Multifocal Metastases Research Articles

Abstract C061: Loss of CaMK2B accelerates tumor formation and enhances metastatic competency in genetically engineered mouse models of PDAC

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer- related deaths in the United States and is often not diagnosed until it has already metastasized. Our prior work established that calcium signaling pathways facilitate a pro-metastatic phenotype through the induction of an epithelial-to-mesenchymal transition (EMT) program in PDAC tumor cells, but the downstream signaling molecules mediating this phenotype have remained elusive. MethodsUsing a novel genetically engineered model of pancreatic cancer, we demonstrate that loss of Calcium/calmodulin-dependent kinase-II B (CaMK2B), a downstream effector kinase activated by calcium, enhances cellular plasticity, and increases metastasis. To this end, we generated a genetically engineered mouse model where Camk2b was knocked out in tumor cells in a lineage-labeled Kras- and p53-driven PDAC mouse model (herein KPCY-Camk2bcKO). Results Genetic deletion of Camk2b in the KPCY genetically engineered model accelerated tumor formation and dramatically reduced the overall median survival of KPCY- Camk2b cKO mice (78 days) relative to KPCY controls (136 days). Pathological and immunofluorescence analysis of KPCY-Camk2b cKO animals showed an increased number of poorly differentiated tumor regions and a higher metastatic burden, with >85% of KPCY- Camk2b cKO animals presenting with multi-focal metastases. Further analysis of tumor cells in KPCY-Camk2b cKO mice showed enhanced expression of markers of the highly aggressive squamous PDAC subtypes. Strikingly, Camk2b deletion combined with oncogenic Kras G12D (in the absence of p53 alterations), was sufficient to form lethal metastatic PDAC tumors, while age-matched control Kras G12D tumors with intact Camk2b only progressed to the acinar-to-ductal metaplasia (ADM) or Pancreatic Intraepithelial Neoplasia (PanIN) stage. Collectively, these results establish Camk2b loss as a new oncogenic and pro-metastatic mechanism in PDAC Conclusion This work demonstrates that Camk2b loss enhances tumor cell evolution and plasticity within PDAC to promote metastasis. In this context, we speculate that loss of Camk2b rewires calcium signaling to drive an aggressive subtype of PDAC with increased metastasis. Citation Format: Jessica Peura, Nikita Bhalerao, Calvin Johnson, Yamini Ogoti, Faith Keller, Emma Watson, Zhen Zhao, Jason Pitarresi. Loss of CaMK2B accelerates tumor formation and enhances metastatic competency in genetically engineered mouse models of PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C061.

The Pancreas as a Target of Metastasis from Renal Cell Carcinoma: Is Surgery Feasible and Safe? A Single-Center Experience in a High-Volume and Certified Pancreatic Surgery Center in Germany.

Background: Secondary malignant tumors of the pancreas are rare, representing 2-5% of all pancreatic malignancies. Nevertheless, the pancreas is one of the target organs in cases of metastatic clear cell renal cell carcinoma (CCRCC). Additionally, recurrent metastasis may occur. Surgical resection remains the best and prognostically most favorable therapeutic option in cases of solitary pancreatic metastasis. Aim: To review retrospectively the clinical tumor registry of the University Hospital of Magdeburg, Germany, for this rare entity, performing a clinical systematic single-center observational study (design). Methods: A retrospective cohort analysis of consecutive patients who had undergone pancreatic resection for metastatic CCRC was performed in a single high-volume certified center for pancreatic surgery in Germany from 2010 to 2022. Results: All patients (n = 17) included in this study had a metachronous metastasis from a CCRCC. Surgery was performed at a median time interval of 12 (range, 9-16) years after primary resection for CCRCC. All 17 patients were asymptomatic at the time of diagnosis. Three of those patients (17.6%) presented with recurrent metastasis in a different part of the pancreas during follow-up. In a total of 17 patients, including those with recurrent disease, a surgical resection was performed; Pancreatoduodenectomy was performed in 6 patients (35%); left pancreatectomy with splenectomy was performed in 7 patients (41%). The rest of the patients underwent either a spleen-preserving pancreatic tail resection, local resection of the tumor lesion or a total pancreatectomy. The postoperative mortality rate was 6%. Concerning histopathological findings, seven patients (41%) had multifocal metastasis. An R0 resection could be achieved in all cases. The overall survival at one, three and five years was 85%, 85% and 72%, respectively, during a median follow-up of 43 months. Conclusions: CCRC pancreatic metastases can occur many years after the initial treatment of the primary tumor. Surgery for such a malignancy seems feasible and safe; it offers very good short- and long-term outcomes, as indicated. A repeated pancreatic resection can also be safely performed.

