Metastatic Spread In Patients Research Articles

Abstract PO1-06-06: Underestimation of metastatic spread in patients with lobular breast cancer: results from the post-mortem tissue donation program UPTIDER

Abstract Background: Invasive lobular carcinoma (ILC) accounts for 15% of all invasive breast cancers (BC) and has a peculiar metastatic spread in comparison to BC of no-special type. Since ILC is less likely to disrupt normal tissue architecture and is usually non-mass forming, imaging of ILC lesions entails many challenges. Insights into pathologic versus radiological metastatic invasion can lead to better diagnostic and monitoring tools for patients with ILC. Here, we compare microscopical findings during autopsy with clinical findings prior to death in patients with metastatic ILC included in our post-mortem tissue donation program UPTIDER (NCT04531696). Methods: UPTIDER was started in November 2020 in University Hospitals Leuven/KU Leuven with inclusion of patients with stage IV BC who were willing to participate. One of the predefined subgroups consisted of patients with primary pure (i.e. not mixed) ILC. Samples were taken from different macroscopically invaded and non-invaded sites. Clinical data on disease progression, imaging, biochemistry and treatment regimens were extracted from patient files. The number of samples that were preregistered as pathological served as a surrogate for lesions that were seen on imaging performed during the treatment of the patient. These samples are compared to microscopical findings of the autopsy. Results: Since the start of UPTIDER, an autopsy has been performed on 6 patients with pure ILC (26.1% of all autopsies). Median age at initial diagnosis was 52 years (range: 37 – 80 years). Three patients (50.0%) had stage IV disease at diagnosis, the others relapsed on average 162.7 months (range: 55 – 358 months) after initial diagnosis. The average time between clinical occurrence of metastases and death was 44.8 months (range: 15 – 83 months). Median number of treatment lines for stage IV disease was 5 (median endocrine lines 2; median chemotherapy regimens 3.5). To follow disease evolution, computed tomography of thorax and abdomen was used for 4 (66.7%) patients and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) for the remaining 2 (33.3%). Median time between last premortem imaging and death was 5.9 weeks (range: 1.6 – 16.6 weeks). At autopsy, a median of 26 unique metastases (range: 12-36) were sampled per patient. Table 1 gives an overview on the unique microscopically invaded metastases that were sampled per patient. Only 47.3% of the sampled unique metastases was preregistered. Of all unique metastases, 26.7% appeared macroscopically normal during autopsy. Tissues that appeared normal but turned out to be microscopically infiltrated included liver, stomach, adrenal glands, heart, pericardium, visceral and subcutaneous fat tissue. There were 2 patients with normal appearing, microscopically infiltrated livers. In these patients, elevation of γGT and transanimases was seen in the months prior to death. Conclusions: The disease burden of metastatic ILC reported on premortem imaging does not reflect the microscopical findings at autopsy. One of the priorities of metastatic ILC research should be the development of diagnostic tools to better estimate the extent of the disease. Future analyses of the performed postmortem MRIs in our study can aid in improving the interpretation of WB-DWI/MRI for patients with ILC. For now, clinicians should consider that unexplained clinical and/or biochemical findings might indicate progression of ILC. Table 1: patient overview on performed imaging and unique metastases sampled during autopsy CT = computed tomography; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; pt = patient; WB-DWI MRI = whole-body diffusion-weighted magnetic resonance imaging *exclusion of samples of patient 2012 since no preregistration was performed for this patient due to unexpected death Citation Format: Karen Van Baelen, Gitte Zels, Maxim De Schepper, Marion Maetens, Josephine Van Cauwenberge, Tatjana Geukens, Kristien Borremans, François Richard, Amena Mahdami, Ha-Linh Nguyen, Sophia Leduc, Anirudh Pabba, Ann Smeets, Ines Nevelsteen, Patrick Neven, Hans Wildiers, Vincent Vandecaveye, Wouter Van Den Bogaert, Giuseppe Floris, Christine Desmedt. Underestimation of metastatic spread in patients with lobular breast cancer: results from the post-mortem tissue donation program UPTIDER [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-06.

