Multiple Organ Metastases Research Articles

Abstract 2738: Role of KLF8 for drug-resistant metastasis of breast cancer

Abstract Metastasis and drug resistance are intertwined processes that are responsible for the vast majority of patient deaths from breast cancer. The underlying mechanisms still need to be investigated extensively. We previously demonstrated that KLF8 activates CXCR4 transcription in metastatic breast cancer. Here, we report a novel signaling mechanism that turns a localized metastasis into multiple organ metastases in response to chemotherapy. We show that KLF8 expression in breast cancer cells can be over-induced by chemotherapeutic drugs. Data from large-cohorts of patients indicates that post-chemotherapy there is a close correlation between the aberrant high levels of KLF8 and CXCR4, and this correlation is well associated with drug resistance, metastasis, and poor prognosis. To mimic this upregulation, we overexpressed KLF8 or CXCR4 in a human breast cancer cell line known to metastasize to the lungs only after i.v. injection in the nude mice. Surprisingly, we found that these KLF8 or CXCR4 overexpressing cells metastasized all over the body after orthotopically implanted. Tube formation assay, Ki67 staining, and western blotting revealed that KLF8 or CXCR4 overexpression promoted angiogenic vascular growth involving increased expression and secretion of VEGF protein. We also performed the matrigel-on-top 3-D culture to mimic the colonization step of metastasis and found that KLF8 or CXCR4 overexpression strongly enhances the formation of filopodium-like protrusions and proliferation via CXCR4 stimulation. Taken together, these results suggest that the chemo-induction of KLF8 upregulation is critical for drug resistance and systemic metastasis through enhanced tumor angiogenesis and colonization via CXCR4 over-activation. This discovery identifies the KLF8-CXCR4 signaling axis as a potentially new therapeutic target for breast cancer. Citation Format: Jie Hao, Heng Lu, Debarati Mukherjee, Aiqin Sun, Lin Yu, Jihe Zhao. Role of KLF8 for drug-resistant metastasis of breast cancer [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 2738.

Tumor Biology is King: Secondary Tumors of the Thyroid From 2 Medical Centers in China.

Background:We studied the clinical characteristics, diagnosis, treatment, and prognosis of secondary tumors of the thyroid (STTs) and analyzed this rare phenomenon based on our clinical experience.Methods:We reviewed 16 000 malignant thyroid tumors diagnosed at 2 medical centers in China from 1978 to 2018, including 55 patients with STTs.Results:The most frequent primary tumor sites included lung (21.8%), gastrointestinal (18.2%), breast (14.5%), and kidney (12.7%). The median age at STT diagnosis was 56 years. The time from diagnosis of primary tumor to metastases to the thyroid ranged from 0 to 108 months, with the longest interval being for renal cell carcinoma (RCC; mean: 49 months). There were 22 cases of single metastatic foci and 33 cases of multiple metastatic foci. At the time of STT diagnosis, 42 patients had multiple organ metastases and 13 patients had only thyroid metastases. Thyroid function was examined in 50 patients, including 23 with Hashimoto’s thyroiditis. Metastases were diagnosed histologically and confirmed by negative immunohistochemistry for thyroid markers. Twenty-one patients were treated with resection, including total thyroidectomy in 14 and unilateral lobectomy in 7. Thirty-four patients were treated without resection, but 2 were treated with tracheotomy. The median survival time of all patients with metastasis was 10 months (range: 1-96 months). Patients with primary RCC had the best prognosis (median survival time: 52 months), followed by patients with breast cancer (33 months). Patients who underwent thyroid surgery had a better prognosis than patients without thyroid surgery. Patients with single metastatic foci or single organ metastases had a better prognosis than patients with multiple metastatic foci or multiple organ metastases.Conclusions:Metastasis to the thyroid is a rare clinical phenomenon, and sometimes a diagnosis of STT is difficult; so, we need to pay more attention to it. While prognosis appears to be related to surgery or some characteristics of metastatic spread, these data suggest it is more complex. Tumor biology is king; in fact, prognosis was mainly related to the biological behavior of the primary tumor. We cannot only opt for surgery; thus, case selection is important, and the treatment strategy for STT patients should be determined individually according to their specific biological behaviors.

Characterizations of Cancer Gene Mutations in Chinese Metastatic Breast Cancer Patients.