Apport de l’IRM corps entier au bilan initial du liposarcome myxoïde

IntroductionMyxoid liposarcoma is a soft tissue sarcoma associated with multifocal metastases at diagnosis. These metastases are asymptomatic and occult on CT and FDG-PET and can alter the therapeutic management and prognosis. In this context, we evaluated the contribution of whole-body MRI to the initial workup of patients with myxoid liposarcoma. MethodThis retrospective study was conducted between January 2015 and December 2020 at the Oscar Lambret Center. We enrolled 22 patients who were diagnosed with myxoid liposarcoma and underwent whole-body MRI at diagnosis. The number of metastases at diagnosis, their location, and the visibility of these lesions on CT were evaluated. Associations between clinical features, presence of metastasis, and their impact on management were assessed. ResultsSixteen patients (72.7%) had non-metastatic disease at the initial diagnosis, and 15 of these patients were managed using local treatment. Six patients (27.3%) had metastases at multiple locations and received chemotherapy. The main locations were the bones (n=5) and lungs (n=3). In five patients with metastases, whole-body MRI demonstrated additional lesions that were not visible on CT (bone and soft tissue lesions). Only the presence of a round cell contingent (P=0.009) was found as a criterion associated with the presence of metastases. ConclusionThe patients’ young age, absence of reliable prognostic factors at diagnosis, asymptomatic nature of the lesions, and the benefits of early and targeted therapeutic management encourage the use of whole-body MRI as part of the initial work-up as it seems to provide a better initial staging compared with conventional imaging.

NCMP-02. RENAL CELL CARCINOMA WITH METASTASIS TO THE CHOROID PLEXUS

Abstract BACKGROUND Intraventricular brain tumors make up only 0.9–4.5% of all cases of metastatic brain cancer.1 Involvement of the choroid plexus (CP) is even rarer with only a handful of documented cases. 2,3 Here we describe a case of bilateral multifocal metastasis to the choroid plexus appearing 10 years after nephrectomy in a male with stage IV renal cell carcinoma (RCC). CASE PRESENTATION: Our patient is a 74-year-old male with stage IV RCC diagnosed in 2006 and treated with radical nephrectomy and immunotherapy in 2011. In 2020, he presented to the emergency department with altered mental status. Brain magnetic resonance imaging (MRI) revealed an enhancing hemorrhagic lesion in the trigone of the right lateral ventricle (LV) and nodular thickening in the center of the right LV and trigone of the left LV, suggestive of metastatic disease. In 2021, the patient developed refractory seizures, and serial MRIs showed disease progression. He underwent several craniotomies with pathology confirming metastatic clear cell carcinoma, consistent with a renal primary. In 2022, the patient again presented with altered mental status. MRI revealed new avidly enhancing subcentimeter solid nodules in the CP of both LVs consistent with metastatic disease. Per the wishes of the family, palliative measures were pursued, and the patient was discharged home. CONCLUSION RCC can reappear several years after nephrectomy. 4 Metastatic RCC appears to have a unique propensity to spread to the ventricular system and the CP, which indicates late progression of disease. 1,5,6 While surgery may be viable if tumor burden is low, therapeutic options are limited in the advanced disease stages, as in our patient. Palliative care should be offered early to maximize remaining quality of life.

