Removal Of Primary Tumor Research Articles

Application of rigid curved laryngoscope in the examination of hypopharynx and the treatment of early hypopharyngeal cancer

Objective: To evaluate the efficacy of curved suspension laryngoscope assistant transoral surgery (CLATOS) in the examination of hypopharynx, and diagnosis and surgery of early hypopharyngeal carcinoma. Methods: Thirty-four patients who underwent detailed examination for lower part of hypopharynx and surgery for early hypopharyngeal carcinoma with CLATOS technique in the Second Affiliated Hospital of Harbin Medical University from January 2019 to January 2020 were analyzed retrospectively. The age ranged from 42 to 74 years old including 28 males and 6 females. Among them, 25 patients complaining of foreign body sensation in the pharynx for more than half a year with a poor exposure of the lower pharynx in the examination with flexible laryngoscope in the outpatient department were admitted to the hospital for the further examination with rigid curved laryngoscopy and 9 patients with stage T1-2 hypopharyngeal squamous cell carcinoma were operated with CLATOS technique. Preoperative, intraoperative and postoperative data were analized. Results: One case of squamous cell carcinoma in esophageal entrance (T1N0M0) and one case of carcinoma in pyriform sinus (T1N0M0) with cervical esophageal carcinoma (T1N0M0) were found in the 25 patients with foreign body sensation in the pharynx. En bloc resection of cancer was obtained in 9 patients with stage T1-2 hypopharyngeal carcinomas and 2 of them underwent tracheotomy. One patient with T1 retrocricoid carcinoma was found to have a carcinoma in situ at the lower part of posterior hypopharyngeal wall in the examination during follow-up, which was resected simultaneously. Postoperatively this patient developed a stenosis in the esophageal entrance, which was dilated twice until swallowing normally. Two patients of T2N0M0 and one of T2N1M0 underwent bilateral neck lymph node dissection just after the removal of primary tumors. During follow-up, none of the 9 patients showed tumor recurrence and complications such as dysphonia and dyspnea. Conclusion: CLATOS technique can provide a promising way in the examination of hypopharynx and the detection of early lesions of hypopharynx and esophageal entrance, and this technique has also the advantages such as full visual angle and easy operation for the resection of early hypopharyngeal carcinoma. The quality of life of patients can be improved while the tumor is removed en bloc with this technique.

Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice

BackgroundImmunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not...

Aggressive Local Treatment Improves Survival in Stage IV Breast Cancer With Synchronous Metastasis.

IntroductionTo investigate the effect of local treatment strategy on survival outcome in de novo stage IV breast cancer patients who received chemotherapy.MethodsWe identified stage IV breast cancers that presented with synchronous metastasis from the Surveillance, Epidemiology, and End Results database. Binomial logistic regression, Kaplan–Meier survival curves, propensity score matching (PSM), and multivariate Cox regression model were used for statistical analyses.ResultsWe identified 5,374 patients in total, including 2,319 (43.2%), 2,137 (39.8%), and 918 (17.1%) patients who received surgery alone, surgery+radiotherapy, and radiotherapy alone, respectively. The probability of patients receiving surgery alone decreased over time, and the probability of patients receiving radiotherapy alone increased over time. However, no significant difference was observed in the probability of patients receiving postoperative radiotherapy (P = 0.291). The 3-year breast cancer-specific survival (BCSS) in patients treated with surgery alone, radiotherapy alone, and surgery+radiotherapy was 57.1, 35.9, and 63.9%, respectively (P < 0.001). The local treatment strategy was the independent prognostic factor related to BCSS. Using surgery alone as the reference, radiotherapy alone was related to lower BCSS (P < 0.001), while additional radiotherapy after surgery improved BCSS (P < 0.001). Similar results were observed using PSM.ConclusionsCompared to radiotherapy alone, surgery to the primary site may confer a survival benefit in stage IV breast cancer with synchronous metastasis, and additional postoperative radiotherapy further improves outcome after primary tumor removal. Local treatment can only be an option in highly selected patients with de novo stage IV disease in the treatment guidelines. More prospective studies are needed to investigate the role of local management for this patient subset.