Background: Breast cancer (BC) is a type of disease with high heterogeneity. Molecular profiling, by revealing the intrinsic nature of its various subtypes, has extensively improved the therapeutic management of BC patients. However, the genomic mutation landscape of Chinese metastatic BC has not been fully explored.Methods: Matched plasma and mononuclear cells from 290 Chinese women with metastatic BC were sequenced using either of the two commercially-available panels consisting of 520 cancer-related and 108 BC-related genes. Both panels cover the same critical regions of 91 genes. The circulating tumor DNA mutation profile from our cohort was then compared with publicly-available metastatic BC datasets from Memorial Sloan Kettering Cancer Center (MSKCC) and Pan-cancer analysis of whole genomes (PCAWG).Results: A total of 1,201 mutations spanning 91 genes were detected from 234 patients, resulting in a mutation detection rate of 80.7%. TP53 (64.1%) was the gene with highest mutation frequency, followed by PIK3CA (31%), PTEN (11%), and RB1 (10%). Copy number amplifications (CNAs) in MYC (14.1%), FGFR1 (13.3%), CCND1 (6.6%), FGF3 (6.6%), FGF4 (6.2%) and FGF19 (6.2%) were also detected from our cohort. TP53 mutations were significantly more frequent among triple negative BC (TNBC), HR−/HER2+, and HR+/HER2+ BC, while less common in HR+/HER2– (P < 0.01). Meanwhile, PIK3CA mutations were significantly more frequent among HR+/HER2+, HR+/HER2–, and HR−/HER2+ BC, while less common in TNBC (P < 0.01). Pathogenic or likely pathogenic BRCA1/2 germline mutations were detected in 5.9% of the cohort and 4.4% in TNBC subgroup. Maximum allelic fraction (maxAF) of TP53, RB1, and PIK3CA mutations were associated with multiple organ metastasis. Patients with PIK3CA, PTEN, and RB1 mutation were more likely to have liver metastasis (P < 0.02). Compared with MSKCC and PCAWG dataset, Chinese patients had observably difference in genetic variation rates in different molecular subtypes (TNBC: TP53 73.0 vs. 91.5%, P < 0.001; PIK3CA 21.2 vs. 13.2%, P = 0.061; HR+/HER2−: FGFR1 3.3 vs. 0.7%, P = 0.035; TP 53 46.2 vs. 27.7%, P < 0.001; RB1 6.6 vs. 2.7%, P = 0.046; CDKN2A 7.7 vs. 1.0%, P < 0.001; PIK3CA 30.8 vs. 44.2%, P = 0.012; CDH1 1.1 vs. 18.2%, P < 0.001; GATA3 7.7 vs. 17.2%, P = 0.02).Conclusions: A distinct gene mutation profile was elucidated in Chinese women with metastatic BC, justifying further research. Liquid biopsy provides a quick, real-time, and minimally invasive tool for future clinical trial and routine practice.

Comparing the fate of brain metastatic breast cancer cells in different immune compromised mice with cellular magnetic resonance imaging.

Metastasis is the leading cause of mortality in breast cancer patients, with brain metastases becoming increasingly prevalent. Studying this disease is challenging due to the limited experimental models and methods available. Here, we used iron-based cellular MRI to track the fate of a mammary carcinoma cell line (MDA-MB-231-BR) in vivo to characterize the growth of brain metastases in the nude and severely immune-compromised NOD/SCID/ILIIrg-/- (NSG) mouse. Nude and NSG mice received injections of iron-labeled MDA-MB-231-BR cells. Images were acquired with a 3T MR system and assessed for signal voids and metastases. The percentage of signal voids and the number and volume of metastases were quantified. Ex vivo imaging of the liver, histology, and immunofluorescence labeling was performed. Brain metastases grew more rapidly in NSG mice. At day 21 post cell injection, the average number of brain tumors in NSG mice was approximately four times greater than in nude mice. The persistence of iron-labeled cells, visualized as signal voids by MRI, was also examined. The percentage of voids decreased significantly over time for both nude and NSG mice. Body images revealed that the NSG mice also had metastases in the liver, lungs, and lymph nodes while tumors were only detected in the brains of nude mice. This work demonstrates the advantages of using the highly immune-compromised NSG mouse to study breast cancer metastasis, treatments aimed at inhibiting metastasis and outgrowth of breast cancer metastases in multiple organs, and the role that imaging can play toward credentialing these models that cannot be done with other in vitro or histopathologic methods alone.

