Primary Solid Malignancies Research Articles

Can a fast T2-Dixon sequence surpass the time obstacle of whole-body MRI in the evaluation of skeletal metastases?

BackgroundWhole-body magnetic resonance imaging (WB-MRI) has shown its accuracy in the diagnosis of skeletal metastases in patients with known primary solid cancers. The standard protocol was a combination of T1 and short tau inversion recovery (STIR) sequences. Herein, this study was conducted to elucidate the role of the T2-Dixon sequence as a rapid alternative to the standard protocol with the assessment of its diagnostic accuracy and comparability to the established methodology.MethodsThis prospective study included 30 patients with primary solid malignancies who underwent WB-MRI. The sequences obtained were T1WI, STIR, and T2-Dixon (fat-only and water-only images). Skeletal metastases were evaluated in each sequence. Results were compared between the T1-STIR combination and T2-Dixon fat and water reconstructions.ResultsThe sensitivity of fat and water reconstructions from a single T2-Dixon in the detection of lytic skeletal metastases was marginally superior to a combination of T1WI and STIR sequences (0–7%). Detection of mixed lesions demonstrated equally high sensitivity in both protocols. Sclerotic metastases detection in WB-MRI showed low sensitivity in both protocols. However, specificity surpassed 95% for all lesion types in both protocols. Overall image quality was favored (in 87–90% of patients) in T2-Dixon images. The overall estimated acquisition timing using T2-Dixon appeared to be approximately half that of the standard T1-STIR combination.ConclusionsWB-MRI using T2-Dixon fat and water reconstructions showed similar accuracy to T1WI and STIR combination in the evaluation of skeletal metastases in patients with primary solid cancers with significantly shorter acquisition time.

Virtual Reality and 3D Simulation in the Treatment of Pediatric Patients with Central Nervous System Tumors

Pediatric central nervous system tumors are the primary solid malignancies in children and remain a leading cause of mortality in infancy. Advances in pediatric neuro-oncology, driven by molecular oncology research, emphasize the critical need for high-quality pathological tissue to support advanced molecular investigations. However, the vast heterogeneity of these tumors requires precise discrimination of collection sites, aligning with preoperative imaging data. Surgical resection, a pivotal step in diagnosis and treatment, could result in potential morbidities influencing children's neurological status. This, in turn, affects the feasibility of subsequent oncological treatments, influencing overall prognosis and quality of life. To address these challenges, technological tools enhance neurosurgeon orientation in pre-surgical planning and resection. While stereotactic navigation systems reduce morbidity, limitations persist in providing only two-dimensional anatomical information. Recent developments in 3D surgical simulation and virtual reality revolutionize procedural planning, offering real-time integration with intraoperative navigation systems. Beyond surgery, virtual reality has potential in case discussions, preoperative planning, and operative guidance, aiming to improve care and patient outcomes. The virtual reality experience, coupled with detailed anatomical visualization, facilitates meticulous surgical strategy planning for minimal invasiveness. Despite expanding literature on virtual reality applications in neurosurgery, pediatric neurosurgical oncology experiences remain limited. Scientific evaluation of simulation systems' impact on techniques and outcomes, combined with advances in neuroimaging, offers promise for adapting surgical approaches based on neoplastic brain lesion behavior.
 In conclusion, incorporating 3D surgical simulation and virtual reality technologies in pediatric neurosurgical oncology holds substantial benefits, offering improved procedural planning, enhanced precision, and patient-specific adaptation. Despite limited reported experiences, the compelling advantages underscore the need for further exploration and consideration in the evolving landscape of pediatric neuro-oncology.

Visualization of hypoxia in cancer cells from effusions in animals and cancer patients.

Tumor hypoxia is frequently observed in primary solid malignancies, but the hypoxic status of tumor cells floating in body cavity effusions is largely unknown, especially in patients. This study was to observe the hypoxia and proliferation status of cancer cells floating in effusions in mice and patients. The distribution of hypoxia in cancer cells floating in ascites was first studied in nude mice. Hypoxia was detected by immunofluorescent visualization of pimonidazole and GLUT-1. For cancer patients, we retrospectively collected 21 ascites and 7 pleural effusion sample blocks of cancer patients, which were confirmed to contain tumor cells. Immunohistochemistry was performed to detect the expression of endogenous hypoxic markers HIF-1α and GLUT-1, proliferation index Ki-67. 18F-FDG PET/CT was performed to detect the glucose metabolism status of tumor cells in effusions. The tumor cells collected from ascites were positive for pimonidazole and GLUT-1, which suggesting that the cancer cells floating in ascites were hypoxic. Patterns of tumor hypoxia in human patients are similar to those observed in animal. HIF-1α and GLUT-1 were expressed by tumor cells in nearly all 28 cytological cases. For Ki-67 index, ascites tumor cells had a relatively low expression level compared with their corresponding primary or its metastatic lesions. Tumor cells in effusions showed high 18F-FDG uptake indicated the enhanced activity of glucose metabolism. Tumor cells in body cavity effusions, as a unique subgroup of tumor, are in a state of hypoxia and low proliferation, which would be one of the driven causes of chemo-radiotherapy resistance. Novel therapeutic interventions are urgently needed to overcome tumor hypoxia.