The effect of local anesthetic technique on breast cancer - related outcomes: a systematic review

Introduction: Breast cancer is the most incident cancer in women worldwide. A multidisciplinary therapeutic approach may increase survival rates and quality of life, and surgery remains its main support. Surgical removal of the primary tumor occurs with the risk of dispersal of neoplastic cells into the blood and lymphatic systems, as well as the risk of permanence of residual neoplastic cells. Despite curative intent, a combination of perioperative factors leads to a release of chemical mediators that may, paradoxically, be direct or indirectly associated with tumor progression. Local anesthetic technique, as thoracic paravertebral block (TPVB), attenuates neuroendocrine response to surgical stress and may preserve perioperative immune function. Given that surgical stress response seems to increase opportunities for cancer dissemination and metastasis, this anesthetic approach is hypothesized as beneficial to long-term prognosis. The objective of this study was to evaluate the effect of local anesthetic technique on breast cancer-related outcomes in the clinical setting.Methodology: The PubMed database was assessed through Mesh descriptors: “mastectomy”, “mastectomy, radical”, “anesthesia, local”, “recurrence”, “neoplasm recurrence, local”. Reviews, editorials and comments were excluded. The search provided 65 articles, from which 11 were identified as potentially relevant after title and abstract reading. After integral articles analysis, 6 studies were selected.Results: The articles were published from 2006 to 2019, with total samples varying between 129 and 2108 patients. Of these studies, 4 were retrospective, 1 presented a retrospective review of prospective database, and only 1 was a multicenter randomized clinical trial. The average observation time varied between 28.8 to 72 months, and 1 study was stopped after a preplanned futility boundary was crossed. Discussion: The majority of the selected studies are retrospective, being conditioned to the accuracy and availability of the information. Also, some assessed outcomes may be influenced by unmeasured factors, what could be confounding. The majority of the studies did not show improvement in cancer-related outcomes with the usage of TPVB, however, it may reduce the administration of perioperative opioids and be a feasible therapeutic approach to reduce postoperative pain intensity in breast cancer treatment, becoming a relevant intervention to facilitate recovery, accelerate hospital discharge and reduce care costs after the surgery.Conclusion: Although preclinical studies have suggested potential benefits of local anesthesia to reduce cancer recurrence and improve overall survival, this review did not find enough clinical evidence to support thoracic paravertebral block for this purpose in breast cancer surgery. However, local anesthesia may impact the reduction of intraoperative opioid and support pain management in the postoperative period, potentially improving patient’s health-related quality of life.

Colorectal Tumor Microenvironment‐Activated Bio‐Decomposable and Metabolizable Cu2O@CaCO3 Nanocomposites for Synergistic Oncotherapy

Rational design of tumor microenvironment (TME)-activated nanocomposites provides an innovative strategy to construct responsive oncotherapy. In colorectal cancer (CRC), the specific physiological features are the overexpressed endogenous H2 S and slightly acidic microenvironment. Here, a core-shell Cu2 O@CaCO3 nanostructure for CRC "turn-on" therapy is reported. With CaCO3 responsive to pH decomposition and Cu2 O responsive to H2 S sulfuration, Cu2 O@CaCO3 can be triggered "on" into the therapeutic mode by the colorectal TME. When the CaCO3 shell decomposes and releases calcium in acidic colorectal TME, the loss of protection from the CaCO3 shell exposes the Cu2 O core to be sulfuretted by H2 S to form metabolizable Cu31 S16 nanocrystals that gain remarkably strong near-infrared absorption. After modifying hyaluronic acid, Cu2 O@CaCO3 can achieve synergistic CRC-targeted and TME-triggered photothermal/photodynamic/chemodynamic/calcium-overload-mediated therapy. Moreover, it is found that the generation of hyperthermia and oxidative stress from Cu2 O@CaCO3 nanocomposites can efficiently reprogram the macrophages from the M2phenotype to the M1 phenotype and initiate a vaccine-like immune effect after primary tumor removal, which further induces an immune-favorable TME and intense immune responses for anti-CD47 antibody to simultaneously inhibit CRC distant metastasis and recurrence by immunotherapy.

Primary tumor removal improves the prognosis in patients with stage IV breast cancer: A population-based study (cohort study).