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non–small-cell Lung Cancer

BackgroundOnly a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival. Patients and MethodsInformation about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals. ResultsA total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis. ConclusionDutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib.

A Case Report of Huge Sacrum Undifferentiated Pleomorphic Sarcoma Treated with Two Separate Surgeries of Decompression and Stabilization

Primary sacrum undifferentiated pleomorphic sarcoma (UPS) is an extremely rare malignant lesion. Furthermore, sacral tumor is often an uncontrollable condition, because the first diagnosis is usually made at advanced stage in the patients of sacral tumors. In this article, we report a patient with sacrum UPS, who showed aggressive local recurrence and early progression of multiple metastases in major organs after palliative surgery, resulting in the occurrence of a U-shaped sacrum pathological fracture requiring stabilization from the fourth lumbar to the ilium. An 87-year-old male patient showed progressively worsening gait difficulty following bladder and bowel dysfunction because of the presence of a sacrum tumor. Palliative surgery (laminectomy) from the first to the third sacrum (S) and tumor excision were performed. His neurological dysfunction tended to recover after surgery. However, a U-shaped sacrum pathological fracture occurred. Percutaneous stabilization from the fourth lumbar to the ilium was performed during the second postoperative week. The findings were consistent with those of a UPS. The patient was able to transfer from the bed to a wheel chair. However, his general condition deteriorated, with multiple organ metastases, and he expired because of respiratory insufficiency caused by the UPS 2 months after stabilization. Sacral stabilization should be considered for patients with an invaded S1–2 pedicle because of the potential occurrence of S1 pedicle and sacrum fractures. Palliative treatment with only radiation and analgesic agents after needle biopsy might have been another option, considering the age and the biological nature of sacral UPS.

Modified Glasgow Prognostic Score, Prognostic Nutritional Index and ECOG Performance Score Predicts Survival Better than Sarcopenia, Cachexia and Some Inflammatory Indices in Metastatic Gastric Cancer

Background: Gastric carcinoma (GC) patients usually present with locally advanced or metastatic disease; therefore treatment aim is mainly palliation. In this study our purpose is to analyze the prognostic values of the sarcopenia index (SI), cachexia index (CIn) and other inflammatory indexes (advanced lung cancer inflammation index [ALI], modified Glasgow Prognostic Score [mGPS], prognostic index [PI], prognostic nutritional index [PNI] and neutrophil-to-lymphocyte ratio [NLR]) in metastatic GC patients.Methods: Data from the files of metastatic GC patients, who applied to Medical Oncology outpatient clinic in Marmara University Pendik Education and Research Hospital between January 2011 and June 2016, were retrospectively reviewed. Five hundred seventy patients with gastric cancer were detected. Exclusion criteria were the inability to reach the patient surveys for prognostic index calculations, the presence of additional comorbidities to affect the laboratory parameters, and the absence of metastatic disease. Finally, 87 of these patients were included in this study. For SI calculation L3 level muscle area was measured from patients’ computed tomography (CT) by a radiologist. SI reference value was obtained from western-EGWSOP (The European Working Group on Sarcopenia in Older People) and eastern (Harada Y, et al.) sources separately, as Turkey doesn’t have a reference value for SI. NLR cutoff value was accepted as the median value of patients’ NLR measurements. Statistical analysis was conducted using SPSS. Kaplan-Meier and Cox regression models were used to assess independent prognostic factors. The area under the curve was used to compare the prognostic value of indexes.Results: The median length of follow-up of 87 patients was nine months (1-64 mo,/s), and 78 patients died during follow-up. Fifty-nine patients were male (63%), and the median age was 62 (range, 23-88). According to univariate analysis high mGPS and PI score, PNI level <45, NLR level ≥ 3.41, ALI level <18, CI level under 35, SI (Harada Y, et al) ≤44.5 for males and ≤36.5 for females, ECOG score ≥ 2, weight loss more than 10% during last 6 mo, BMI under 24 were poor prognostic factors. Age, gender, having multiple organ metastasis, history of gastric surgery, positivity C-erb-B2, SI (EGWSOP) ≤52.4 for males, and ≤38.4 for females did not have any impact on survival. According to multivariate analysis, high mGPS (score 2) (HR 2,494, 95% CI 1.25–4 .94, p = 0.02), PNI (score 1) (HR 4.2, 95% CI 1.73–10.1, p < 0.001) and ECOG score (≥2) (HR 1.541, 95% CI 1,089-4,214, p = 0.004) have been found to be independent prognostic factors which are determining the survival. mGPS was found to be more valuable than other indexes for predicting mortality by measuring the AUC with ROC analysis.Conclusions: In our study, mGPS, PNI and ECOG score were independent indicators for shorter survival in metastatic gastric cancer patients. mGPS and PNI, which can be done by using only serum CRP, albumin level and complete blood count, might be inexpensive, practical and beneficial to use in routine clinical practice to determine survival.