A Descriptive Study of the Types and Survival Patterns of Saudi Patients with Multiple Primary Solid Malignancies: A 30-Year Tertiary Care Center Experience.

Background and Objective: Cancer survival has improved significantly, which reflects the achievements in screening, diagnosis, and treatment. As a consequence, multiple primary malignancies are diagnosed more frequently, with an incidence ranging from 0.52–11.7%. The types of malignancy that coexist and survival patterns vary notably in different countries and geographical areas. Due to the limited literature in Saudi Arabia, a baseline of prevalent malignancy combinations and their survival patterns would support early detection and disease management. Method: This was a retrospective descriptive study conducted from 1993–2022 at King Abdulaziz Medical City, Department of Medical Oncology, Riyadh, Saudi Arabia. Patients with at least two biopsy-proven solid malignancies were included. Patients with hematological malignancies, missing data, or an uncertain or indecisive pathology report were excluded. Result: In total, 321 patients were analyzed. More than half (57.3%) of the patients were female. A third (33%) of the cases were synchronous, and 67% were metachronous. The most frequent site of the first primary malignancy was breast cancer, followed by colorectal, skin, and thyroid cancers. The most frequent site of the second primary malignancy was colorectal cancer, followed by thyroid, breast, and liver cancers. Only 4% of the cases had a third primary malignancy, with colorectal and appendiceal cancers being the most frequent. The most frequently observed histopathology in the synchronous and metachronous malignancies was adenocarcinoma. Breast–colorectal, breast–thyroid, and kidney–colorectal were the most frequently observed malignancy combinations. Conclusion: The current study offers a baseline of multiple primary malignancies in Saudi Arabia and provides supporting evidence that the pattern of multiple primary malignancies varies among different countries and ethnicities. The possibility of developing another primary malignancy should be considered when treating and monitoring cancer patients.

Multi-detector computed tomography evaluation of synchronous hepatocellular carcinoma and other solid malignancies.

To review the findings of multi-detector computed tomography (MDCT) in synchronous hepatocellular carcinoma (HCC) and other solid malignancies. A total of 74 cases were included in this retrospective analysis, all of them confirmed with a diagnosis of synchronous HCC and other solid malignancies. They were 41 women and 33 men (mean age, 63.36 years). The whole body and triphasic abdominal CT scanning utilized 128 MDCT scanners in all 74 patients. The pathological diagnoses of all 148 malignancies were confirmed in all 74 cases. Out of 3480 patients with HCC, 74 patients (2.1%) were diagnosed with another synchronous primary solid malignancy. The pathology of all 148 cancers was verified, and each one was correctly characterized, assessed, and staged. Hepatocellular carcinoma was detected in all 74 patients. The most frequent extra-hepatic primary malignant sites were breast (18/74, 24.3%), followed by kidney (15/74, 20.3%), lymphoma (9/74, 12.2%), uterus (7/74, 9.5%), ovary (5/74, 6.8%), colon (5/74, 6.8%), prostate (5/74, 6.8%), urinary bladder (3/74, 4.1%), thyroid (2/74, 2.7%), gall bladder (1/74, 1.4%), stomach (1/74, 1.4%), pancreas (1/74, 1.4%), esophagus (1/74, 1.4%) and lung (1/74, 1.4%). The possibility of synchronous double malignancies with HCC should always be considered during pretreatment evaluation. Using an MDCT scanner, researchers were able to assess this occurrence accurately. An increased number of such findings may lead to an improved therapeutic method for these patients.

Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma.

