous hemorrhage. High expression of EphA7 was associated with a more frequent primary tumor location in the posterior pole. High EphA5 expression was associated with longer overall survival time. The above findings indicate that high expression of EphA1 and EphA5 can be considered a beneficial prognostic factor in uveal melanoma.

Clinicopathologic Features of Cutaneous Malignant Melanoma and Their Impact on Prognosis.

Introduction: Melanoma ranks 19th among malignancies overall and second among cutaneous types. The incidence worldwide has been on the rise over the last seven decades. Various prognostic factors have been assessed and found to have a profound impact on patient outcome. However, no such studies have been attempted in our population. Our study aimed to have an insight into the behavior of malignant melanoma in our population.Materials and Methods: Cases of cutaneous malignant melanoma treated and followed up at our institute were included in this study. Cases of mucosal and choroidal melanoma were excluded. The parameters noted were age, gender, tumor thickness, Clark level, and presence of ulceration. These parameters were individually correlated with development of distant metastasis, two-year survival, survival duration, and primary tumor and lymph node stage. Appropriate statistical analyses were done.Results: Thirty patients of cutaneous malignant melanomas were treated and followed up at our institution. There was male predilection of 1:1.5. Mean age at diagnosis was 50.1 years. Two-year survival was significantly better in females. Sun-exposed areas of the skin were most commonly involved followed by anal canal that has an unusually high incidence in our society. Majority of our cases were pT4(25) on tumor, nodal status, metastasis (TNM) staging at time of diagnosis. Increasing tumor thickness in terms of primary tumor staging was not found to have any significant impact on two-year survival, distant metastasis, lymph node stage, or survival duration. Sixty percent of cases had ulceration. There was no statistically significant effect on two-year survival (78% in ulcerated group vs 75% in nonulcerated group) and distant metastasis (61% vs 58.3%). In terms of Clark level, 20 cases were level V, seven cases were level IV, two were level III, and one was level I. There was no statistically significant difference between the Clark levels in terms of two years survival, development of distant metastasis, and lymph node stages.Conclusion: Melanoma is an aggressive malignancy that causes high morbidity and morality. It commonly presents at an advanced stage at time of diagnosis in our population. Broader studies are required with early-stage melanomas to compare the various prognostic factors and their impact on prognosis.

Machine learning and treatment outcome prediction for oral cancer.

The natural history of oral squamous cell carcinoma (OSCC) is complicated by progressive disease including loco-regional tumour recurrence and development of distant metastases. Accurate prediction of tumour behaviour is crucial in delivering individualized treatment plans and developing optimal patient follow-up and surveillance strategies. Machine learning algorithms may be employed in oncology research to improve clinical outcome prediction. Retrospective review of 467 OSCC patients treated over a 19-year period facilitated construction of a detailed clinicopathological database. 34 prognostic features from the database were used to populate 4 machine learning algorithms, linear regression (LR), decision tree (DT), support vector machine (SVM) and k-nearest neighbours (KNN) models, to attempt progressive disease outcome prediction. Principal component analysis (PCA) and bivariate analysis were used to reduce data dimensionality and highlight correlated variables. Models were validated for accuracy, sensitivity and specificity, with predictive ability assessed by receiver operating characteristic (ROC) and area under the curve (AUC) calculation. Out of 408 fully characterized OSCC patients, 151 (37%) had died and 131 (32%) exhibited progressive disease at the time of data retrieval. The DT model with 34 prognostic features was most successful in identifying "true positive" progressive disease, achieving 70.59% accuracy (AUC 0.67), 41.98% sensitivity and a high specificity of 84.12%. Machine learning models assist clinicians in accessing digitized health information and appear promising in predicting progressive disease outcomes. The future will see increasing emphasis on the use of artificial intelligence to enhance understanding of aggressive tumour behaviour, recurrence and disease progression.