Evolution of structural rearrangements in prostate cancer intracranial metastases

Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) of 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n = 6) and nonbrain prostate cancer metastases (n = 36). This first study focused on WGS of prostate intracranial metastases led to several new insights. First, there was a higher diversity of complex structural alterations in prostate cancer intracranial metastases compared to primary tumor tissues. Chromothripsis and chromoplexy events seemed to dominate, yet there were few enrichments of specific categories of structural variants compared with non-brain metastases. Second, aberrations involving the AR gene, including AR enhancer gain were observed in 7/10 (70%) of intracranial metastases, as well as recurrent loss of function aberrations involving TP53 in 8/10 (80%), RB1 in 2/10 (20%), BRCA2 in 2/10 (20%), and activation of the PI3K/AKT/PTEN pathway in 8/10 (80%). These alterations were frequently present in tumor tissues from other sites of disease obtained concurrently or sequentially from the same individuals. Third, clonality analysis points to genomic factors and evolutionary bottlenecks that contribute to metastatic spread in patients with prostate cancer. These results describe the aggressive molecular features underlying intracranial metastasis that may inform future diagnostic and treatment approaches.

Abstract B009: Tumoral activation of endothelium drives macrophages-mediated metastatic niche formation and promotes lung metastasis

Abstract Primary tumor induces macrophages-enriched environment to establish metastatic niche which enhances homing and colonization of circulating tumor cells. However, the molecular mechanism underlying endothelial remodeling that favors macrophages infiltration and subsequent niche formation is not fully understood. Here, we found that tumor-derived factors activated endothelial cells to increase adhesive efficacy of monocytes to the endothelium, leading to macrophage infiltration. In mouse models of pulmonary metastasis, this endothelial activation triggered formation of premetastatic niche via accumulation of macrophages in the lungs. Of note, macrophages primed the metastatic microenvironment through enhancing expression of niche-related genes including S100A8, S100A9, MMP9 and fibronectin within the premetastatic lungs and directly transmitted survival signal to tumor cells in a contact-dependent manner. Furthermore, we demonstrated that depletion of macrophages specifically during premetastatic stages reduced niche formation and also resulted in reduced metastatic burden. These findings suggest that endothelial remodeling at metastatic site is a key step for initiation of premetastatic niche formation supported by macrophages. Targeting this step could present an opportunity for therapeutic intervention of metastatic spread in patients with malignant cancers. Citation Format: Hyewon Chung, Sang Wha Kim, Seung Hyeok Seok. Tumoral activation of endothelium drives macrophages-mediated metastatic niche formation and promotes lung metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B009.

Tumor cellularity beyond the visible in soft tissue sarcomas: Results of an ADC-based, single center, and preliminary radiomics study.

PurposeSoft tissue sarcomas represent approximately 1% of all malignancies, and diagnostic radiology plays a significant role in the overall management of this rare group of tumors. Recently, quantitative imaging and, in particular, radiomics demonstrated to provide significant novel information, for instance, in terms of prognosis and grading. The aim of this study was to evaluate the prognostic role of radiomic variables extracted from apparent diffusion coefficient (ADC) maps collected at diagnosis in patients with soft tissue sarcomas in terms of overall survival and metastatic spread as well as to assess the relationship between radiomics and the tumor grade.MethodsPatients with histologically proven soft tissue sarcomas treated in our tertiary center from 2016 to 2019 who underwent an Magnetic Resonance (MR) scan at diagnosis including diffusion-weighted imaging were included in this retrospective institution review board–approved study. Each primary lesion was segmented using the b50 images; the volumetric region of interest was then applied on the ADC map. A total of 33 radiomic features were extracted, and highly correlating features were selected by factor analysis. In the case of feature/s showing statistically significant results, the diagnostic accuracy was computed. The Spearman correlation coefficient was used to evaluate the relationship between the tumor grade and radiomic features selected by factor analysis. All analyses were performed applying p<0.05 as a significant level.ResultsA total of 36 patients matched the inclusion criteria (15 women; mean age 58.9 ± 15 years old). The most frequent histotype was myxofibrosarcoma (16.6%), and most of the patients were affected by high-grade lesions (77.7%). Seven patients had pulmonary metastases, and, altogether, eight were deceased. Only the feature Imc1 turned out to be a predictor of metastatic spread (p=0.045 after Bonferroni correction) with 76.7% accuracy. The value -0.16 showed 73.3% sensitivity and 71.4% specificity, and patients with metastases showed lower values (mean Imc1 of metastatic patients -0.31). None of the examined variables was a predictor of the overall outcome (p>0.05, each). A moderate statistically significant correlation emerged only between Imc1 and the tumor grade (r=0.457, p=0.005).ConclusionsIn conclusion, the radiomic feature Imc1 acts as a predictor of metastatic spread in patients with soft tissue sarcomas and correlates with the tumor grade.