Adjuvant therapy including chemotherapy, hormonal therapy, and radiotherapy were often used as a common stereotypy for female stage IV breast cancer rather than surgery. This study aimed to define the role of local surgery in metastatic breast cancer. Female metastatic breast cancer patients were identified in the Surveillance, Epidemiology, and End Results (SEER) program data (2010-2013). We compared survival time between patients who received primary tumor removal (PTR) versus those who did not. Multivariate Cox regression models and competitive risk models were built to adjust potential confounders. Of 7669 female stage IV breast cancer patients, 2704 (35.3%) had surgery on their breast tumor and 4965 (64.7%) did not. In the entire cohort, women who underwent PTR had a 45% reduced risk of breast cancer-related death (multi-adjusted hazard ratio [HR], 0.55; 95% CI, 0.50 to 0.60) compared with women who did not undergo PTR (P<0.001). In a cause-specific hazard model (CS model), the multivariable HRs (95% CI) for the association of PTR with breast cancer related-death were 0.54 (0.50-0.60) in the multivariate-adjusted analysis. Similar results were also observed in the sub-distribution hazard function model (SD model) with corresponding multivariate HRs (95%CI) of 0.57 (0.52-0.63). Our study suggested that PTR was associated with improved survival in female stage IV breast cancer patients. The role of PTR in these patients needs to be re-evaluated.

Interpreting Breast Cancer Survival Data by the Hazard Function: Remarkable Findings from Event Dynamics.

The report addresses the role of the hazard function in the analysis of disease-free survival data in breast cancer. An investigation on local recurrences after mastectomy provided evidence that uninterrupted growth is inconsistent with clinical findings and that tumor dormancy could be assumed as working hypothesis to understand the clinical course of the disease. Additionally, it was deemed that the lag-time between primary tumor removal and tumor recurrence is dynamically dependent on the subclinical metastasis development within the host-tumor system and, therefore, may be informative about the biology of the disease. Accordingly, the hazard function, which estimates the event risk pattern through the time, was adopted to analyze survival data. The multipeak pattern of the hazard function suggested that the process metastasis development has discontinuous features. A new paradigm of breast cancer metastatic development was proposed, involving the notions of tumor homeostasis, tumor quiescence in specific metastatic microscopic phases and surgery-related acceleration of the metastatic process. All analyses by prognostic factors (e.g., by menopausal status) or treatment modalities (e.g., by adjuvant chemotherapy) or other parameters (e.g., site of metastasis), provided coherent data in agreement with the model. The hazard rate function allowed addressing several clinical questions including meaning of ipsilateral breast tumor recurrence (IBTR), oncologic effect of delayed breast reconstruction, surgery related metastasis acceleration, possible role of anti-inflammatory drugs and body mass index (BMI) to modulate the recurrence risk. We conclude that the hazard function is a powerful tool to investigate the post-surgical course of early breast cancer and other operable tumors and to make inferences on their biology.

Preclinical efficacy of CIGB-300, an anti-CK2 peptide, on breast cancer metastasic colonization

CK2 is a serine/threonine kinase that is overexpressed in breast cancer and its inhibition is associated to reduced tumor growth and disease progression. CIGB-300 is an antitumor peptide with a novel mechanism of action, since it binds to protein kinase CK2 catalytic subunit alpha and to CK2 substrates thus preventing the enzyme activity. Our aim was to evaluate the potential therapeutic benefits of CIGB-300 on breast cancer disease using experimental models with translational relevance. We demonstrated that CIGB-300 reduces breast cancer cell growth in MDA-MB-231, MCF-7 and F3II cells, exerting a pro-apoptotic action and cell cycle arrest. We also found that CIGB-300 decreased cell adhesion, migration and clonogenic capacity of malignant cells. Effect on experimental breast cancer lung metastasis was evaluated after surgical removal of primary F3II tumors or after tail vein injection of tumor cells, also we evaluated CIGB-300 effect on spontaneous lung metastasis in an orthotopic model. Systemic CIGB-300 treatment inhibited breast cancer colonization of the lung, reducing the size and number of metastatic lesions. The present preclinical study establishes for the first time the efficacy of CIGB-300 on breast cancer. These encouraging results suggest that CIGB-300 could be used for the management of breast cancer as an adjuvant therapy after surgery, limiting tumor metastatic spread and thus protecting the patient from distant recurrence.