PD64-08 LYSOSOMAL PROTEIN TRANSMEMBRANE 5 MEDIATES LUNG-SPECIFIC METASTASIS OF RENAL CANCER BY REGULATING BMP/SMAD1 PATHWAY

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III (PD64)1 Apr 2020PD64-08 LYSOSOMAL PROTEIN TRANSMEMBRANE 5 MEDIATES LUNG-SPECIFIC METASTASIS OF RENAL CANCER BY REGULATING BMP/SMAD1 PATHWAY Bo Jiang*, Wei Chen, Xiaozhi Zhao, and Hongqian Guo Bo Jiang*Bo Jiang* More articles by this author , Wei ChenWei Chen More articles by this author , Xiaozhi ZhaoXiaozhi Zhao More articles by this author , and Hongqian GuoHongqian Guo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000981.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite progression in cancer control and survival, metastases are still diagnosed in a notable proportion of renal cancer (RCC) patients with a significant tendency to lung. Lung metastasis seriously affects the prognosis of patients and the current clinical drugs fail to achieve satisfactory therapeutic effects. It is urgent to develop new drugs based on the molecular theory of lung metastasis of RCC for better personalized treatment. However, the research on the mechanism of lung-specific metastasis of RCC is still blank. METHODS: Left ventricular injection of luci-labeled murine RCC cells (Renca-Luci) was used to establish the multiple organ metastasis model of RCC, metastases were measured by in vivo imaging system, then metastatic tumor cells in lung and other organs were primarily cultured. After verification, metastatic cells from lung (LuM), brain (BrM) and bone (BoM) along with untreated parental Renca cells were sent for high-throughput RNA-seq analysis. Sphere formation assay and subcutaneous tumor formation assay were conducted to test the stemness of RCC cells. In addition, we further evaluated the effect of lysosomal inhibitor (chloroquine) on the regulation of the BMP/SMAD1 pathway by LAPTM5, and attempted to explore its application prospect of anti-pulmonary metastasis. RESULTS: LuM, BrM, BoM and parental Renca-Luci cells were re-injected into left ventricular of mice, LuM cells showed greater ability to invade the lungs than other cells. LAPTM5 revealed significantly higher mRNA level according to the RNA-seq data and further validated by western-blotting assay at protein level. Overexpression of LAPTM5 in Renca and 786-O cells facilitated the formation of pulmonary metastases in mice, conversely, down-regulation of LAPTM5 in Renca cells significantly reduced lung metastatic lesions. Meanwhile, the ability to invade the brain and bone of Renca-Luci cells was not significantly affected which suggested that LAPTM5 mediates lung-specific metastasis of RCC. BMP/SMAD1 signal suppressed cancer stem cell behavior and was responsible for tumor cell dormancy in the lungs, we provided evidence that LAPTM5 inhibited phosphorylation of smad1 of RCC cells after stimulated with recombinant BMP4 and thereby enhancing the self-renewal capability of RCC cells, the inhibitory effect disappeared after chloroquine treatment. CONCLUSIONS: Our results unraveled that LAPTM5 mediates lung-specific metastasis of RCC by inhibiting BMP/SMAD1 pathway and represents therapeutic targets for RCC. Source of Funding: This work was supported by grants from the National Natural Science Foundation of China (81502203, 81772710), the National Natural Science Foundation of Jiangsu Province (BK20150097), the Project of Invigorating Health Care through Science, Technology and Education Jiangsu Provincial Key Medical Discipline (ZDXKB201601 4), the “Summit of the Six Top Talents” Program of Jiangsu Province (SWYY-084), Postdoctoral Scientific Research Project of China (2017M621729) and the Postdoctoral Research Foundation of Jiangsu Province (1701021B), Nanjing Medical Science and technique Development Foundation (QRX17139). © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1303-e1303 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bo Jiang* More articles by this author Wei Chen More articles by this author Xiaozhi Zhao More articles by this author Hongqian Guo More articles by this author Expand All Advertisement PDF downloadLoading ...