Abstract 5178: Multifocality is an independent predictor of regional lymph node metastasis in Middle Eastern papillary thyroid carcinoma

Abstract Background: Papillary thyroid carcinoma (PTC) is treatable, with favorable prognosis and very low disease-specific mortality. However, PTC recurrence is relatively common in loco-regional and distant sites. Although multifocality is a common occurrence in PTC, its prognostic impact remains controversial. In addition, data on prevalence and prognostic significance of multifocality in PTC from Middle Eastern ethnicity is unknown. Therefore, the aim of this study was to investigate the prognostic value of multifocality in PTC larger than 1cm and papillary thyroid microcarcinoma (PTMC) in our center. Methods: A cohort of 1515 patients who underwent total thyroidectomy were retrospectively reviewed. Aggressive histopathologic variants of PTC were excluded to avoid their potential confounding effect on clinical outcomes. We identified 1087 patients who had PTC with primary tumor exceeding 1cm and 150 patients with PTMC, with medium follow up of 9.2 years. In each group, we compared patients with unifocal and multifocal disease. Clinico-pathological and molecular correlations were analyzed. Logistic regression analysis was used to assess the relation between multifocal tumors and lymph node metastasis. Results: The incidence of multifocality in PTC larger than 1cm was 48.3% (525/1087), whereas it was 38.7% (58/150) in PTMCs. In patients with PTC > 1cm, multifocality was significantly associated with aggressive markers such as extrathyroidal extension (p < 0.0001), lymphovascular invasion (p = 0.0047), lymph node (LN) metastasis (p = 0.0006), distant metastasis (p = 0.0305) and BRAF mutation (p = 0.0113). In analogous analysis of patients with PTMC, multifocality was significantly associated with extrathyroidal extension (p < 0.0001), LN metastasis (p = 0.0005) and BRAF mutation (p = 0.0006). In both sub-groups, disease recurrence and overall survival did not differ between unifocal and multifocal group. Multivariate analysis showed that multifocality was an independent predictor of LN metastasis (Odds ratio (OR) = 1.31; 95% confidence interval (CI) = 1.00 - 1.71; p = 0.0472 for PTC > 1cm and OR = 1.88; 95% CI = 1.00 - 3.54; p = 0.0491 for PTMC). Conclusions: Tumor multifocality is frequently observed in Middle Eastern PTC and PTMC and is a predictive factor for LN metastasis in PTC. Given the predictive value of multifocality in Middle Eastern ethnicity, aggressive therapy and intensive follow-up should be considered for both PTC and PTMC with multifocality. Regional LN metastasis should be closely monitored and prophylactic central lymph node dissection could be considered in these patients. Citation Format: Pratheeshkumar Poyil, Abdul K Siraj, Sandeep Kumar Parvathareddy, Divya Padmaja, Saravanan Thangavel, Rafia Begum, Roxanne Diaz, Khadija Al-Obaisi, Khawla S. Al-Kuraya. Multifocality is an independent predictor of regional lymph node metastasis in Middle Eastern papillary thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5178.

Cardiophrenic Lymph Node Metastasis of Ovarian High-grade Serous Carcinoma Showing Wild-type p53 Immunostaining Pattern and Aberrant CD56 Expression.

Patterns of p53 immunostaining are used as a surrogate marker for tumor protein 53 (TP53) mutations in the diagnosis of ovarian high-grade serous carcinoma (HGSC). We present a rare case of ovarian HGSC that metastasized to the diaphragm and cardiophrenic lymph nodes and showed the immunostaining pattern of wild-type p53 and aberrant neural cell adhesion molecule (CD56) expression. A 63-year-old woman developed multifocal metastases in the diaphragmatic pleura and cardiophrenic lymph nodes. Because she had a history of ovarian HGSC and pulmonary adenocarcinoma, we considered the possibility that the metastatic carcinoma was of either ovarian or pulmonary origin. Immunostaining revealed that the tumor cells were negative for thyroid transcription factor 1 but positive for Wilms tumor 1. The tumor additionally exhibited strong membranous CD56 expression and patchy p53 expression, both of which were inconsistent with the characteristics of ovarian HGSC. However, targeted sequencing analysis revealed that the tumor harbored a pathogenic mutation at the splice acceptor site of TP53 intron 9 (c.994-1G>C).