Molecular Subgroups of Endometrial Carcinoma in Romanian Patients

Molecular classification of endometrial carcinoma (EC) has represented a breakthrough ever since the TCGA (The Cancer Genome Atlas) project published it in 2013. Four distinct molecular subgroups were recognized based on somatic copy number alterations and tumor mutational burden: POLE (polymerase-epsilon) ultramutated, MSI (microsatellite instability) hypermutated (MSI-H), copy number low (CNL) and copy number high (CNH). However, implementing a standardized algorithm in current practice is far from being definitive. Our purpose in this study was to determine different molecular subgroups in a cohort of Romanian patients using cost effective and available immuno-histochemistry markers and outline statistical associations with different parameters. Tissue microarrays encompassing 50 cases with previously diagnosed ECs were tested for ER, PR, HER2, p53, MSH6 and PMS2 and results showed 68% MSI-H cases with statistical correlation with tumor size ] 2 cm (p=0.028) and no association with overall survival. CNH ECs were reported in 26% of cases and showed important statistical significance with TILs (p=0.041) and no correlations with overall survival. The CNL subgroup was reported in 74% of ECs cases and showed statistical significance with the histopathological subtype (p=0.006), pT (removal of primary tumor according to AJCC/UICC convention) (p=0.033), risk category according to ESMO (European Society of Medical Oncology) criteria (p=0.022) and ER expression (p=0.002). Five-year overall survival was 84%. Molecular classification is an important additional tool in current pathology guidelines for reporting ECs, but it is not currently standardized or available in all laboratories. Its importance in evolving treatment strategies for this disease is well documented so we strongly recommend routine testing for molecular prognostic factors.

Abstract 6232: Preclinical efficacy of CIGB-300, an anti-CK2 peptide, on breast cancer metastasic colonization

Abstract CK2 is a serine/threonine kinase that is overexpressed in breast cancer and its inhibition is associated to reduced tumor growth and disease progression. With more than three hundred substrates, this kinase is involved in a large number of cellular functions, such as replication, cell proliferation, differentiation, regulation of apoptosis and angiogenesis. CIGB-300 is an antitumor peptide with a novel mechanism of action, since it binds to the phospho-acceptor domain of CK2 substrates impairing the correct phosphorylation by the enzyme. Our aim was to evaluate the potential therapeutic benefits of CIGB-300 on breast cancer disease using experimental models with translational relevance. We demonstrated that CIGB-300 reduces breast cancer cell growth in MDA-MB-231, MCF-7 and F3II cells, exerting a pro-apoptotic action. We found that CIGB-300 increased Bax and decreased Bcl-2 expression, so the intrinsic pathway was involved in the proapoptotic effect of CIGB-300 in breast cancer cells. Moreover, CIGB-300 inhibits the CK2-mediated phosphorylation of B23, such phosphorylation impairment was correlated with the ability of CIGB-300 to induce nucleolar disassembly. Also, we investigate whether CIGB-300 affects the sensitivity of tumor cells to chemotherapeutic agents. We evaluated the effects of the combination of CIGB-300 and cisplatin on cell viability and apoptosis. We demonstrated that CIGB-300 sensitize breast cancer cells to cisplatin, reducing cell viability and increasing apoptosis. In vivo, the effect on experimental breast cancer lung metastasis was evaluated after surgical removal of primary F3II tumors or after tail vein injection of tumor cells. Systemic CIGB-300 treatment inhibited breast cancer colonization of the lung, reducing the size and number of metastatic lesions. The present preclinical study establishes for the first time the efficacy of CIGB-300 on breast cancer. These encouraging results suggest that CIGB-300 could be used for the management of breast cancer as an adjuvant therapy after surgery, limiting tumor metastatic spread and thus protecting the patient from distant recurrence. Citation Format: Maria F. Gottardo, Johanna E. Sidabra, Carla S. Capobianco, Juan Garona, Silvio Perea Rodriguez, Daniel F. Aonso, Hernan G. Farina. Preclinical efficacy of CIGB-300, an anti-CK2 peptide, on breast cancer metastasic colonization [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 6232.