Treatment and prognosis for patients with differentiated thyroid carcinoma bone metastases.

BackgroundTo investigate reasonable treatment modalities and prognostic factors for patients with differentiated thyroid carcinoma (DTC) bone metastases (BM).MethodsThe clinicopathological characteristics and follow-up data for all patients with DTC BM who received treatment in the Third Affiliated Hospital of Kunming Medical University between November 1, 1993 and December 31, 2016 were analyzed retrospectively with respect to mortality and survival rates. Multivariate analysis was performed using the Cox proportional hazard model.ResultsThe 5- and 10-year overall survival (OS) rates were 51.5% and 17.2%, respectively, for all 60 patients. Univariate analysis showed that patients diagnosed with BM at <45 years of age, with controlled thyroid-stimulating hormone (TSH) levels and those undergoing surgery or 131I therapy had better prognoses. Patients with cervical vertebra metastases, multiple organ metastases other than bone, and those receiving chemotherapy had worse prognoses. Gender, pathological type, number of BM lesions, skeletal-related events (SREs) and whether or not the patient received radiotherapy were not related to prognosis. Cox regression analysis showed that age at diagnosis of BM, undergoing surgery for bone lesions, and not receiving chemotherapy were independent factors of favorable prognosis for patients with DTC BM.ConclusionsPatients with DTC BM have poor prognoses. Age at diagnosis with BM <45 years old, undergoing surgery for bone lesions, and not receiving chemotherapy were independent factors of favorable prognosis for patients with DTC BM. 131I combined with surgery for bone metastatic lesions may be the best treatment model for most patients with DTC BM disease.

Synchronous NET and colorectal cancer development: a case report

BackgroundThe incidence of synchronous gastrointestinal neuroendocrine tumors (GI-NETs) and colorectal cancer is very low.Case presentationWe present a 72-year-old man diagnosed with a rectal neuroendocrine tumor (NET) with multiple organ metastases and simultaneous sigmoid colon cancer. Although the NET was his prognostic factor, he underwent a laparoscopic sigmoidectomy at first because it was expected that the colon cancer would cause obstruction or bleeding during NET treatment. Subsequently, he started taking everolimus.ConclusionsWe should consider surgical resection of the synchronous cancer before systemic therapy for a GI-NET regardless of the difference in prognosis between synchronous tumors, if the cancer may impair the continuation of systemic therapy.

The Clinical Characteristics of Endometrial Cancer With Extraperitoneal Metastasis and the Value of Surgery in Treatment.

Objective:To describe the clinical and pathological features of endometrial carcinoma with extraperitoneal metastasis and examine whether surgery could improve the prognosis.Methods:The Surveillance, Epidemiology, and End Results database was used to analyze 730 patients who were diagnosed with extraperitoneal metastasis of endometrial cancer from 2010 to 2015, including metastasis to the lung, bone, or brain.Results:Of the 730 patients, 372 (50.96%) patients had single lung metastases, and 196(26.85%) patients had multiple organ metastases that included pulmonary invasion. Therefore, the lung was the most common target organ for extraperitoneal metastasis of endometrial cancer. In multivariate risk factor analysis, grade 3 tumor (odds ratio = 3.39, P < .001), positive peritoneal cytology (odds ratio = 2.02, P < .001), and cervical stromal invasion (odds ratio = 1.42, P = .030) were independent risk factors for extraperitoneal metastasis. Once metastasis occurred in the brain or multiple organs, the prognosis was often poor. Of the patients, 362 underwent surgery, and surgery was performed only for primary tumors of the reproductive organs in almost all patients (97.23%) with extraperitoneal metastasis. The median cancer-specific survival periods of patients with solitary pulmonary metastasis undergoing surgery and those without surgery were 23 (16.43-29.57) months and 9 (6.21-11.79) months, respectively (P < .001), and survival superiority also existed in patients with bone metastasis (19 vs 8 months, P = .015) and multiple organs metastases (15 vs 4 months, P < .001). However, patients with brain metastasis had the same median survival period in the 2 groups (6 months, P = .146).Conclusions:The lung was the most common target organ for extraperitoneal metastasis in patients with endometrial cancer. Surgery was associated with improved survival in women with extraperitoneal metastasis, except for patients with brain metastasis.