Abstract 5420: Multiomics approach identifies the SP8-FGF8 axis as an important promoter of metastatic features in hepatoblastoma

Abstract Introduction Hepatoblastoma (HB) is the most common pediatric liver tumor with a general good prognosis, but if associated with multifocal growth, vessel invasion or metastasis, outcome is still poor. The molecular mechanisms causing this high-risk profile are still unknown. The aim of our study was to gain insight into the neoplastic continuation towards more aggressive tumor phenotypes and to aid identification of biomarkers for high-risk patients. Experimental procedures Tumor specimens of seven non-metastasized and four metastasized HB patients were analyzed by RNA-sequencing and the Human Methylation 450 BeadChip microarray to assess global expression and methylation levels. Integration of both datasets identified new candidate genes, which were further verified in a cohort of 34 HB patients using real-time PCR. Gain and loss of function experiments of SP8 were conducted in five HB cell lines to evaluate its effects on proliferation, mobility, self renewal, migration and invasion. Chromatin-immunoprecipitation was used to assess binding of SP8 to the FGF8 promoter. Kaplan-Meier estimates of specific survival time in various groups were compared using the log-rank Mantel-Cox test. Results Global integration of expression and methylation levels identified the transcription factor SP8 and the fibroblast growth factor FGF8 as significantly upregulated genes accompanied with strong methylation changes in metastatic HB. In an independent cohort of 34 HB patients expression of both candidates was highly correlated (R² = 0.74, P < 0.0001) and could be positively associated with metastasis, the aggressive C2 subtype of the 16-gene signature and poor overall survival. Chromatin-immunoprecipitation identified binding of SP8 to the FGF8 promoter. Following SP8 overexpression in liver tumor cells, we found a significant increase in cell motility, self renewal and invasive growth together with the acquisition of a mesenchymal phenotype. In turn, CRISPRi-mediated knockdown of FGF8 rescued the phenotype. Conclusions We showed that elevated levels of SP8 induced cell motility, self renewal and mesenchymal characteristics by targeting FGF8, thereby implicating an important functional role of the SP8-FGF8 axis for the progression and metastasis of malignant childhood liver tumors. Moreover, SP8 might serve as a new biomarker in metastatic HB with poor prognosis. Citation Format: Alexandra Wagner, Beate Häberle, Irene Schmid, Christian Vokuhl, Dietrich von Schweinitz, Roland Kappler. Multiomics approach identifies the SP8-FGF8 axis as an important promoter of metastatic features in hepatoblastoma [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 5420.

Primary angiosarcoma of the breast with multifocal metastasis to contralateral breast: A diagnostic enigma.

Primary angiosarcoma of the breast with multifocal metastasis to contralateral breast: A diagnostic enigma.

Possible local treatment for liver metastases of adenoid cystic carcinoma (ACC): single-centre experience and literature review.

BackgroundAdenoid cystic carcinoma (ACC) is a relatively indolent cancer, for which the major cause of death is distant metastases. The median survival time of patients with distant metastases of ACC is approximately 20 months. Although the liver is not the most common site of secondary ACC, effective treatment of liver metastases could improve patient survival. This study explored the clinical features and treatment of liver metastases of ACC in one centre and performed a literature review.MethodsThis is a retrospective cohort study. The records of 25 ACC patients with liver metastases in our hospital from January 2000 to September 2018 and 13 case reports (from 2000 to 2018) from PubMed published in English were reviewed together. Survival curves were estimated by the Kaplan-Meier method. Multivariate cox regression analysis was used to identify risk factors for overall survival (OS).ResultsPatients with liver metastases of ACC had a poor prognosis. The median survival time of patients with ACC liver metastases was 14 months (4–26 months), and the 1-, 2-, and 3-year survival rates were 55.8%, 28.5%, and 15.2%, respectively. Isolated liver metastases were more likely to benefit from local treatment, such as surgery and radiofrequency ablation (RFA), than multifocal metastases. The prognosis was worse for patients who received systemic treatment for multifocal liver metastases than for those who received other treatment. Synchronous liver metastases were the predictive factor for OS both in univariate and multivariate analysis.ConclusionsLocal treatment, such as surgical resection or RFA, may prolong the survival time of ACC patients with liver metastases. The definition of resectability for liver metastases needs further investigation.