Abstract 2852: A gene activating in vivo screen identifies EBAG9 as novel metastasis regulator in human colorectal cancer

Abstract As colorectal cancer (CRC) mortality remains high due to metastatic spread in patients with advanced disease stages, we here aimed at identifying novel metastasis regulators in CRC and at understanding their mechanism of action. In CRC, tumor progression and metastasis formation are driven by cells that possess tumor-initiating cell (TIC) activity. We therefore employed a collection of primary patient-derived CRC tumor spheroid cultures (TSC) that are enriched for cells with TIC activity to perform a gene activating in vivo screen, intending to identify genes that enhance metastasis formation. To this end, TSC (n=4) were transduced with a lentiviral trapping vector that integrates into the genome and thereby drives the overexpression of genes located in the vicinity of the integration site (IS). Transduced TSC were then serially transplanted under the kidney capsule of immunodeficient mice (NSG) and monitored for the induction of metastasis formation. Analysis of lentiviral IS by linear amplification-mediated (LAM)-PCR revealed an enrichment of an IS within the gene locus of Estrogen Receptor Binding Site Associated Antigen 9 (EBAG9) in metastases. RNA sequencing confirmed the trapping vector mediated upregulation of a truncated version of the EBAG9 gene (exon 5-7), which strongly suggested a contribution of EBAG9 to metastatic spread. To validate these findings, both the truncated (TR) as well as the physiologically occurring full length (FL) EBAG9 gene were overexpressed in TSC (n=4) and serially transplanted into NSG mice. In addition to an augmentation in metastasis upon EBAG9 overexpression compared to controls (FL: 1.4-fold, TR: 2.4-fold), we also detected the occurrence of lymphogenous metastases when EBAG9 levels were increased, indicating that EBAG9 not only contributes to metastatic spread but also modulates tropism. To further characterize the underlying processes, global gene and protein expression analyses were performed in primary TSC as well as in the CRC cell line DLD1. Compared to control transduced cells, EBAG9 overexpression induced expression changes in cell adhesion and microtubule molecules, which led us to investigate cell migration and adhesion as potential contributing mechanisms to metastasis formation. We here observed an increase both in cell migration as well as in adhesion to the extracellular matrix protein collagen I upon EBAG9 overexpression in DLD1. Interestingly, DLD1 adhesion to lymphatic endothelial cells was significantly higher in EBAG9 FL (p=0.008) and EBAG9 TR (p=0.016) overexpressing cells, underscoring the role of EBAG9 in tropism modulation. In summary, we here identified EBAG9 as novel metastasis regulator in CRC which will not only contribute to a better mechanistic understanding of metastatic spread but also to the development of novel future strategies for preventing and targeting advanced disease stages. Citation Format: Karin Laaber, Taronish D. Dubash, Anna Maria Melzer, Tania Christiansen, Nati Ha, Benedikt Brors, Martin Schneider, Friederike Herbst, Hanno Glimm, Claudia R. Ball. A gene activating in vivo screen identifies EBAG9 as novel metastasis regulator in human colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2852.

Comparison of the clinicopathological characteristics and prognosis between Chinese patients with breast cancer with bone-only and non-bone-only metastasis.

Bone is the most common site of metastatic spread in patients with breast cancer. Patients with bone-only metastasis (BOM) are a unique group. The aim of the present study was to compare the clinicopathological characteristics, survival and prognostic factors of patients with BOM and non-BOM. The clinical data of 1,290 patients with metastatic breast cancer treated at the Tianjin Medical University Cancer Institute and Hospital (Tianjin, China) between January 2008 and December 2017 were reviewed. The clinical data were divided into a BOM group (n=208 cases) and a non-BOM group (n=1,082 cases). Patients with BOM had longer disease-free survival, progression-free survival (PFS) and overall survival (OS) compared with patients in the non-BOM group. The hormone receptor (HR) status and number of metastases were significant influencing factors of PFS in the BOM group. Furthermore, the HR status, location of bone metastasis and number of bone metastases were significantly associated with OS of patients in the BOM group. Age at diagnosis of metastasis, HR status and tumor stage were significantly associated with OS in the non-BOM group. In the BOM group, patients with HR+/human epidermal growth factor receptor 2 (HER2)− tumors had the most favorable prognosis. In the non-BOM group, patients with HR+/HER2− and HER2+ tumors had improved prognosis. In the BOM with HR+/HER2− subgroup, the PFS and OS of patients receiving endocrine therapy or sequential therapy (chemotherapy followed by endocrine therapy) was significantly improved compared with those receiving chemotherapy alone (P<0.05). Skeletal-related events were significantly associated with the number of bone metastases (P<0.001). The most common secondary metastatic site in the BOM group was the liver. The prognosis of the patients in the BOM group was improved compared with that in the non-BOM patients. HR− and multiple bone metastases, as well as combined axial and appendicular bone metastases, were significantly associated with poor prognosis in the patients with BOM. For patients in the HR+/HER2− BOM subgroup, endocrine therapy alone resulted in satisfactory results.

Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing.

Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here, we establish a robust method for the identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA sequencing and patient-derived-xenograft models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity but micrometastases harbour a distinct transcriptome program conserved across patient-derived-xenograft models that is highly predictive of poor survival of patients. Pathway analysis revealed mitochondrial oxidative phosphorylation as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of oxidative phosphorylation dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of oxidative phosphorylation in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in patients with breast cancer.

Letter to the editor

Free AccessLetter to the EditorLetter to the editorNoman Khan, Muhammad Arif Saeed and Muhammad Salman KhanNoman Khanhttp://orcid.org/0000-0002-8343-6445 Aga Khan University Hospital Karachi Sindh Pakistan, Search for more papers by this author, Muhammad Arif Saeed Aga Khan University Hospital Karachi Sindh Pakistan, Search for more papers by this author and Muhammad Salman Khan Aga Khan University Hospital Karachi Sindh Pakistan, Search for more papers by this authorPublished Online:21 Jun 2019https://doi.org/10.1259/bjr.20190308SectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail AboutRe: Distinguishing adrenal adenomas from non-adenomas with multidetector CT: evaluation of percentage washout values at a short time delay triphasic enhanced CTWe are writing to you about the original article published in November issue of BJR titled “Distinguishing adrenal adenomas from non-adenomas with multidetector CT: evaluation of percentage washout values at a short time delay triphasic enhanced CT”. The study retrospectively evaluated use of a short time delay CT protocol to distinguish adrenal adenomas from non-adenomas. As discussed in manuscript document, there are inconsistencies in CT protocol that we think requires further clarification from authors.We thank you for your time and consideration.It was with great interest that we read the paper published in November issue of The British Journal of Radiology titled “Distinguishing adrenal adenomas from non-adenomas with multidetector CT: evaluation of percentage washout values at a short time delay triphasic enhanced CT”.The article presents an important advance in CT imaging of adrenal glands. The authors retrospectively evaluated use of triphasic CT with short delayed phase of 200 secs. The authors mention limitations of study however further clarification of the study protocol would be helpful.A routine triphasic CT protocol with short delayed Phase is not performed routinely and it’s unlikely to be the case at the institution where this study was conducted. It only stands to reason that patients undergoing CT for surveillance of metastatic disease would be subjected to a different protocol than those with suspicion of or known history of adrenal masses. This could have been mitigated by tabulating clinical indications of all scans.This is additionally complicated by statement in discussion section that “most cases of adenomas carried out both unenhanced and enhanced CT scans” implying that not all cases were subjected to the same triphasic protocol. This requires clarification.Response to letter: “Distinguishing adrenal adenomas from non-adenomas with multidetector CT: evaluation of percentage washout values at a short time delay triphasic enhanced CT” by Khan et alLiu et al., Department of Radiology, China-Japan Friendship HospitalWe appreciate the comments of Dr Khan et al, and we thank them for the interest in our recent publication in the British Journal of Radiology. We would like to make further clarification of the CT scan protocol in our study. Firstly, the unenhanced CT and enhanced CT are carried out separately at different time in our institution. It means that some patients receive unenhanced CT only, whereas others first receive unenhanced CT, then receive enhanced CT for further differential diagnosis. Secondly, abdomen enhanced CT use the same triphasic scan protocol after the bolus administration of the contrast agent in our institution, and this protocol is not specialized for adrenal lesions. Finally, this is a retrospective study, so we reviewed the patients with adrenal masses and selected cases carrying out both unenhanced and enhanced CT scans. Most of the adrenal lesions were discovered incidentally (incidentalomas) for other clinical problems. Some of the patients took only unenhanced CT and then underwent surgical operation or imaging follow-up. These patients were excluded in our study. Others took unenhanced CT at first and enhanced CT later, not only for differential diagnosis of adrenal lesions, but also for assessment of lesions in other organs, especially for detecting metastatic spread in patients with prior history of malignant diseases. We reviewed and analyzed these adrenal lesions in our article. Previous article FiguresReferencesRelatedDetails Volume 92, Issue 1100August 2019 © 2019 The Authors. Published by the British Institute of Radiology History ReceivedMarch 24,2019AcceptedApril 08,2019Published onlineJune 21,2019 Metrics Download PDF