Carcinoma Showing Thymus-Like Differentiation (CASTLE) Arising in the Sublingual Gland

Carcinoma showing thymic-like differentiation (CASTLE) is a rare tumor most commonly occurring in the thyroid and soft tissues of the neck. We report the first case of CASTLE occurring in the sublingual gland. The patient, a 35-year-old healthy man, presented with a submucosal lesion located in the anterior right floor of the oral cavity and an ipsilateral neck mass. The lesion had been previously investigated by neck computed tomography and ultrasound-guided fine needle aspiration cytology and diagnosed as metastatic squamous cell carcinoma. After oral cavity magnetic resonance imaging, positron emission tomography, and a non-diriment, fine needle aspiration cytology of the sublingual mass, the patient was treated as affected by a sublingual gland malignancy with removal of primary tumor and neck dissection. Morphological and immunohistochemical findings were diagnostic for primary sublingual gland CASTLE. The patient received adjuvant radiotherapy and is free of disease 2 years after treatment. We describe the pathological features of the lesion and discuss the possible differential diagnoses.

Abstract PR13: Surgical excision of the primary tumor in osteosarcoma model results in enhanced metastatic growth by modulating the lung immune microenvironment

Abstract Surgery has been shown to enhance metastasis in a number of cancers. To examine this in the context of osteosarcoma, we implanted syngeneic murine K7M2 cells into the tibia of BALB/c mice, which we had shown previously to result in immediate seeding of K7M2 cells into the lung. One week post-implantation, mice were assigned to either control or surgical groups and all mice were euthanized at week 4 post-implantation. Mice that underwent amputation of the primary tumor displayed an increase in the number of pulmonary surface nodules as compared to tumor-bearing control animals (17 vs. 9.5; p&amp;lt;0.05), showing that excision of the primary tumor indeed enhances metastasis in this model. As we previously showed that K7M2 metastasis without surgical intervention is strongly inhibited by re-educating tumor-associated macrophages (TAMs) with gefitinib, we also examined the effect of gefitinib on surgery-accelerated metastasis. We found that perioperative gefitinib abrogated the effects of primary tumor removal on the development of pulmonary metastases (17 vs. 6; p&amp;lt; 0.01), strongly suggesting that TAMs also mediate surgery-accelerated metastasis. To examine changes in the pulmonary immune milieu, we utilized the same model of surgery-accelerated metastasis. Lungs were homogenized and immune cell populations were analyzed using flow cytometric analysis at 48 hours and 3 weeks after surgery. We found that surgery caused a significant reduction in antitumor macrophages, identified by MHCII positivity (21.1% vs. 13.2%; p&amp;lt;0.01), and a significant increase in protumor macrophages, identified by CD206 positivity (33.0% vs. 42.4%; p&amp;lt;0.01), at 48 hours after surgical resection. There was no change in the proportion of CD4+ or CD8+ T cells at this time point. At 3 weeks post-surgery the proportion of macrophage populations became similar for both groups, but there was now a small but significant reduction in the CD4+ and CD8+ T cells in the surgical group (68.4% vs. 60.3%; p&amp;lt;0.05 and 25.0% vs. 19.3%; p&amp;lt;0.01). In conclusion, surgical removal of the primary tumor accelerated the growth of pulmonary metastases in a murine model of OS. Gefitinib was able to abrogate this effect, suggesting macrophages as key cellular mediators. Furthermore, surgery altered the macrophage phenotype within the lungs in the acute postoperative period toward a protumor state, subsequently reducing the CD4+ or CD8+ T-cell populations. Taken together these data suggest that surgery contributes to enhanced metastatic outgrowth by altering the immune microenvironment to an immunosuppressive and protumor state. This abstract is also being presented as Poster B38. Citation Format: Michelle P. Kallis, Caroline Maloney, Morris Edelman, Samuel Z. Soffer, Marc Symons, Bettie M. Steinberg. Surgical excision of the primary tumor in osteosarcoma model results in enhanced metastatic growth by modulating the lung immune microenvironment [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 PR13.

Prostate cancer liver metastasis: Dormancy and resistance to therapy.