Perioperative and long-term outcomes of laparoscopic liver resections for non-colorectal liver metastases

Liver is a common metastatic site not only of colorectal but of non-colorectal neoplasms, as well. However, resection of non-colorectal liver metastases (NCRLMs) remains controversial. The aim of this retrospective study was to analyze the short- and long-term outcomes of patients undergoing laparoscopic liver resection (LLR) for NCRLMs. From a prospectively maintained database between 2000 and 2018, patients undergoing LLR for colorectal liver metastases (CRLMs) and NCRLMs were selected. Clinicopathologic, operative, short- and long-term outcome data were collected, analyzed, and compared among patients with CRLMs and NCRLMs. The primary tumor was colorectal in 354 (82.1%), neuroendocrine in 21 (4.9%), and non-colorectal, non-neuroendocrine in the remaining 56 (13%) patients. Major postoperative morbidities were 12.7%, 19%, and 3.6%, respectively (p = 0.001), whereas the mortality was 0.6% for patients with CRLMs and zero for patients with NCRLMs. The rate of R1 surgical margin was comparable (p = 0.432) among groups. According to the survival analysis, 3- and 5-year recurrence-free survival (RFS) rates were 76.1% and 64.3% in the CRLM group, 57.1% and 42.3% in the neuroendocrine liver metastase (NELM) group, 33% and 20.8% in the non-colorectal, non-neuroendocrine liver metastase (NCRNNELM) group (p = 0.001), respectively. Three- and 5-year overall survival (OS) rates were 88.3% and 82.7% in the CRLM group, 85.7% and 70.6% in the NELM group, 71.4% and 52.9% in the NCRNNELM group (p = 0.001), respectively. In total, 113 out of 354 (31.9%) patients with CRLMs, 2 out of 21(9.5%) with NELMs, and 8 out of 56 (14.3%) patients with NCRNNELMs underwent repeat LLR for recurrent metastatic tumors. LLR is safe and feasible in the context of a multimodal management where an aggressive surgical approach, necessitating even complex procedures for bilobar multifocal metastases and repeat hepatectomy for recurrences, is the mainstay and may be of benefit in the long-term survival, in selected patients with NCRNNELMs.

Ovarian dysgerminoma causing multifocal metastases in young bitch

The ovarian neoplasias are unusual in canine species, mainly originated from germinative cells. Among these, dysgerminoma is a rare neoplasm in bitches, predominantly affecting senile and small and medium breeds. They are large, rounded, smooth surface, painless and firm in consistency. The clinical signs commonly demonstrated by patients with this neoplasia are abdominal distension and secondary signs of hyperestrogenism. The diagnosis should be based on the association of history, clinical signs, radiographic, ultrasonographic, cytological, histopathological and immunohistochemical exams. The treatment is the surgical castration and metastases are uncommon. Due to the rarity in bitches, specifically the young animals, this study aimed to describe a case of left ovarian dysgerminoma, of considerable size and adherence in adjacent organs, in a Brazilian Fila, whose showed considerable increase in abdominal volume and progressive weight loss. The diagnosis was confirmed by means of complementary x-ray, ultrasound, histopathological and immunohistochemical tests. Even with the recommended surgical treatment (castration), the patient demonstrated severe respiratory symptoms and increased abdominal volume after two months, and the complementary exams suggested pulmonary and multifocal metastases and the tutor chose euthanasia. As presented by the results, although rare in bitches, dysgerminoma should be included in the differential of ovarian neoplasias, including the young ones.

Simultaneous resection of gastric and gallbladder metastasis from renal cell carcinoma treated by laparoscopic and endoscopic cooperative surgery: a case report

BackgroundMetastases to the stomach or gallbladder from any malignancy is rarely noted, and simultaneous metastases to both organs are atypical. We present a unique case of simultaneous multifocal metastases of the stomach and gallbladder from renal cell carcinoma (RCC).Case presentationThe case involved a 60-year-old man, with a past history of RCC (clear cell type, G2, T1b N0 M0 Stage I) treated by a right nephrectomy. Three years after the nephrectomy, a routine gastrointestinal endoscopy found an ulcerative lesion in the greater curvature of the gastric body. The gastric tumor was pathologically proven to be a metastasis from RCC. Furthermore, computed tomography incidentally revealed a mass lesion in the fundus of the gallbladder, which was also diagnosed as a potential metastasis from RCC. As endoscopic ultrasonography of the gastric tumor suggested the tumor potentially invaded to the submucosal layer, gastric wedge resection via a laparoscopic and endoscopic cooperative surgery (LECS) technique was applied to the gastric tumor, and laparoscopic cholecystectomy to the gallbladder tumor was simultaneously performed. Histological examination confirmed that the tumors of the stomach and gallbladder were both metastatic RCC. The hospitalization period after surgery was not eventful, and the patient was discharged on postoperative day 7. Thereafter, the patient required examination every 3 months, did not use anticancer agents, and has survived without relapse to 9 months after the surgery.ConclusionsFor patients with locally resectable RCC metastases, complete metastasectomy may bring long-term tumor control. Moreover, LECS for gastric metastasis is a reasonable approach for minimal invasiveness and an oncologically feasible outcome.