The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation

EPHB6 is a metastasis inhibitory gene that is frequently decreased or deficiency in non-small cell lung cancer (NSCLC), which contributed to the subsequent development of distant metastasis. These suggested the possibility that reactivation of EPHB6 might prevent the metastasis of NSCLC. Nevertheless, EPHB6 expression might also promote cancer cell growth and inhibit cell apoptosis by activating Akt and ERK pathway, apart from inhibition of migration and invasion. In the present study, we developed a novel quinazolin-4(3H)-one analog (DFX24) as a potential PI3Kα inhibitor, which inhibited both cell proliferation and metastasis of NSCLC cell lines. Investigation to the molecular mechanisms revealed DFX24 inhibited the cell growth and metastasis via inhibition of PI3Kα and ERK activity, as well as the increase in EPHB6 expression. In addition, DFX24 also induced cell cycle arrest and tumor cell apoptosis by inhibiting PI3K/Akt pathway and activating mitochondria-dependent pathway, respectively. These findings suggested that DFX24 might be considered as a novel drug candidate and may provide a potential therapy for NSCLC.

Abstract 1175: Race informs survival disparities in head and neck cancer clinical trials

Abstract Background: Survival disparities between blacks and whites in head and neck cancer are well documented, with access to care and socioeconomic status (SES) as major contributors. However, the impact of race alone on survival is much less clear. Previous attempts to evaluate the role of race have been limited by access to care/SES as major confounders. We set out to directly assess the role of race in head and neck cancer by evaluating treatment outcomes of subjects enrolled in clinical trials. In this population, access to care and socioeconomic confounders are minimized because all patients receive identical treatments. Methods: Clinical trial data from the Radiation Therapy Oncology group (now NRG) studies were obtained by request. Seven RTOG Studies (RTOG 0129, 0234, 9003, 9111, 9501, 9512, 9703) were included for study. Studies were included if they were phase II or III trials that employed survival as an endpoint, e.g. progression free survival (PFS), disease free survival (DFS), overall survival (OS). Studies that were small (&amp;lt;200 patients) or did not use survival as an endpoint (e.g. side effect trial) were excluded. For each black patient enrolled in a clinical trial, a white patient matched in the same arm of that trial was used as a control. The study null-hypothesis was that there would be no race derived impact on survival and thus the chance of survival favoring either whites or blacks in each matched pair would be 50%. Results: Across the seven trials, 468 blacks were identified and matched with 468 white study arm specific controls. Whites had better outcomes than blacks in 60% of matched pairs (p&amp;lt;0.001). Blacks were consistently more likely to have worse outcomes. When outcomes were collapsed by PFS/DFS, the failure rate was significantly higher in blacks (HR=1.46, p&amp;lt;0.001)). Failure was largely due to locoregional failure, and blacks were at higher risk (sHR =1.43, p=0.002). The development of distant metastasis within the paired cohorts was not significantly different (sHR=1.15, p=0.38), suggesting that locoregional failure was the major driver of failure. Conclusions: In this analysis of head and neck cancer patients in clinical trials, blacks consistently had worse outcomes in comparison to study arm specific white controls. This suggests that race alone confers a worse survival independent of socioeconomic and access to care factors. Further study is needed to confirm these findings, and to explore other causes underlying this disparity. Citation Format: Jeffrey C. Liu, Brian Egleston, Elizabeth Blackman, Camille Ragin. Race informs survival disparities in head and neck cancer clinical trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1175.

Abstract 1106: Cisplatin-induced activation of SDF-1/CXCR4 axis sustains lung cancer metastasis by promoting co-recruitment of metastasis initiating cells and inflammatory monocytes