IMAGING TECHNIQUES FOR THE DETECTION OF LYMPH NODE METASTASIS IN PATIENTS WITH LARYNGEAL ANF HYPOPHARYNGEAL CANCER

The purposeof the study was a systematic literature review of imaging assessment of lymph node metastasis in patients with laryngeal and hypopharyngeal cancer.Material and methods.In order to review the most relevant scientific literature available, we searched Elibrary, Medline databases (from January 2005 to December 2017). Of 735 identified studies, 32 were assessed.Results. The role of ultrasonography, spiral computer tomography, magnetic resonance tomography, positron emission tomography in the assessment of regional metastatic spread in patients with laryngeal and hypopharyngeal cancer was analyzed. All these imaging techniques failed to reliably identify clinically occult lymph node metastases. However, the choice of treatment options for laryngeal and hypopharyngeal cancer depends considerably on the diagnostic accuracy. In this context, the concept of sentinel lymph nodes deserves special attention.Conclusion.Further studies of the sentinel lymph node concept using various radiopharmaceutical drugs in the detection of preclinical regional metastasis in patients with laryngeal and hypopharyngeal cancer are required.

Patterns of spread and prognostic implications of lung cancer metastasis in an era of driver mutations.

In the present study, we examined the pattern of metastatic spread in patients with advanced non-small-cell lung cancer (nsclc) and the effect of EGFR mutations. Patients were identified from a provincial cancer registry, and individual medical records were reviewed. Patients were included if they had stage iv nsclc and underwent diagnostic EGFR mutation testing. Patients were divided into EGFR mutation-positive (EGFR+) and EGFR wild type (wt) cohorts. The primary endpoint was the cumulative incidence for each metastatic site: lung, bone, brain, liver, adrenal glands, distant nodes, and other. Cumulative incidence curves were estimated using a competing-risks method. The secondary outcome was survival. Of the 543 identified patients, 121 (22.3%) tested as EGFR+, and 422 (77.7%) tested as EGFR wt. The incidence of brain (39.2% vs. 28.2%, p = 0.038) and lung (61.2% vs. 51.0%, p = 0.048) metastasis was higher in the EGFR+ cohort than in the EGFR wt cohort. In the EGFR+ cohort, a higher incidence of liver metastasis was associated with the exon 21 mutation subtype than with the exon 19 deletion subtype [23% vs. 7%, p < 0.01; hazard ratio (hr): 3.47]. Median survival was significantly longer for the EGFR+ cohort than for the EGFR wt cohort (22.4 months vs. 7.9 months, p < 0.001). In multivariable analysis, brain (hr: 1.73), liver (hr: 1.69), and bone (hr: 1.89) metastases were associated with worse survival. Rates of lung and brain metastases are higher in EGFR mutation carriers, even when adjusted for differences in survival. Brain, liver, and bone metastases are independent negative prognostic factors for survival.

Basal oxidative stress ratio of head and neck squamous cell carcinomas correlates with nodal metastatic spread in patients under therapy.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a type of cancer that is strongly associated with oxidative damage and oxidative stress. Tobacco and alcohol – sources of massive quantities of reactive oxygen species (ROS) – have been clearly identified as etiologic factors that contribute to these malignancies. Considering the role of glutathione (GSH) in ROS detoxification, we hypothesized that potential biological markers can be found in addition to the parameters of oxidative stress. In line with previous studies that emphasized the accumulation of GSH in tumor cells, in this study, we have reported a lower ratio of oxidized versus reduced GSH in head and neck tumors.ObjectiveThe aim of the paper was to evaluate the prognostic and clinical significance of the ratio of oxidized versus reduced GSH in patients with head and neck cancers.MethodsThirty-six patients with HNSCC were included in this study. The tumoral redox status was determined by measuring the ratio of oxidized/reduced GSH (GSSG/GSH) by capillary electrophoresis. Statistical analysis was performed to assess the correlation between patient, clinical factors and the redox status.ResultsThe results showed a low tumoral ratio of GSSG/GSH and a better locoregional control. Moreover, a significant correlation between the tumoral redox status ratio (GSSG/GSH) and nodal stage (N0 versus N1, N2 and N3) was also observed. A higher tumoral redox status ratio was found to be associated with the presence of lymph node metastasis (N1, N2 and N3).ConclusionA strong correlation was observed between the oxidative status and locoregional control of the tumors. Moreover, a higher basal tumoral redox status ratio was found to be correlated with the presence of lymph node metastasis.