Prognostic value and impact of cerebral metastases in pancreatic cancer

Background: Pancreatic cancer is a fatal disease most often diagnosed at an advanced stage. Most patients already suffer from irresectable tumor or distant metastases being most commonly found in the liver or the lung. However, cerebral metastases occur extremely rare.Methods: We performed a retrospective analysis of our database to identify all patients diagnosed with pancreatic cancer and cerebral metastases who underwent surgical treatment in our department from January 2004 to November 2016.Results: Only 0.2% (4 of 2492) were diagnosed with cerebral metastases. Two patients had surgical resection of the cerebral metastases. One patient underwent palliative radiation therapy and the fourth patient received only palliative therapy. Mean interval between initial diagnosis and development of brain metastases was 8.5 months (range 1–20). Mean survival period after diagnosis of brain metastases was 4.75 months (range 1–10).Conclusions: Cerebral metastases of pancreatic cancer occur extremely rare. They are associated with an advanced tumor stage, commonly liver and lung metastases. All patients presenting with neurological symptoms, multifocal metastases, and significantly elevated CA 19-9 levels are suspicious of sustaining cerebral metastases and should undergo brain imaging.

FDG PET/CT as a survival prognostic factor in patients with advanced renal cell carcinoma

Accurate prediction of the outcome of molecular target-based treatment in advanced renal cell carcinoma (RCC) is an important clinical problem. Positron emission tomography/computed tomography using [18F]-2-fluoro-2-deoxyglucose (FDG PET/CT) is a noninvasive tool for the assessment of glucose accumulation which can be a marker of the biological characteristics of the tumor. In this paper, we assess FDG PET/CT as a survival prognostic marker in patients with advanced RCC. The study included 121 patients treated in the years 2011–2016 with a diagnosis of advanced renal cell carcinoma (stage IV, multifocal metastases in all patients). Assessment using FDG PET/CT was conducted by measuring the maximum standard uptake value (SUVmax) for the marker used (the highest SUV measurement result for each patient in a single examination). SUVmax measurements were compared with various clinical risk factors used as prognostic markers. The median follow-up period was 19 months (ranging from 3 to 61 months). SUVmax measurements in all patients ranged from 1.3 to 30.0 (median 6.9). Higher SUVmax was correlated with poorer prognosis. Multi-way analysis with standard risk factors revealed that SUVmax was an independent factor for overall survival (OS; p < 0.003, hazard ratio 1.312, 95% CI 1.147–1.346). For SUVmax < 7.0, median OS was 32 months. For 7.0 ≤ SUVmax < 12.0, median OS was 12.5 months. For SUVmax ≥ 12.0, median OS was 10 months. The differences were statistically significant. A preliminary SUVmax assessment conducted using FDG PET/CT can provide information useful in the prediction of survival of patients with advanced RCC.

Epidural Metastases From Follicular Thyroid Cancer Mimicking Meningiomas in 68Ga-DOTATATE PET

We report a woman with multifocal lesions suggestive of meningiomas in MRI, which also presented with high Ga-DOTATATE uptake in PET, a finding characteristic for meningioma. A whole-body staging due to a pathological fracture revealed multiple neoplastic lesions throughout the body without detection of a primary site. Subsequent pathological workup of a lung lesion revealed multifocal metastases from follicular thyroid cancer despite thyroidectomy 10 years ago (without pathological finding), and posttreatment scans after radioiodine therapy confirmed the multiple brain lesions to be metastases as well. Our case shows that epidural metastases from endocrine origin might represent a clinical pitfall in Ga-DOTATATE PET.