Simple SummaryOsteosarcoma is the most common form of primary solid bone malignancy, with the highest incidence in adolescence. The therapeutic management includes surgical resection combined with adjuvant/neoadjuvant chemotherapy regimens. Despite this multimodal combination, about two patients out of five are still not cured (5-year overall survival rate at 60%). Complementary therapeutic approaches are required to overcome the frequent resistance to conventional chemotherapy. The aim of the present study was to assess the potential benefit of statins as an adjuvant to chemotherapy. We show that simvastatin synergizes with conventional chemotherapy drugs in terms of cell viability, tumor growth, and dissemination and represents valuable alternative adjuvant therapy that needs further investigation in clinical trials.Context: Osteosarcoma is the most common primary solid malignancy of the bone, mainly affecting pediatric patients. The main clinical issues are chemoresistance and metastatic spread, leading to a survival rate stagnating around 60% for four decades. Purpose: Here, we investigated the effect of simvastatin as adjuvant therapy on chemotherapy. Methods: Cell viability was assessed by the MTT test, and a combination index was evaluated by an isobologram approach. Cell motility was assessed by wound-healing assay. Cell-derived xenograft models were established in mice. FFPE tumor samples were assessed by immunohistochemistry. Results: In vitro experiments indicate that simvastatin synergized the conventional chemotherapy drugs’ inhibitory effect on cell viability. Functional assays reveal that simvastatin supplementation favored the anticancer mechanism of action of the tested chemotherapy drugs, such as DNA damage through intercalation or direct alkylation and disorganization of microtubules. Additionally, we show that even though simvastatin alone did not modify tumor behavior, it potentiated the inhibitory effect of doxorubicin on primary tumor growth (+50%, p < 0.05) and metastatic spread (+50%, p < 0.05). Our results provide evidence that simvastatin exerted an anti-tumor effect combined with chemotherapy in the preclinical murine model and represents valuable alternative adjuvant therapy that needs further investigation in clinical trials.

MDCT evaluation of synchronous breast carcinoma and other solid malignancies.

Multiple primary malignancies are two or more malignancies in an individual without any relationship between the tumors. The development of improved diagnostic techniques, increased survival of cancer patients and the growing life expectancy have all contributed to the increased frequency of this phenomenon. The aim of this study is to review the multidetector computed tomography (MDCT) findings of synchronous breast carcinoma and other solid malignancies. This retrospective study included 65 patients confirmed with diagnosis of synchronous breast carcinoma and other solid malignancies. CT scanning was performed using 128 MDCT in all patients. All one hundred-thirty malignancies underwent pathological evaluation. Out of 4120 patients with breast carcinoma; 65 patients were diagnosed with other synchronous primary solid malignancy. All one hundred-thirty malignancies were confirmed pathologically. Breast carcinoma detected in all 65 patients; of them metastatic breast carcinoma detected in 8 patients. Hepatocellular carcinoma was detected in 18 patients, Non-Hodgkin lymphoma (NHL) in 12 patients, endometrial carcinoma in 8 patients, uterine sarcoma in 3 patients, malignant mixed Müllerian tumor in one patient, ovarian carcinoma in 5 patients, renal cell carcinoma in 4 patients, thyroid carcinoma in 4 patients, gastric carcinoma in 2 patients, colonic carcinoma in 2 patients, ano-rectal carcinoma in one patient, hilar cholangiocarcinoma in 2 patients, malignant melanoma in 2 patients and bronchogenic carcinoma in one patient. Patients with breast carcinoma have a risk of other synchronous primary malignancy. So, careful preoperative examination is recommended to improve the patients' prognosis. MDCT scanning is accurately imaging modality for evaluation of synchronous breast carcinoma and other solid malignancies. The aim of treatment in cancer patients should always be curative even in the presence of multiple malignancies.

Cancer-directed surgery in malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication

Malignant pleural mesothelioma (MPM) is a primary solid malignancy related to inhalational asbestos exposure. Despite advances in therapy, MPM remains challenging to treat with a post-treatment survival of only 15% at 5-year. In recent years, extra-pleural pneumonectomy has decreased in popularity due to a high morbidity rate and mortality compared to pleurectomy/decortication and other therapeutic alternatives. In this review, we will discuss both procedures, outcomes, ongoing studies, and the roles of surgery in the future treatment of this disease.