Metastatic spread in patients with gastric cancer

BackgroundThe epidemiology of metastatic gastric cancer is unexplored because cancer registries seldom cover metastatic involvement apart from “present or not”. We used a novel approach by utilizing Swedish registers to assess metastatic spread in gastric cancer. To our knowledge, this is the first nationwide description of metastases in gastric cancer.ResultsThe most common sites of metastasis were liver (in 48% of metastatic cancer patients), peritoneum (32%), lung (15%), and bone (12%). Metastases to the lung, nervous system, and bone were more frequent in cardia cancer and men, whereas non-cardia cancer more frequently metastasized within the peritoneum. Signet ring adenocarcinomas more frequently metastasized within the peritoneum, bone and ovaries, and less frequently to the lungs and liver compared with generic adenocarcinoma. The liver and the peritoneum were commonly single metastases while lung metastases occurred frequently together with liver metastases. The median survival in metastatic gastric cancer was 3 months, worst among those with bone and liver metastases (2 months).MethodsA total of 7,559 patients with gastric cancer were identified. Metastatic patterns and survival depending on sex, age, stage, anatomical location (cardia and non-cardia), and histological type were assessed.ConclusionsThe patterns of metastasis differ notably depending on histological type. Cardia cancer exhibits a completely different metastatic behavior than non-cardia cancer. Awareness of the differing patterns may guide in tailored diagnosis of metastases. Survivors from cardia cancer would benefit from increased surveillance of extraperitoneal metastases. Bone metastases should be considered in patients with signet ring adenocarcinoma if symptoms emerge.

Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells.

Tumor-infiltrating lymphocytes play an important role in cell-mediated immune destruction of cancer cells and tumor growth control. We investigated the heterogeneity of immune cell infiltrates between primary non-small cell lung carcinomas (NSCLC) and corresponding metastases. Formalin-fixed, paraffin-embedded primary tumors and corresponding metastases from 34 NSCLC patients were analyzed by immunohistochemistry for CD4, CD8, CD11c, CD68, CD163 and PD-L1. The percentage of positively stained cells within the stroma and tumor cell clusters was recorded and compared between primary tumors and metastases. We found significantly fewer CD4(+) and CD8(+) T cells within tumor cell clusters as compared with the stromal compartment, both in primary tumors and corresponding metastases. CD8(+) T cell counts were significantly lower in metastatic lesions than in the corresponding primary tumors, both in the stroma and the tumor cell islets. Of note, the CD8/CD4 ratio was significantly reduced in metastatic lesions compared with the corresponding primary tumors in tumor cell islets, but not in the stroma. We noted significantly fewer CD11c(+) cells and CD68(+) as well as CD163(+) macrophages in tumor cell islets compared with the tumor stroma, but no difference between primary and metastatic lesions. Furthermore, the CD8/CD68 ratio was higher in primary tumors than in the corresponding metastases. We demonstrate a differential pattern of immune cell infiltration in matched primary and metastatic NSCLC lesions, with a significantly lower density of CD8(+) T cells in metastatic lesions compared with the primary tumors. The lower CD8/CD4 and CD8/CD68 ratios observed in metastases indicate a rather tolerogenic and tumor-promoting microenvironment at the metastatic site.

CEACAM1-4L Promotes Anchorage-Independent Growth in Melanoma.

Widespread metastasis is the leading course of death in many types of cancer, including malignant melanoma. The process of metastasis can be divided into a number of complex cell biological events, collectively termed the “invasion-metastasis cascade.” Previous reports have characterized the capability of anchorage-independent growth of cancer cells in vitro as a key characteristic of highly aggressive tumor cells, particularly with respect to metastatic potential. Biological heterogeneity as well as drastic alterations in cell adhesion of disseminated cancer cells support escape mechanisms for metastases to overcome conventional therapies. Here, we show that exclusively the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) splice variant CEACAM1-4L supports an anchorage-independent signature in malignant melanoma. These results highlight important variant-specific modulatory functions of CEACAM1 for metastatic spread in patients suffering malignant melanoma.