Comprehensive molecular profiling of multi-focal prostate cancer and concomitant lymph node metastasis: Implications for tissue-based prognostic biomarkers.

5061 Background: Current tissue-based prognostic biomarker assays claim that assessment of a single biopsy focus is sufficient to predict disease behavior. We analyzed and compared the genetic profiles of multifocal prostate cancer (PCa) with concordant lymph node metastasis (LNM) to determine if expression-based prognostic tests are robust to multifocality. Methods: This IRB-approved study comprised patients who underwent radical prostatectomy and lymph node dissection that revealed N1 or discordant multifocal (low- and high-grade foci) disease. DNA and RNA were co-isolated from each tumor focus pre-identified on formalin fixed paraffin embedded specimens. High depth, targeted DNA and RNA next generation sequencing was performed to characterize the molecular profile of each sample, using the Oncomine Comprehensive (11 patients) or Comprehensive Cancer (DNA, 3 patients) Panels and a custom targeted RNAseq panel comprising genes for deriving prognostic signatures. Results: A total of 67 primary tumor and 17 LNM foci from 14 patients were analyzed. We observed significant intra- and inter-patient molecular heterogeneity. For example, in patient #1, while all 4 regions of high-grade primary tumor showed TP53 somatic mutations and some copy number alterations (CNAs) with two samples from the LNM, tumor areas near the positive margin showed more complete concordance than intraprostatic regions. Critically, a low-grade primary tumor focus in this case showed no somatic mutation or CNA overlap with the high-grade or LNM samples. In patient #4, all tumor and LNM foci shared a large number of somatic mutations, including a frameshift mutation in PTEN, with no high level CNA, consistent with a hypermutated genotype. By targeted RNAseq, low- and high-grade tumors from the same patient showed distinct expression profiles using genes included in prognostic signatures. Conclusions: Our results challenge the claim that expression-based prognostic tests are robust to multifocality. Further studies are needed to better characterize the biologically dominant lesion in multifocal PCa and hold promise for the development of improved prognostic biomarkers.

Is It Appropriate to Treat Sarcoma Metastases With Intramedullary Nailing?

Patients with primary bone and soft tissue sarcoma are at risk for skeletal metastases. Although uncommon, these metastases can result in impending or pathologic fractures. Intramedullary nailing traditionally has been an accepted form of palliative treatment for patients with metastatic carcinoma, but we could find no studies that report specifically on intramedullary nailing of metastatic sarcoma lesions. We asked: (1) What is the survival of patients with an impending or pathologic fracture from a sarcoma metastasis? (2) What proportion of patients treated with intramedullary nailing subsequently underwent a revision procedure or nail removal during their lifetimes? Between 1996 and 2014, we performed 40 intramedullary nailing procedures in 34 patients with multifocal metastases from sarcomas who showed signs or symptoms of impending fracture or who presented with a pathologic fracture. All of these patients are accounted for, either through the time of death or to the present, and all are included at a mean of 13months (range, 0.3-86months) in this retrospective study. During the study period, we generally applied the same surgical indications for patients with nailing of metastatic sarcoma lesions as we did for patients with metastatic carcinoma; in general, we used intramedullary nailing (with or without cement) rather than resection for diaphyseal lesions with less cortical destruction and no substantial soft tissue mass or metadiaphyseal lesions that could be adequately supplemented with cementation. The goal was to use this approach when it would allow immediate weightbearing, or in patients whose medical conditions were such that a more-extensive procedure seemed unsafe. During the same period, an additional 58 patients underwent resection procedures for metastatic sarcomas to long bones because they either did not meet the above indications, had a solitary resectable metastasis, or because of surgeon preference; these patients were excluded from this study. The median age of the patients was 52years (range, 27-81years). Eleven patients with 11 impending or pathologic fractures were documented to have received either preoperative or postoperative radiation therapy and 29 patients received some form of chemotherapy. Thirty (88%) patients died during the period of observation, at a median of 5months (range, 0.3-80months) after surgery. Twenty-nine patients (85%) underwent no additional surgery and retained their original intramedullary nail. One patient (3%) underwent nail removal for infection, and four patients (12%) underwent further surgical revision secondary to local progression. Patients with an impending or pathologic fracture from multifocal metastatic sarcoma to a long bone have a dismal prognosis, but they may gain short-term benefit from surgical fixation with the goal of reducing pain and maintaining mobility. Although we have no group for comparison, such as treating with radiotherapy alone or resection and an endoprosthesis, our findings suggest that use of intramedullary nails is helpful for providing fixation that in most instances lasts for the lifetime of patients with multifocal bone metastases from sarcomas. Level IV, therapeutic study.