Abstract Background: Platinum-based treatment of locally advanced non-small cell lung cancer (NSCLC) provides some clinical benefit in controlling local disease but is ineffective on metastatic dissemination. Rising evidence suggests that chemotherapy can promote an inflammatory reaction supportive of metastasis growth.We previously demonstrated that cisplatin treatment of mouse xenografts enriches for the chemoresistant fraction of CD133+CXCR4+ lung cancer metastasis initiating cells (MICs), increasing distant metastasis development. We hypothesize here that the SDF-1/CXCR4 axis, implied in MICs migration and in stromal cells trafficking, could play a critical role in cisplatin-induced pro-metastatic effects. Results: To study the effects of cisplatin in promoting a pre-metastatic niche, tumor-free naïve SCID mice were treated with cisplatin plus/minus peptide R, a novel inhibitor of CXCR4. Cisplatin resulted in a rapid expansion of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM) in the bone marrow, concomitantly with their recruitment to murine lungs guided by enhanced endothelial release of SFD-1. Tail-vein injection of H460 human lung cancer cells 72h after cisplatin administration resulted in augmented number of lung metastases enriched in CD133+CXCR4+ MICs. We proposed that the abundance of CXCR4+IM together with increased endothelial permeability caused by cisplatin favors tumor cells extravasations and the expansion of MICs through SDF-1/CXCR4 axis activation. Combination treatment with a CXCR4 inhibitor prevented IM recruitment, MICs expansion and consequently abolished metastasis overgrowth induced by cisplatin. Combination treatment of H460 subcutaneous xenografts in a regimen mimicking clinical setting revealed that cisplatin also caused tumor release of SDF-1 able to trigger local expansion of MICs subset and to recruit CXCR4+tumor associated macrophages involved in tumor cells intravasation. Stromal SDF-1 induced by cisplatin at distant site also co-recruited MICs and CCR2+CXCR4+IM, promoting spontaneous metastasis formation that can be counteracted by CXCR4 blockade. We confirmed in clinical setting that platinum-based neoadjuvant treatment of NSCLC patients significantly increases tumor SDF-1 expression. Moreover, an higher expression of tumor SDF-1 after cisplatin neo-adjuvant treatment was associated with patients' shorter DFS (p=0,0056; Hazards Ratio= 3,1) and poor OS (p=0,029; Hazards Ratio= 3,46). Conclusions: Our data reveal a paradoxical pro-metastatic effect of cisplatin that fosters MIC-IM recruitment and cross-talk via SDF-1/CXCR4 axis activation. A new combination strategy based on CXCR4 inhibition may disrupt these interactions, providing more effective results for lung cancer treatment Citation Format: Giulia Bertolini, Valeria Cancila, Orazio Fortunato, Giuseppe Lo Russo, Monica Tortoreto, Giovanni Centonze, Massimo Milione, Claudio Tripodo, Stefania Scala, Gabriella Sozzi, Luca Roz. Cisplatin-induced activation of SDF-1/CXCR4 axis sustains lung cancer metastasis by promoting co-recruitment of metastasis initiating cells and inflammatory monocytes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1106.

Clinicopathologic and survival analysis of patients with adenoid cystic carcinoma of vulva: single-institution experience.

The purpose of this study was to elucidate our experience in the diagnosis and treatment of adenoid cystic carcinoma of the vulva (ACC-vulva) and to assess the clinicopathological characteristics and prognosis among ACC-vulva patients. A retrospective study of seventeen patients was performed to illustrate the demographic information, clinical performance, pathological characteristics, treatment modality, and development of local recurrence or distant metastasis, as well as the survival outcome. The median age at diagnosis was 56years (range, 26-71years). Radical local excision was performed on fifteen patients, and two patient received radical hemi-vulvectomy. Six patients received ipsilateral inguinal lymphadenectomy. Involvement of the resection margin was observed in six patients. The postoperative pathologic diagnosis showed no proof of inguinal lymph node metastasis in all the six patients receiving lymphadenectomy. However, the perineural invasion was observed in all patients. Postoperative adjuvant radiotherapy was applied to five patients who had positive resection margin. The mean survival time except for that in four patients (recent case) was 47.8months (range, 23-78months). Radical resection towards negative margins seems to be acceptable as initial treatment. Adjuvant radiotherapy is a preferable treatment modality for patients with high-risk factors pathologically or patients with local recurrence.

Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients.