Serum CEA and CYFRA Levels in ALK-rearranged NSCLC Patients: Correlation With Distant Metastasis.

To clarify the correlation between serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA) and metastasis and survival in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients. CEA and CYFRA levels in 131 ALK-rearranged NSCLC patients were determined using fluorescence in situ hybridization (FISH), real time-reverse transcription polymerase chain reaction, and immunohistochemistry, using biopsy specimens, cytology specimens, and plasma specimens. Cut-off value of each marker was determined as 10 ng/ml. In logistic regression analysis, higher levels of both markers had a positive relationship with bone metastases, and higher levels of CYFRA was relevant to liver metastases, and multiple-organ metastases. However, these markers were not proven to be poor prognostic factors in Cox's proportional model analysis. Elevated serum CEA and CYFRA levels seem to provide useful clinical information about presence of bone and liver metastasis and multiple-organ metastases, although they were not a powerful indicator of prognosis. These two markers may suggest the extension of metastasis and would be helpful in considering treatment options.

Prognostic model and optimal treatment for patients with stage IVc nasopharyngeal carcinoma at diagnosis

The treatment for patients with stage IVc nasopharyngeal carcinoma (NPC) at diagnosis was still controversial. In this study, we tried to build a prognostic score model and optimize the treatment for the patients. The prognostic model was based on the primary cohort involving 289 patients from 2002 to 2011 and the validation involving another 156 patients from 2012 to 2015.The prognostic model was built based on the hazard ratios of significant prognostic factors for overall survival (OS). By multivariate analysis, factors associated with poor OS were Karnofsky performance score ≤70, liver metastases, multiple-organ metastases, ≥2 metastatic lesions, lactate dehydrogenase >245 IU/I and poor response to chemotherapy (all P < 0.01). Based on these prognostic factors, patients were divided into the low-risk (0–2 points), intermediate-risk (3–6 points) and high-risk (≥7 points) groups. Five-year OS rates for the low-, intermediate- and high-risk groups were 49.3%, 9.7% and 0.0%, respectively (P < 0.01). Furthermore, loco-regional radiotherapy was associated with significantly better OS in low- and intermediate-risk patients, but not in high-risk patients. These results demonstrated that the prognostic score model based on six negative factors can effectively predict OS in patients with stage IVc NPC at diagnosis. Loco-regional radiotherapy may be beneficial for low- and intermediate-risk patients, but not for high-risk patients.

Ovarian Primary and Metastatic Tumors Suppressed by Survivin Knockout or a Novel Survivin Inhibitor.

Survivin, a member of the inhibitor of apoptosis family, is upregulated in multiple cancers including ovarian cancer, but is rarely detectable in normal tissues. We previously reported that survivin promoted epithelial-to-mesenchymal transition (EMT) in ovarian cancer cells, suggesting that survivin may contribute to ovarian tumor metastasis and chemoresistance. In this study, we tested whether knockout or pharmacologic inhibition of survivin overcomes chemoresistance and suppresses tumor metastasis. The genetic loss of survivin suppressed tumor metastasis in an orthotopic ovarian cancer mouse model. To pharmacologically test the role of survivin on ovarian tumor metastasis, we treated chemo-resistant ovarian cancer cells with a selective survivin inhibitor, MX106, and found that MX106 effectively overcame chemoresistance in vitro MX106 inhibited cell migration and invasion by attenuating the TGFβ pathway and inhibiting EMT in ovarian cancer cells. To evaluate the efficacy of MX106 in inhibiting ovarian tumor metastasis, we treated an orthotopic ovarian cancer mouse model with MX106, and found that MX106 efficiently inhibited primary tumor growth in ovaries and metastasis in multiple peritoneal organs as compared with vehicle-treated control mice. Our data demonstrate that inhibition of survivin using either genetic knockout or a novel inhibitor MX106 suppresses primary ovarian tumor growth and metastasis, supporting that targeting survivin could be an effective therapeutic approach in ovarian cancer.

ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis

BackgroundAspartate β-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer.MethodsStable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied.ResultsThrough physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH’s β-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis.ConclusionsASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH’s pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.