Quantitation of Intra-peritoneal Ovarian Cancer Metastasis

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Mortality is due to diagnosis of 75% of women with late stage disease, when metastasis is already present. EOC is characterized by diffuse and widely disseminated intra-peritoneal metastasis. Cells shed from the primary tumor anchor in the mesothelium that lines the peritoneal cavity as well as in the omentum, resulting in multi-focal metastasis, often in the presence of peritoneal ascites. Efforts in our laboratory are directed at a more detailed understanding of factors that regulate EOC metastatic success. However, quantifying metastatic tumor burden represents a significant technical challenge due to the large number, small size and broad distribution of lesions throughout the peritoneum. Herein we describe a method for analysis of EOC metastasis using cells labeled with red fluorescent protein (RFP) coupled with in vivo multispectral imaging. Following intra-peritoneal injection of RFP-labelled tumor cells, mice are imaged weekly until time of sacrifice. At this time, the peritoneal cavity is surgically exposed and organs are imaged in situ. Dissected organs are then placed on a labeled transparent template and imaged ex vivo. Removal of tissue auto-fluorescence during image processing using multispectral unmixing enables accurate quantitation of relative tumor burden. This method has utility in a variety of applications including therapeutic studies to evaluate compounds that may inhibit metastasis and thereby improve overall survival.

Quantitation of Intra-peritoneal Ovarian Cancer Metastasis.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Mortality is due to diagnosis of 75% of women with late stage disease, when metastasis is already present. EOC is characterized by diffuse and widely disseminated intra-peritoneal metastasis. Cells shed from the primary tumor anchor in the mesothelium that lines the peritoneal cavity as well as in the omentum, resulting in multi-focal metastasis, often in the presence of peritoneal ascites. Efforts in our laboratory are directed at a more detailed understanding of factors that regulate EOC metastatic success. However, quantifying metastatic tumor burden represents a significant technical challenge due to the large number, small size and broad distribution of lesions throughout the peritoneum. Herein we describe a method for analysis of EOC metastasis using cells labeled with red fluorescent protein (RFP) coupled with in vivo multispectral imaging. Following intra-peritoneal injection of RFP-labelled tumor cells, mice are imaged weekly until time of sacrifice. At this time, the peritoneal cavity is surgically exposed and organs are imaged in situ. Dissected organs are then placed on a labeled transparent template and imaged ex vivo. Removal of tissue auto-fluorescence during image processing using multispectral unmixing enables accurate quantitation of relative tumor burden. This method has utility in a variety of applications including therapeutic studies to evaluate compounds that may inhibit metastasis and thereby improve overall survival.

Distant Multifocal Bony Metastasis of a Grade II Meningioma: Case Report

Introduction Meningioma is the most frequent neoplasm of the central nervous system, accounting for nearly one-third of all intracranial tumors. The vast majority are benign and cured by surgical resection. Grade II meningiomas may show local invasion involving the brain, intracranial venous channels, bones, soft tissue and paranasal sinuses. Distant metastasis, on the other hand, is quite rare. Case Presentation We report distant, multifocal bony metastasis of an atypical meningioma, World Health Organization grade II, from a primary occipital lobe location in a patient who initially underwent stereotactic radiosurgery followed by surgical resection 4 years prior. The patient presented clinically with pain in the lower back and gluteal region. Distant metastases were noted radiologically in the lumbar spine, pelvis, and femur and were confirmed pathologically following biopsy. Conclusion Metastasis from meningiomas is exceedingly uncommon. In the present case, hematogenous spread to the lumbar spine, pelvis, and femur may have occurred due to a residual nodular remnant within the superior sagittal sinus.