11. ASSOCIATION OF TUMOR EXPOSURE TO CEREBROSPINAL FLUID SPACES TO LEPTOMENINGEAL DISEASE IN PATIENTS WITH BRAIN METASTASES

BACKGROUNDDevelopment of leptomeningeal disease in patients with brain metastases is associated with extremely poor survival. Identification of the underlying pathogenesis of leptomeningeal disease is unknown.METHODSThis retrospective case control study included consecutive adult patients with at least one cerebral metastasis from a known extracranial primary solid malignancy and at least 3 month follow up (n=366). Patients were treated with radiotherapy with or without surgical resection and primary outcome was development of leptomeningeal disease.RESULTSThe overall rate of leptomeningeal disease was 15.0%. Rates of development of leptomeningeal disease correlated with the presence of a dural based lesion (65.7% vs. 9.7%; P<0.0001), intraventricular lesion (29.4% vs. 14.3%; P=0.0897), and with dural based lesions with sulcal or cortical enhancement (100% vs. 12.9%; P<0.0001). Rates of developing leptomeningeal disease were not independently associated with surgical resection (17.2% vs. 14.2%; P=0.4859), however did occur significantly more often with piecemeal, as opposed to en bloc, resection (31.3% vs. 8.1%; P=0.0138) or when the ventricle was entered (61.5% vs. 18.9%; P<0.0001).CONCLUSIONSMetastases that are in contact with cerebrospinal fluid spaces are associated with a higher rate of subsequent leptomeningeal disease, with or without surgical resection. Future studies should investigate the use of neoadjuvant radiation, whole brain radiation therapy or adherence to strict surgical technique in high risk brain metastasis patients to mitigate this probability.

Abstract B079: The Affordable Care Act and cancer stage in an underserved population

Abstract Background: The Patient Protection and Affordable Care Act (ACA), particularly provisions enacted in 2014 including the health insurance exchange and Medicaid expansion, aimed to reduce the number of uninsured individuals in the United States. The ACA has increased insurance coverage and improved cancer stage at diagnosis for certain populations, but unknown is the effect of ACA on cancer stage at diagnosis specifically among the underserved (i.e., socioeconomically disadvantaged). Therefore, we aimed to assess the effect of ACA enactment on advanced-stage cancer diagnosis among underserved cancer patients. Methods: We used data from the JPS Center for Cancer Care institutional registry (accredited by the Commission on Cancer). This center is part of an urban public hospital network that serves Tarrant County, TX (population &amp;gt;2 million) and is a primary source of care for underserved individuals. Our eligible population included individuals aged ≥18 years who were diagnosed with a first primary solid malignancy between 2008 and 2015. We compared the effect of ACA implementation on advanced stage diagnosis for overall, screen-detectable, and non-screen-detectable cancers using a natural experiment framework and interrupted time-series analysis to estimate prevalence differences (PD) and 95% confidence limits (CL), where January 2014 differentiated the pre- and post-ACA periods in 6-month intervals. Results: Our study population comprised 6,679 underserved patients, of whom 46% were aged &amp;lt;55 years, 55% were female, 25% were non-Hispanic Black, and 24% were Hispanic. Private insurance coverage increased from 4.6% to 10% after ACA enactment. The overall prevalence of advanced stage diagnosis increased 2.5% following ACA enactment (95% CL: -2.0%, 7.0%), which modestly varied for screen-detectable cancers (PD = 4.3%, 95% CL: -0.3%, 8.8%) and non-screen-detectable cancers (PD = 1.4%, CL: -3.7%, 6.6%). Discussion: Our results do not suggest a reduction in late-stage diagnosis after ACA enactment among underserved cancer patients. The small increase in prevalence of late-stage diagnosis post-ACA could be an initial consequence of increased access to care (i.e., recognition of previously undiagnosed cases) given the small increase in private insurance coverage, but longer follow-up is necessary to interpret this result. Texas did not expand Medicaid coverage as part of ACA enactment, and thus our findings raise questions about whether Medicaid expansion would have affected late-stage diagnosis among underserved cancer patients. Citation Format: Yan Lu, Bradford E. Jackson, Deanna Cross, Latha Neerukonda, Bhavna Tanna, Bassam Ghabach, Rohit P. Ojha. The Affordable Care Act and cancer stage in an underserved population [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B079.