High-grade serous ovarian carcinoma (HGSOC) usually spreads directly into the peritoneal cavity following a transcoelomic dissemination route, although distant hematogenous metastasis exist and have been reported. However, no tumor markers can currently predict the risk of distant metastases in HGSOC. Claudins, belonging to tight-junction proteins, are dysregulated in HGSOC and functionally related to cancer progression. Here we analyzed claudin-3, -4, and -7 expression as potential markers of distant metastases. Using quantitative RT-PCR and immunohistochemistry we assessed the expression of claudins in primary HGSOC tissues, normal ovarian, and normal fallopian tube epithelia and correlated it with clinicopathological features, including the site of metastasis and the route of dissemination. Gene set enrichment analysis was performed on microarray-generated gene expression data to investigate key pathways in patients with distant metastases. We found the overall expression level of claudin-3, -4, and -7 mRNA decreased in HGSOC compared to normal tubal epithelium, currently considered the potential site of origin of many HGSOC. The reduced expression of claudin-7 is significantly associated with the development of distant metastases (p = 0.016), mainly by hematogenous route (p = 0.025). In patients with diminished expression of claudin-7, immunohistochemical staining revealed a heterogeneous pattern of membranous staining with discontinuous expression of claudin-7 along the cell border, indicative of a dischoesive architecture. The estimated reduction in the probability of distant disease is of 39% per unit increase in the level of claudin-7 (p = 0.03). Genes involved in epithelial to mesenchymal transition, hypoxia, and angiogenesis processes resulted strongly associated to hematogenous recurrence. Our data suggest a potential role of claudin-7 in discriminating distant metastatic events in HGSOC patients. The quantification of its expression levels could be a useful tool to identify patient deserving a personalized follow-up in terms of clinical and radiological assessment.

The role of cell adhesion molecule in cancer progression and its application in cancer therapy.

Multiple and diverse cell adhesion molecules take part in intercellular and cell-extracellular matrix interactions of cancer. Cancer progression is a multi-step process in which some adhesion molecules play a pivotal role in the development of recurrent, invasive, and distant metastasis. A growing body of evidence indicates that alterations in the adhesion properties of neoplastic cells play a pivotal role in the development and progression of cancer. Loss of intercellular adhesion and the desquamation of cells from the underlying lamina propria allows malignant cells to escape from their site of origin, degrade the extracellular matrix, acquire a more motile and invasion phenotype, and finally, invade and metastasize. In addition to participating in tumor invasiveness and metastasis, adhesion molecules regulate or significantly contribute to a variety of functions including signal transduction, cell growth, differentiation, site-specific gene expression, morphogenesis, immunologic function, cell motility, wound healing, and inflammation. Cell adhesion molecule (CAM), a diverse system of transmembrane glycoproteins has been identified that mediates the cell-cell and cell-extracellular matrix adhesion and also serves as the receptor for different kinds of virus. We summarize recent progress regarding the role of CAM, particularly, immunoglobulin-CAMs and cadherins in the progression of cancer and discuss the potential application of CAMs in the development of cancer therapy mainly on urogenital cancer.

Abstract A64: Functional genomics of metastatic Ewing sarcoma

Abstract Ewing sarcoma (ES) is a poorly differentiated bone and soft tissue tumor of high metastatic potential. ES mainly affects children, adolescents, and young adults (AYAs) at a frequency of ~1.5 cases per million globally. Ewing neoplasms strikingly converge on a single recurrent initiating event, which is a chromosomal translocation that generates a fusion transcript between the EWSR1 gene and a gene of the ETS family of transcription factors, most commonly FLi1 (85%). After 20 years since the discovery of the EWS-FLi1 fusion, ES remains a clinical challenge with unacceptably low survival rates, primarily due to metastasis. The bulk of research conducted to date (&amp;gt;95%) being focused on the primary tumor has resulted in a critical knowledge gap. To address this issue and unravel the dysregulated pathways in ES tumor evolution and metastatic dissemination, we harnessed the genome-wide insertional mechanism of transposons and the transduction efficiency of lentiviruses to engineer ES cell models. Human mesenchymal stem cells (hMSC), the putative cells of origin of ES, were engineered to constitutively express EWS-Fli1 accompanied by the inducible expression of a highly active transposase. Upon activation of the former, transposon-mediated mutagenesis will activate oncogenes and inactivate tumor suppressor genes, to mediate transformation of the transduced that can now engraft when implanted in recipient mice. Xenografted tumors are resected and the mice observed for development of distant metastases. Matching primary and metastatic tumors are sequenced to uncover the genes commonly affected by transposition in the two compartments. Pathway-oriented bioinformatic analysis will further reveal candidate metastatic driver genes. Matching of the targeted pathways with drugs will be used to validate the candidates by in vitro and in vivo metastasis assays. Citation Format: Wajih Jawhar, Paul Waterhouse, Rama Khokha, Takeaki Ishii, Robert Turcotte, Nada Jabado, Livia Garzia. Functional genomics of metastatic Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A64.