Liver metastasis causes nearly half of death from solid tumors. Metastatic lesions, to the liver in particular, can become detectable years or decades after primary tumor removal, leaving an uncertain long-term prognosis in patients. Prostate cancer (PCa), a prominent metastatic dormant cancer, has the worst prognosis when found in the liver compared to other metastatic sites. These metastatic nodules display a therapy resistance in the liver pro-metastatic microenvironment; the resistance appears to be conferred by both dormancy and independent of dormancy when the nodules emerge. Within the review, the molecular underpinnings of how the liver aids and protects PCa cells seeding, colonization and resistance will be discussed.

Abstract B34: Defining an orthotopic, syngeneic metastatic melanoma model for characterizing the immunotherapeutic activity of the prostamide, 15dPMJ2

Abstract Metastatic melanoma (MM) is the deadliest form of skin cancer in the United States, with one person dying from the disease every hour. Metastasis occurs when cells from the primary tumor enter the systemic circulation and grow at local and distant organ sites. The most common sites of melanoma metastasis are the lymph nodes, bone, brain, and lungs. Melanoma that has metastasized is not effectively treated with cytotoxic therapeutics that are currently available, although immunotherapeutic and targeted agents produce more favorable outcomes. Despite the availability of these effective agents, MM is still associated with high mortality rates. In order to develop new and highly effective agents that robustly eliminate MM, current models of metastatic disease in immunocompetent animals must be improved. Several in vivo models, including those that look at endocannabinoids and their metabolites, focus on injecting tumor cells directly into the circulation via the tail vein to allow lesions to form within the lungs. While these models permit rapid metastasis at relevant sites, they lack primary tumor formation and therefore do not mimic the clinical disease. Other MM models employ subcutaneous tumor inoculation to permit primary tumors to spontaneously metastasize. However, the subcutaneous space is not an orthotopic site for melanoma. Therefore, well-established models of spontaneous metastasis from orthotopic sites must be improved to more accurately recapitulate MM and study the effect of endocannabinoids and their metabolites in this disease. The goal of the current study is to modify an existing syngeneic, orthotopic model of spontaneous MM to more precisely reproduce clinical features of metastasis. In this model, B16F10 melanoma cells that expressed firefly luciferase were inoculated on the dorsal ear of C57BL/6 mice. Spontaneous metastasis was then facilitated by removing the primary lesion to prolong the duration before humane endpoints were reached. Metastatic tumor formation in the draining lymph node and at distant sites was observed by using the IVIS Lumina imaging system and by gross examination of target organs after euthanasia. According to our preliminary data, primary tumors developed after an average of 2-3 weeks and metastatic lesions formed in the draining lymph node approximately 8 weeks after inoculation. Phenotypic characteristics that served as markers of metastasis and determinants of primary tumor removal were also identified. Histopathologic analysis of the primary and metastatic tumors revealed that the morphologic appearance of the lesions was consistent with patient melanoma. Further optimization of this model will allow us to mimic MM more precisely. Animal tumor models with greater translational value will provide a more comprehensive understanding of the metastatic process and, ultimately, the effects of endocannabinoids and their metabolites in MM. Citation Format: Rukiyah T. Van Dross, Ariel Myers, Kathleen Thayne. Defining an orthotopic, syngeneic metastatic melanoma model for characterizing the immunotherapeutic activity of the prostamide, 15dPMJ2 [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B34.

Mathematically modelling inflammation as a promoter of tumour growth.

Inflammation is now known to play a significant role in tumour growth and progression. It is also difficult to adequately quantify systemic inflammation and the resulting localized effects in cancer. Here, we use experimental data to infer the possible contributions of inflammation in a mouse model of cancer. The model is validated by predicting tumour growth under anti-inflammatory treatments, and combination cancer therapies are explored. We then extend the model to consider simultaneous tumour implants at two distinct sites, which experimentally was shown to result in one large and one small tumour. We use this model to examine the role inflammation may play in the growth rate separation. Finally, we use this predictive two-tumour model to explore implications of inflammation on metastases, surgical removal of the primary and adjuvant anti-inflammatory treatments. This work suggests that improved tumour control can be obtained by targeting both the cancer and host, through anti-inflammatory treatments, including reduced metastatic burden post-surgical removal of primary tumours.

In vitro Models of Breast Cancer Metastatic Dormancy.