Synchronous Breast Carcinoma and Other Solid Malignancies: MDCT Evaluation

Background and Objectives: The incidence of synchronous primary malignant tumors is increasing due to the ageing of the population and advances in medical technology. In this retrospective study; we review the multidetector computed tomography (MDCT) findings of synchronous breast carcinoma and other solid malignancies. Methods and Materials: This retrospective study included 65 patients confirmed with diagnosis of synchronous breast carcinoma and other solid malignancies. The patients aged ranged from 35 – 78 years. CT scanning was performed using 128 MDCT in all patients. All one hundred-thirty malignancies were underwent pathological evaluation. Results: Out of 4120 patients with breast carcinoma; 65 patients were diagnosed with other synchronous primary solid malignancy. All one hundred-thirty malignancies were confirmed pathologically. Breast carcinoma detected in all 65 patients; of them metastatic breast carcinoma detected in 8 patients. Hepatocellular carcinoma detected in 18 patients. Non-Hodgkin lymphoma (NHL) detected in 12 patients. Endometrial carcinoma detected in 8 patients. Uterine sarcoma detected in 3 patients. Malignant mixed Mullerian tumor detected in one patient. Ovarian carcinoma detected in 5 patients. Renal cell carcinoma detected in 4 patients. Thyroid carcinoma detected in 4 patients. Gastric carcinoma detected in 2 patients. Colonic carcinoma detected in 2 patients. Ano-rectal carcinoma detected in one patient. Hilar cholangiocarcinoma detected in 2 patients. Malignant melanoma detected in 2 patients. Bronchogenic carcinoma detected in one patient. Conclusions: Patients with breast carcinoma have a risk of other synchronous primary malignancy. So, careful preoperative examination is recommended to improve the patients’ prognosis. MDCT scanning is accurately imaging modality for evaluation of synchronous breast carcinoma and other solid malignancies. The aim of treatment in cancer patients should always be curative even in the presence of multiple malignancies. Funding Statement: There was no financial support for this research and publication. Declaration of Interests: The author declares that there is no conflict of interest. Ethics Approval Statement: The study was approved by the institutional research ethics review committee (Mansoura University/Faculty of Medicine/ Egypt). IRB reference number is “R.20.02.753

Abstract P3-12-14: Incidence of radiation induced sarcoma attributable to radiotherapy in adults: A population-based study of the SEER cancer registry across 17 primary tumor sites

Abstract Background: More than half of cancer patients will receive radiotherapy during the treatment of their cancer; however, a rare and fatal treatment complication is radiation induced sarcoma (RIS). Notably, a large percentage of RIS patients are breast cancer survivors. Previous studies have investigated the incidence of all secondary cancers due to radiotherapy but have not noted the incidence of RIS in a contemporary population-based cohort in the US. To evaluate the relative risk of RIS, we examined data from the Surveillance, Epidemiology, and End Results (SEER) database. We hypothesized that breast cancer would have a higher incidence of RIS compared to 17 other primary cancer sites. Methods: This was a retrospective cohort study that examined SEER registries from 1973 and 2013. We included patients aged 18 years or older who were diagnosed with a primary cancer. We excluded patients with missing information on initial radiotherapy treatment or stage and those who died less than two years from the date of their primary cancer diagnosis. RIS was defined as those who developed a secondary sarcoma near the site of their original malignancy and after a 24-month latency period. Results: Our study included 1,745,867 patients with an average age of 60 years and mean follow up time of 9.2 years. Breast cancer comprised the largest number with 693,701 patients of which 161 (0.02%) had a secondary sarcoma. Prostate cancer comprised the second largest group with 594,271 patients of which 75 (0.01%) had a secondary sarcoma. Of the 359 patients with secondary sarcomas, 242 (67.4%) had RIS. Breast cancer had the highest number of RIS patients at 126 (52.1%) compared to all combined non-breast cancer sites at 116. Interestingly, 172 (71.1%) RIS patients were females, which correlated with the attributable RIS cases from breast and uterine cancer. The relative risk of RIS in breast cancer versus 17 other primary cancer sites was 1.21 (CI: 1.01-1.45, p &amp;lt;0.03, adjusted for age at primary diagnosis, gender, and latency). Conclusions: This study confirms the low incidence of RIS in breast cancer, which has been demonstrated to be around 0.03% - 0.2% in the literature. Our results suggest that breast cancer portends a somewhat higher risk for RIS compared to 17 primary solid malignancies. Although some of the risk is attributable to the high incidence rate of breast cancer, breast cancer patients had a higher relative risk of RIS than other solid tumors after adjusting for covariates. Female gender may be associated with an increased risk for RIS compared to males. Further investigations should be performed to confirm these epidemiological findings given that radiation fields, doses, intention to cure, margin status and systemic therapy are not recorded in SEER. Nonetheless, this study is hypothesis generating in that the majority of RIS cases in solid tumors are attributable to breast cancer in this large population-based series. Citation Format: Snow AE, Struycken LC, Koc M, Greco JP, Zhu Y, In GK, Dorff TB, Lang JE. Incidence of radiation induced sarcoma attributable to radiotherapy in adults: A population-based study of the SEER cancer registry across 17 primary tumor sites [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-14.