The UPMC Hillman Cancer Center Approach to the Management of Colorectal Cancer During the COVID-19 Pandemic Era

The UPMC Hillman Cancer Center Approach to the Management of Colorectal Cancer During the COVID-19 Pandemic Era

Predictive Factors of Positive Circumferential and Longitudinal Margins in Early T3 Colorectal Cancer Resection.

Background Malignant involvement of circumferential resection margin (CRM) and longitudinal resection margin (LRM) after surgical resection of colorectal cancer (CRC) are associated with higher rates of recurrence and development of distant metastasis. This can influence the overall patient's prognosis. The aim of the current study was to identify pathological factors as predictors for the involvement of resection margins in early T3 CRC. Patients and Methods. Fifty patients radiologically diagnosed to have cT3a/b (CRC) were included in the study. After resection, the pathological examination was performed to identify patients with positive CRM and/or LRM. Relations between the different pathological parameters and the CMR and LRM involvements were assessed. Results Positive CRM was present in 17 cases (34%), while positive LRM was found in 6 cases (12%). The involvement of both margins was significantly associated with rectal tumors and tumors with infiltrative gross appearance, grade III, deeper invasion, and positive lymph node metastases. Also, there was a significant association between both margins' positivity and other pathological parameters as signet ring carcinoma, tumor budding, perineural and vascular invasion, high microvessel density (MVD), and sinusoidal vascular pattern, while the presence of necrosis and infiltrative advancing tumor front was significantly associated with CRM involvement only. The depth of tumor invasion and signet ring carcinoma were identified as independent predictor factors for positive CRM and LRM, respectively. Conclusion Preoperative identification of these pathological parameters can be a guide to tailor the management plan accordingly.

MiR-34c downregulation leads to SOX4 overexpression and cisplatin resistance in nasopharyngeal carcinoma

BackgroundA major cause of disease-related death in nasopharyngeal carcinoma (NPC) is the development of distant metastasis (DM) despite combination chemoradiotherapy treatment. We previously identified and validated a four microRNA (miRNA) signature that is prognostic for DM. In this study, characterization of a key component of this signature, miR-34c, revealed its role in chemotherapy resistance.MethodsTwo hundred forty-six NPC patient biopsy samples were subject to comprehensive miRNA profiling and immunohistochemistry (IHC). Two human normal nasopharyngeal cell lines (immortalized; NP69 and NP460), as well as the NPC cell line C666–1, were used for miR-34c gain-of-function and loss-of-function experiments. Signaling pathways were assessed using quantitative real-time PCR (qRT-PCR) and Western blot. Cell viability was measured using the ATPlite assay.ResultsMiR-34c was downregulated in NPC patient samples, and confirmed in vitro to directly target SOX4, a master regulator of epithelial-to-mesenchymal transition (EMT). MiR-34c downregulation triggered EMT-representative changes in NP69 and NP460 whereby Snail, ZEB1, CDH2, and SOX2 were upregulated, while Claudin-1 and CDH1 were downregulated. Phenotypically, inhibition of miR-34c led to cisplatin resistance, whereas miR-34c over-expression sensitized NPC cells to cisplatin. TGFβ1 decreased miR-34c and increased SOX4 expression in vitro. The TGFβ receptor 1 inhibitor SB431542 reduced SOX4 expression and increased cisplatin sensitivity. Finally, IHC revealed that lower SOX4 expression was associated with improved overall survival in chemotherapy-treated NPC patients.ConclusionmiR-34c is downregulated in NPC. Repression of miR-34c was shown to increase SOX4 expression, which leads to cisplatin resistance, while TGFβ1 was found to repress miR-34c expression. Taken together, our study demonstrates that inhibition of the TGFβ1 pathway could be a strategy to restore cisplatin sensitivity in NPC.