Incidence of synchronous and metachronous adrenal metastases following tumor nephrectomy in renal cell cancer patients: a retrospective bi-center analysis

IntroductionSynchronous adrenalectomy has become dispensable since retrospective studies have demonstrated no survival benefit when preoperative imaging was normal. The aim of this large bi-institutional study was to determine the appearance of synchronous and metachronous metastases to the adrenal gland as detected by computed tomography and positron emission tomography or magnetic resonance imaging with consecutive surgical removal of suspicious lesions.Materials and methodsWe retrospectively reviewed the clinico-pathological records of 2720 patients from two urological centers who underwent radical or partial nephrectomy due to kidney cancer disease. Synchronous adrenalectomy was carried out in 548 of all cases (20.2%). Metachronous adrenalectomy was performed in 24 cases due to suspicious imaging in follow-up.ResultsMetastatic spread in patients with synchronous adrenalectomy was found in 29/548 cases (5.3%), as suspected. In metachronous procedures positive pathological results were found in 24 of 24 cases. Among them 54% of all tumor recurrences were detected in the contralateral adrenal gland.ConclusionsIn case of preoperative suspicious imaging an intraoperative frozen section should be performed. Radiological investigations are of high diagnostic value for detecting metachronous tumor growth into the adrenal gland. Surgery in this scenario should be recommended due to the high malignancy rate reported here.

Perioperative epidural analgesia and recurrence-free survival for ovarian cancer surgery: A retrospective analysis.

e16534 Background: Current experimental and clinical data suggest that perioperative factors may influence the long-term outcome after cancer surgery. Recent retrospective analyses have shown the reduction of cancer recurrence and metastatic spread in patients after tumor surgery receiving perioperative regional and neuraxial analgesia. The aim was to investigate whether perioperative epidural anesthesia is associated with the decreased disease recurrence and increased survival after primary tumor debulking in patients with ovarian cancer. Methods: Retrospective analysis of consecutive patients with primary ovarian cancer who underwent radical multivisceral surgery between 01/2003 and 12/2010 under either general anesthesia plus opioid analgesia (group A) or general anesthesia plus epidural anesthesia (group B), was performed. Cancer recurrence-free survival and total survival times after surgery were compared between the groups using Mann-Whitney test. The analysis was strengthened by Kaplan-Meier survival estimates for each group with comparison using the log-rank test. Results: Data of 105 (88%) of patients (group A: 33; group B: 72) were available for analysis. The median (interquartile range-IQR) follow-up time 27 (17-58) months. The groups were comparable regarding age, body-mass index, ASA physiological status, FIGO staging, tumor residual and use of adjuvant platinum-based chemotherapy. The median (IQR) time to recurrence of cancer was 31 (15-63) months in group A vs. 18 (10-35) months in group B (p = 0.017). Longer recurrence-free survival was associated with general anesthesia and opioid analgesia (hazard ratio 1.52; 95% confidence interval 1.4-1.56; p = 0.008). Conclusions: In contrast to previous investigations, perioperative epidural anesthesia was associated with decreased survival in patients after ovarian cancer surgery.

Brain metastases detectability of routine whole body (18)F-FDG PET and low dose CT scanning in 2502 asymptomatic patients with solid extracranial tumors.

As fluorine-18-fluorodesoxyglucose positron emission tomography/computed tomography ( (18)F-FDG PET/CT) is gaining wider availability, more and more patients with malignancies undergo whole body PET/CT, mostly to assess tumor spread in the rest of the body, but not in the brain. Brain is a common site of metastatic spread in patients with solid extracranial tumors. Gold standard in the diagnosis of brain metastases remains magnetic resonance imaging (MRI). However MRI is not routinely indicated and is not available for all cancer patients. Fluorine-18-FDG PET is considered as having poor sensitivity in detecting brain metastases, but this may not be true for PET/CT. The aim of our study was to assess the value of (18)F-FDG PET/CT in the detection of brain metastases found by whole body scan including the brain, in patients with solid extracranial neoplasms. A total of 2502 patients with solid extracranial neoplasms were studied. All patients underwent a routine whole body (18)F-FDG PET/CT scan with the whole brain included in the scanned field. Patients with known or suspected brain metastases were preliminary excluded from the study. Hypermetabolic and ring-like brain lesions on the PET scan were considered as metastases. Lesions with CT characteristics of brain metastases were regarded as such irrespective of their metabolic pattern. Lesions in doubt were verified by MRI during first testing or on follow-up or by operation. Our results showed that brain lesions, indicative of and verified to be metastases were detected in 25 out of the 2502 patients (1%), with lung cancer being the most common primary. Twenty three out of these 25 patients had no neurological symptoms by the time of the scan. The detection rate of brain metastases was relatively low, but information was obtained with a minimum increase of radiation burden. In conclusion, whole body (18)F-FDG PET/CT detected brain metastases in 1% of the patients if brain was included in the scanned field. Brain scanning as a part of whole body scan cannot replace routine imaging techniques, but in case of positive findings provides early and crucial information for further patient management, especially in asymptomatic patients.