A risk score model for the prediction of osteosarcoma metastasis.

Osteosarcoma is the most common primary solid malignancy of the bone, and its high mortality usually correlates with early metastasis. In this study, we developed a risk score model to help predict metastasis at the time of diagnosis. We downloaded and mined four expression profile datasets associated with osteosarcoma metastasis from the Gene Expression Omnibus. After data normalization, we performed LASSO logistic regression analysis together with 10‐fold cross validation using the GSE21257 dataset. A combination of eight genes (RAB1,CLEC3B,FCGBP,RNASE3,MDL1,ALOX5AP,VMO1 and ALPK3) were identified as being associated with osteosarcoma metastasis. These genes were put into a gene risk score model, and the prediction efficiency of the model was then validated using three independent datasets (GSE33383, GSE66673, and GSE49003) by plotting receiver operating characteristic curves. The expression levels of the eight genes in all datasets were shown as heatmaps, and gene ontology gene annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. These eight genes play a role in cancer‐related biological processes, such as apoptosis and biosynthetic processes. Our results may aid in elucidating the possible mechanisms of osteosarcoma metastasis, and may help to facilitate the individual management of patients with osteosarcoma after treatment.

Abstract 4260: Dynamic modeling of macrophage plasticity in bone metastatic prostate cancer

Abstract Tumor-associated macrophages, particularly those with an anti-inflammatory phenotype, have long been implicated in the progression of primary solid malignancies, including prostate cancer. Metastatic prostate cancer typically manifests in the bone where it induces painful osteogenic lesions that are incurable. Bone is naturally rich in myeloid-derived macrophages whose temporal polarization into pro- (M1) and anti-inflammatory (M2) phenotypes is critical for regulating the bone repair program mediated by bone-resorbing osteoclasts and bone-building osteoblasts. However, the dynamics of macrophage polarization in the context of bone metastatic prostate cancer are underexplored and difficult to address with traditional biologic approaches. To address the role of macrophage polarization in the context of bone metastatic prostate cancer, we first investigated the macrophage polarization temporal dynamics in normal bones and analyzed macrophage plasticity in vivo subsequent to intratibial injury. Bone marrows were isolated at several time points and profiled by flow cytometry for pro- and anti-inflammatory monocyte macrophage content. Contralateral tibias were analyzed for bone volume, osteoblast and osteoclast numbers. We then designed a mathematical model describing the different cell population dynamics in the bones. Generation of the model required testing a number of assumptions regarding macrophage polarization behavior. For example, it is unknown whether M1 resolves at the initial stages of bone injury repair through death or by repolarizing into M2. For each aspect, competing mechanistic assumptions were proposed and simulated by sets of ODEs. The best-fitting assumptions for each aspect were integrated into a single comprehensive ODE model to fully describe the dynamics of the bone resident cell populations during bone remodeling. This experimentally validated model is now being used to address how bone resident cells respond to metastatic prostate cancer cells. In conclusion, we have generated an ODE model that describes macrophage polarization over time during bone repair and how pro- and anti-inflammatory macrophages interact with bone stromal cells. The mathematical model predictions are in agreement with our biologic experiments in vivo and will allow us to interrogate how macrophage polarization impacts the behavior of metastatic prostate cancer cells in the bone microenvironment. Citation Format: Etienne A. Baratchart, Chen Hao Lo, Conor Lynch, David Basanta. Dynamic modeling of macrophage plasticity in bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4260.

A support vector machine and a random forest classifier indicates a 15-miRNA set related to osteosarcoma recurrence.