Delayed relapses at distant sites are a common clinical observation for certain types of cancers after removal of primary tumor, such as breast and prostate cancer. This evidence has been explained by postulating a long period during which disseminated cancer cells (DCCs) survive in a foreign environment without developing into overt metastasis. Because of the asymptomatic nature of this phenomenon, isolation, and analysis of disseminated dormant cancer cells from clinically disease-free patients is ethically and technically highly problematic and currently these data are largely limited to the bone marrow. That said, detecting, profiling and treating indolent metastatic lesions before the onset of relapse is the imperative. To overcome this major limitation many laboratories developed in vitro models of the metastatic niche for different organs and different types of cancers. In this review we focus specifically on in vitro models designed to study metastatic dormancy of breast cancer cells (BCCs). We provide an overview of the BCCs employed in the different organotypic systems and address the components of the metastatic microenvironment that have been shown to impact on the dormant phenotype: tissue architecture, stromal cells, biochemical environment, oxygen levels, cell density. A brief description of the organ-specific in vitro models for bone, liver, and lung is provided. Finally, we discuss the strategies employed so far for the validation of the different systems.

Lung cancer surgery in oligometastatic patients: outcome and survival.

A few studies have already demonstrated survival benefits for local treatment in solitary metastatic non-small-cell lung cancer (NSCLC). The aim of this study is to retrospectively investigate the role of surgery in patients with oligometastatic (OM) NSCLC. Between January 1998 and December 2018, 57 patients with OM stage IV NSCLC (1 or 2) underwent a multidisciplinary approach including lung cancer surgery, local treatment of the distant metastasis (DM) and systemic medical treatments. All patients had DM synchronous to lung cancer. Fifty-one (90%) patients had a single DM whereas 6 (11%) patients had 2 DMs. Forty-eight (84%) patients underwent induction chemotherapy. We performed 47 (82%) lobectomies, 4 (7%) segmentectomies and 6 (11%) pneumonectomies. Pathological lymph node involvement was evident in 28 (49%) patients. Adjuvant chemotherapy was administered in 20 (35%) patients. Forty-six (81%) patients had local treatment of the DM before lung resection, and 11 (19%) patients had after lung resection; 6 (11%) patients had both treatments. The median overall survival (OS) was 30 months, with the 2-, 3- and 5-year OS of 57%, 50% and 30%, respectively. OS was significantly related to lymph node involvement (P = 0.04), size of the primary tumour (P < 0.001), neoadjuvant chemotherapy (P = 0.02) and the time period between metastasis diagnosis and primary tumour removal (P = 0.04). Multidisciplinary approach is the gold standard in OM patients. Patients with no lymph node involvement are the best candidates, with an acceptable OS. Thus, patients with OM-NSCLC should not be excluded from surgery as a matter of principle.

ANALYSIS OF OUTCOMES SURGICAL TREATMENT OF PATIENTS WITH NEUROENDOCRINE TUMORS

The aim of the study: evaluate the possibility of surgical method in the treatment of patients with neuroendocrine tumors of the gastrointestinal tract and pancreas. Materials and methods. The results of treatment of 283 patients with neuroendocrine tumors of the gastrointestinal tract (GI NET) and pancreas (PNET) were studied. Women were 60.8 %, the average age - 55.8 years. Examination of patients was carried out using laboratory (chromogranin-A, serotonin, 5-GIUK, insulin, gastrin), instrumental (ultrasound, CT, MRI, EGD, FCS, PET 68Ga-DOTATOC) and morphological (histology, immunohistochemistry) diagnostic methods. Results. Surgical treatment was performed in 233 (82.3 %) cases. Endoscopic tumor removal was performed in 56.7% of patients with localized GI NET. Postoperative complications in localized and locally advanced GI NET developed in 8.1 % and 9.5% of cases. Patients localized PNET enucleation was performed in 54.7 % of cases, median resection - 3.1 %, head resection - 4.7%, distal resection - 26.6%, pancreatoduodenal resection (PD) - 10.9 %. In cases of locally advanced PNET surgical treatment was performed distal resection in 58.3 % of patients, PD - 16.7 %, head resection - 25 %. There were no significant differences in the frequency of postoperative complications in patients with localized (37.9 %) and locally advanced (41.7 %) PNET (p 0.05). In generalized NET cytoreduction was performed in 13.7 % of patients, removal of the primary tumor - 32.6 %. Median survival of patients after cytoreduction, primary tumor removal, drug therapy in an isolated version was 43.4 months., 38.9 months. and 24 months. (p 0.05). The 5-year survival rate of patients with localized NET was 81.9%, locally advanced - 57.1%, generalized - 27.6%. Conclusion. The surgical method is the main in the treatment of patients with localized and locally advanced NET. In cases of generalized NET, multidisciplinary assessment of the possibility of surgical treatment of patients is necessary in all cases.