Incidence of syn- and metachronous adrenal metastasis following tumor nephrectomy: A retrospective bicenter analysis.

417 Background: Metastases of adrenal gland occur in approximately 1.2 - 10% in kidney cancer patients. Synchronous adrenalectomy has become dispensable since studies have demonstrated no clinical benefit. The aim of this large bi-institutional study was to determine the appearance of syn- and metachronous metastasis to the adrenal gland as detected by CT, PET-CT or MRI imaging with consecutively surgically removal of suspicious lesions. Methods: We retrospectively reviewed the clinical and pathological records of 2308 patients (1200 pts. from Medical School Hanover until 2009 and 1108 pts. from University Hospital Plzeň until 2010) who underwent radical/partial nephrectomy. Synchronous adrenalectomy was carried out in 222 of all cases (10.4%). Metachronous adrenalectomy was performed in 11 cases including 8 ipsilateral and 3 contralateral adrenalectomies due to suspicious imaging among follow-up. In cases of metachronous metastasis pre-operative imaging, surgical and histopathological results were correlated. Results: Metastatic spread in patients with synchronous adrenalectomy was found in 17/222 cases (7.6%), as suspected. In metachronous procedures positive pathological results was found in 10 of 11 (91%) cases. In one case it was a benign pathological result. In all positive cases a metastasis from the former clear cell carcinoma was pathologically confirmed. 27% of all cases were detected in the contralateral adrenal gland. Conclusions: Synchronous adrenalectomy is not routinely recommended with nephrectomy. In case of preoperative suspicious imaging an intraoperative frozen section should be performed. Radiological investigations are of high diagnostic value for detecting metachronous tumor growth within the adrenal gland. Surgery in this scenario should be recommended due to the here reported malignancy rate of 91%.

Hydatid cyst of the liver mimicking metastasis on FDG PET/CT scan in a patient with colon cancer

The liver is the most common site for metastatic spread in patients with colorectal carcinoma. In addition to conventional radiological investigations, F-18 FDG PET/CT is being used in staging of the colon cancer with a widely increasing manner. FDG, used in imaging, is not a tumor specific radiopharmaceutic, and it may be uptaken in many benign pathologies. This situation may sometimes cause difficulty in differential diagnosis. In this article findings of the liver cyst hydatid mimicking metastasis on FDG PET/CT scan in a case with colon cancer are presented. Hydatid cyst should be considered in differential diagnosis of liver lesions on PET scan, especially in countries where zoonotic infections are relatively common as in ours. In this case report findings that may contribute to the differential diagnosis of hydatid cyst and metastasis on FDG PET/BT scan are discussed.

Role of serum S100B and PET-CT in follow-up of patients with cutaneous melanoma

BackgroundIncreased level of serum S100B can serve as a marker of metastatic spread in patients with cutaneous melanoma (CM). In patients with elevated S100 B and/or clinical signs of disease progression PET-CT scan is a valuable tool for discovering metastases and planning treatment.The aims of this study were to determine whether regular measurements of serum S100B are a useful tool for discovering patients with CM metastases and to evaluate the diagnostic value of PET-CT during the follow-up.MethodsFrom September 2007 to February 2010, 115 CM patients included in regular follow up at the Institute of Oncology Ljubljana were appointed to PET-CT. There were 82 (71.3%) patients with clinical signs of disease progression and 33 (28.7%) asymptomatic patients with two subsequent elevated values of S100B. Sensitivity, specificity, positive and negative predictive value (PPV, NPV) of S100B and PET-CT were calculated using standard procedures.ResultsDisease progression was confirmed in 81.7% of patients (in 86.5% of patients with clinical signs of disease progression and in 69.7% of asymptomatic patients with elevated S100B). Sensitivity, specificity, PPV and NPV of S100B was 33.8%, 90.9%, 96.0% and 17.5% in patients with clinical signs of disease progression. In 20.0% of patients increased serum S100B was the only sign of disease progression. Sensitivity and PPV of S100 in this group of patients were 100.0% and 69.7%.With PET-CT disease progression was diagnosed in 84.2% of symptomatic patients and in 72.7% of asymptomatic patients with elevated S100B. The sensitivity, specificity, PPV and NPV of PET-CT for symptomatic patients was 98.5%, 90.9%, 98.5% and 90.9% and 100%, 90.0%, 95.8% and 100% for asymptomatic patients with elevated S100.ConclusionsMeasurements of serum S100B during regular follow-up of patients with CM are a useful tool for discovering disease progression in asymptomatic patients. The value of its use increases if measurements are followed by extended whole body PET-CT.