BackgroundOsteosarcoma, which originates in the mesenchymal tissue, is the prevalent primary solid malignancy of the bone. It is of great importance to explore the mechanisms of metastasis and recurrence, which are two primary reasons accounting for the high death rate in osteosarcoma.Data and methodsThree miRNA expression profiles related to osteosarcoma were downloaded from GEO DataSets. Differentially expressed miRNAs (DEmiRs) were screened using MetaDE.ES of the MetaDE package. A support vector machine (SVM) classifier was constructed using optimal miRNAs, and its prediction efficiency for recurrence was detected in independent datasets. Finally, a co-expression network was constructed based on the DEmiRs and their target genes.ResultsIn total, 78 significantly DEmiRs were screened. The SVM classifier constructed by 15 miRNAs could accurately classify 58 samples in 65 samples (89.2%) in the GSE39040 database, which was validated in another two databases, GSE39052 (84.62%, 22/26) and GSE79181 (91.3%, 21/23). Cox regression showed that four miRNAs, including hsa-miR-10b, hsa-miR-1227, hsa-miR-146b-3p, and hsa-miR-873, significantly correlated with tumor recurrence time. There were 137, 147, 145, and 77 target genes of the above four miRNAs, respectively, which were assigned to 17 gene ontology functionally annotated terms and 14 Kyoto Encyclopedia of Genes and Genomes pathways. Among them, the “Osteoclast differentiation” pathway contained a total of seven target genes and was analyzed further.ConclusionThe 15-miRNAs-based SVM classifier provides a potential useful tool to predict the recurrence of osteosarcoma. Our results suggest the possible mechanisms of osteosarcoma metastasis and recurrence and provide fresh DEmiRs as potential biomarkers or therapeutic targets for osteosarcoma.

Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages

ABSTRACTPatients with primary solid malignancies frequently exhibit signs of systemic inflammation. Notably, elevated levels of neutrophils and their associated soluble mediators are regularly observed in cancer patients, and correlate with reduced survival and increased metastasis formation. Recently, we demonstrated a mechanistic link between mammary tumor-induced IL17-producing γδ T cells, systemic expansion of immunosuppressive neutrophils and metastasis formation in a genetically engineered mouse model for invasive breast cancer. How tumors orchestrate this systemic inflammatory cascade to facilitate dissemination remains unclear. Here we show that activation of this cascade relies on CCL2-mediated induction of IL1β in tumor-associated macrophages. In line with these findings, expression of CCL2 positively correlates with IL1Β and macrophage markers in human breast tumors. We demonstrate that blockade of CCL2 in mammary tumor-bearing mice results in reduced IL17 production by γδ T cells, decreased neutrophil expansion and enhanced CD8+ T cell activity. These results highlight a new role for CCL2 in facilitating the breast cancer-induced pro-metastatic systemic inflammatory γδ T cell – IL17 – neutrophil axis.

Clinicopathologic features and survival outcomes of secondary diffuse large b-cell lymphoma after a primary solid malignancy: SEER propensity-matched analysis.

e19022Background: Outcomes of secondary DLBCL (sDLBCL) in patients with a prior diagnosis of a solid malignancy compared to de novo DLBCL (dnDLBCL) are not well understood. We sought to determine f...

Clinicopathologic Features and Survival Outcomes of Secondary Mantle Cell Lymphoma after Primary Solid Malignancy

Background: Mantle Cell Lymphoma (MCL) is a rare sub-type of Non-Hodgkin's Lymphoma (NHL). Outcomes of secondary MCL (sMCL) in patients with a prior diagnosis of a solid malignancy as compared to de novo MCL are not well understood. Differences may be attributable to age, gender, race/ethnicity, extra-nodal involvement, and stage at initial diagnosis. We sought to determine differences in outcome by analyzing data from a large nationwide cancer registry.Methods: The Surveillance Epidemiology and End Results (SEER) database (1973-2012) was used to detect MCL (ICD-O-3 code: 9673/3) adult (>18 years) cases. The variable "First Malignant Primary Indicator" was used to differentiate between de novo and sMCL cases. Primary solid malignancy subtypes categorized included prostate, breast, colorectal, lung bladder, renal, head and neck, thyroid, testicular, and endometrial cancer. Selected sMCL cases included patients with a diagnosis of a primary solid malignancy with a latency period ≥ 2 months. Overall survival (OS) was calculated using the cox regression model to determine the impact of sMCL on survival, adjusting for age at diagnosis, race/ethnicity, primary solid malignancy subtype type and latency period. Chi square test was utilized to ascertain for any significant difference between de novo MCL and sMCL cases.Results: Overall, 8,889 patients were included: 875 (9.8%) sMCL and 8,014 (90.2%) de novo MCL cases. For de novo MCL, 67.1% were males. Race/ethnicity in descending frequency consisted of Non-Hispanic Whites (NHW) (81.8%), Hispanics (8.4%), Blacks (4.4%), Asian and Pacific Islanders(API)(4.1%) and American Indian/Native Indian (AI) (0.4%). The most frequent stage at initial diagnosis for de novo MCL was stage IV (57.9%) followed by stage III (13.4%), stage II (8.1%) and stage I (10.0%). Males consisted of 75.4% of sMCL cases. Cases of sMCL categorized by race/ethnicity in descending frequency were NHW (87.3%), Hispanics (5.1%), Blacks (4.2%), API (3.2%) and AI (0.1%). Stage at diagnosis for sMCL was most frequently stage IV (54.6%), followed by stage III (15.8%), stage II (10.9%) and stage I (11.7%). Compared to de novo MCL, sMCL cases were more likely to occur in patient's ≥75 years (48.3% vs. 28.7%, p<0.01). An absence of extra-nodal involvement at diagnosis was common in both de novo MCL (84.0%) and sMCL (83.7%). Specific to sMCL cases, more than 90% of primary solid malignancies were limited to local/regional involvement. All primary solid malignancy subtypes except for head and neck (48 months) and renal cancer (59 months) had a latency period of greater 5 years. Median OS was significantly worse in sMCL (34 months) compared to de novo MCL (53 months) (HR: 1.375, 95% CI:1.243-1.504).Conclusion: Our analysis demonstrates that elderly age appears to be significantly more common in sMCL cases as compared to de novo MCL. By contrast, race/ethnicity, and extra-nodal involvement were similar between the two groups. Survival was worse in sMCL compared to de novo MCL. This may be due to differences in treatment preferences. Further studies are necessary to elucidate the etiology for such differences in outcomes. DisclosuresKropf:Teva Pharmaceuticals: Consultancy.