Abstract GMM-024: TARGETING THE FORMIN-ASSEMBLED ACTIN CYTOSKELETON AS AN ANTI-INVASION STRATEGY IN OVARIAN CANCER SPHEROIDS

Abstract Due to high rates of recurrent metastasis during EOC progression, there is a critical unmet need to limit advancement of metastatic lesions present at diagnosis and upon initial recurrence. In non-hematogenous dissemination, cancer cells metastasize within the peritoneum and attach to visceral organs. Single cells, multi-cell clusters, or highly invasive multi-cellular spheroids are shed into peritoneal fluid from primary tumors, or are released by mechanical disruption of peritoneal metastases during cytoreductive surgery. Peritoneal EOC metastasis is not halted upon surgical removal of primary or metastatic tumors; it is a dynamic, longitudinal process of recurring tumors in the peritoneal cavity/pleural space. Recurrent peritoneal metastasis likely occurs via tumor cells suspended in the accumulating ascites fluid attaching to and invading the peritoneal mesothelium. Thus, EOC spheroids promote recurrent peritoneal metastasis and must be targeted for therapeutic intervention. We wished to assess the therapeutic utility of small molecules called intramimics (IMM) and Diaphanous-autoregulatory domain (DAD) in EOC spheroid peritoneal metastasis models. Both IMMs and DADs stimulate mDia2 formin function, and are thus classified as agonists. Formins are intracellular cytoskeletal nanomachines that assemble G-actin monomers into F-actin filaments. Formin-mediated F-actin assembly regulates stress fiber formation and generates forces to deform membranes into protrusive structures (i.e., lamellae, filopodia) to enable cell migration. While this process is necessary for normal cell migration (i.e., wound healing, development), it is abnormally invoked in metastasis. mDia proteins also support tumor cell-cell interactions by promoting the assembly of the F-actin architecture underlying cell-cell adherens junctions (AJs) that link cells of epithelial sheets together. IMMs and DADs specifically agonize mDia2 formins, keeping the nanomachine “on”, and in so doing, promote constitutive F-actin assembly within cells. Therefore, we hypothesize that mDia2 formin agonism would effectively block EOC spheroid invasion in 3D matrices by halting single cell invasive egress from spheroids. Using SKOV-3 and OVCA429 adenocarcinoma EOC cells, we demonstrated that mDia2 protein associates with proteins underlying AJ complexes. Specifically, mDia2 protein associates with alpha and beta catenins, yet not E- or N-cadherins. We further show that siRNA-mediated depletion of mDia2 alters the subcellular localization of AJ-associated proteins, impacting F-actin accumulation at the AJ and enhancing spheroid invasive dissemination. In contrast, mDia agonism using IMM and mDia DAD small molecules effectively inhibits EOC spheroid invasion, disallowing single cell egress from spheroids. Collectively, these results indicate a role for mDia formins in regulating invasive egress from EOC spheroids. Thus, there may be therapeutic utility to targeting mDia formin cytoskeleton effectors in halting EOC spheroid invasive egress. Citation Format: Krista M. Pettee, Yuqi Zhang, Kathryn M. Eisenmann. TARGETING THE FORMIN-ASSEMBLED ACTIN CYTOSKELETON AS AN ANTI-INVASION STRATEGY IN OVARIAN CANCER SPHEROIDS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-024.

O11 - Cytoreductive primary tumor removal slows down disease progression in an orthotopic xenograft model of prostate cancer

O11 - Cytoreductive primary tumor removal slows down disease progression in an orthotopic xenograft model of prostate cancer