Unexpected Second Primary Malignancies Detected by F-18 FDG PET/CT During Follow-up for Primary Malignancy: Two Case Reports.

As the survival rate of cancer patients has increased over the last few decades, the risk of cancer survivors developing second primary malignancies has gained attention. We report two rare cases of second primary hematologic malignancy detected by (18)F-fluorodeoxyglucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) during follow-up for primary solid malignancies. Acute lymphoblastic leukemia developed in a breast cancer patient and non-Hodgkin lymphoma in an anal cancer patient. F-18 FDG PET/CT findings led to the diagnosis of unexpected second primary hematologic malignancy in cancer survivors in these two cases.

Phase I safety and pharmacokinetic (PK) study of veliparib in combination with whole brain radiation therapy (WBRT) in patients (pts) with brain metastases.

2013 Background: Veliparib is an oral PARP-1 and -2 inhibitor that enhances the antitumor activity of DNA damaging agents including radiation therapy in vivo. In pre-clinical models, veliparib crosses the blood-brain barrier. This ongoing phase I dose-escalation study evaluates the safety, PK, and provides preliminary antitumor activity of veliparib in combination with WBRT in pts with brain metastases. Methods: Pts with brain metastases from non-CNS primary solid malignancy, adequate organ function, RPA Class 2, and KPS ≥70 were treated with WBRT (37.5 Gy in 15 fractions or 30 Gy in 10 fractions) QD with veliparib BID with every fraction of WBRT in escalating doses of 10, 20, 30, 50, 100, 150, and 200 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety, PK, and tumor response by RECIST were assessed. Results: At the time of reporting 59 pts (M/F, 21/38; median age 57 y) had been treated. Baseline KPS was 70, 80, 90, and 100 in 6.8, 32.2, 40.7, and 20.3% pts, respectively; primary tumor types were breast (n=20), NSCLC (n=20), melanoma (n=9), colorectal (n=2), and others (n=8); 71.2% pts had multiple lesions; and 18.6% had prior brain SRS. Grade 3/4 treatment-emergent adverse events (TEAEs; ≥5%) were fatigue (6.8%), anemia (5.1%), hyponatraemia (5.1%), and thrombocytopenia (5.1%); other TEAEs (≥20%) were fatigue (57.6%), headache (42.4%), nausea (40.7%), alopecia (28.8%), vomiting (22%), radiation skin reactions (22%), and decreased appetite (22%). PK of veliparib were approximately dose-proportional, with oral clearance of 21.6 ± 14.2 L/h (mean ± SD, n=45), minimal drug accumulation at day 15, and no significant effect of food on bioavailability. Tumor response was evaluable in 48 pts. Best tumor response and median survival were 37.5% and 10 months (m) for NSCLC, and 52.9% and 12.5 m for breast cancer (excluding pts with leptomeningeal disease). Conclusions: Addition of veliparib up to 200 mg BID was well tolerated with concurrent WBRT and dose escalation ongoing. The PK of veliparib was dose proportional with no food effect. Preliminary antitumor activity is encouraging and informative for the design of more definitive trials.