Testicular Interstitial Cell Tumor with Disseminated Cutaneous Metastasis in a Dog

Background: Although testicular tumors commonly develop in the genital tract of dogs, only few studies have reported about metastatic testicular tumors in dogs to date. Therefore, the present study aimed to describe the gross, histopathological, and immunohistochemical findings in a dog with metastatic interstitial cell tumor.Case: A 6-year-old male Beagle underwent clinical examination due to enlargement of the left testicle and nodules in the skin of the left inguinal region and of the scrotum. The left testicle was cryptorchid (inguinal), and the right testicle was intrascrotal. Both testicles and affected skin fragments were surgically removed. The right testicle was normal in size and did not exhibit gross changes. However, the left testicular parenchyma had been completely replaced by a firm, grayish-to-white neoplastic mass with an irregular surface. The inguinal and scrotal skin fragments were thickened by the neoplastic masses. Histologically, the left testicular parenchyma was completely obliterated by a neoplastic mass consisting of round-to-oval and polygonal cells. The neoplastic cells generally had abundant eosinophilic cytoplasm with indistinct cell limits. The nuclei were round and small, with aggregated chromatin. However, some cells exhibited high degrees of atypia and pleomorphism and large nuclei with granular chromatin. Mitotic figures were observed at high frequencies of up to 11 per high-power field (400×). The mass in the left testicle was diagnosed as malignant interstitial cell tumor. The sections of the inguinal skin and scrotum presented with neoplastic cells similar to those observed in the left testicle, which is consistent with the metastasis of the malignant testicular interstitial cell tumor. On the basis of necropsy, multiple cutaneous and subcutaneous nodules were randomly distributed throughout the body, primarily in the prepuce, head, and limbs. Histological evaluations of the skin nodules, internal iliac lymph nodes, and abdominal skeletal muscles also revealed metastases of the testicular interstitial cell tumor.Discussion: The histopathological findings associated with the immunohistochemical results observed in the present case helped in establishing the diagnosis of malignant interstitial cell tumor. Regarding the histological evaluations, although most neoplastic cells exhibited appearances that are characteristic of Leydig cells, several features indicative of malignancy were also observed. In dogs, malignant interstitial cell tumors are rare, and multiple organ metastases have been described. Among the immunohistochemical markers that were examined (calretinin, vimentin, cytokeratin, placental alkaline phosphatase, and octamer-binding transcription factor 3/4), only vimentin staining produced a positive result. In one study, the antibody against vimentin stained both normal Sertoli and Leydig cells and tumors arising from these cells, but not seminomas, which is an important differential diagnosis in the case described in this study. The negativity for placental alkaline phosphatase also allowed to rule out seminoma in the differential diagnosis of the primary tumor. The skin sections (distant metastases) were negative for T and B lymphocytes and macrophages, thereby ruling out possible differential diagnoses, such as lymphomas or histiocytic tumors, among the cutaneous neoplasms. Therefore, this case report described a malignant testicular interstitial cell tumor with an uncommon disseminated pattern of metastases to the skin in a dog.

Combination Immuno-therapy in Melanoma

Abstract The prognosis of malignant melanoma in advanced stage used to be quite pessimistic, but there has been a paradigm shift going on in the lately, due to the newly-developed drugs. Especially, immuno-therapy with immune-checkpoint inhibitors including PD-1 have brought dramatic changes in various cancer chemotherapy, not limited to treatment for melanoma. However, when it is monotherapy, the response rate is lower (ORR: less than 30%) and the duration until the effect onset is longer (more than 3 months) for Japanese patients than those for Caucasian patients. These problems result in further advancing of the disease or dropout from the therapy detected among 15% of the patients. Based on these circumstances in Japan, combination therapy (Nivolumab + Ipilimumab) as a primary therapy has been introduced since August, 2018. This combination therapy has been given high expectations, as it has proven potent effect and early effect onset. However, it has strong and heavy adverse events and requires caution and prudent planning (i.e. biomarkers and selection of patients) for the proper application. In this symposium, I would like to present my own opinions by keywords including BRAF mutation positive, LDH, brain metastasis, multiple organ metastasis and primary therapy.

Patient-derived xenografts of central nervous system metastasis reveal expansion of aggressive minor clones.

The dearth of relevant tumor models reflecting the heterogeneity of human central nervous system metastasis (CM) has hindered development of novel therapies. We established 39 CM patient-derived xenograft (PDX) models representing the histological spectrum, and performed phenotypic and multi-omic characterization of PDXs and their original patient tumors. PDX clonal evolution was also reconstructed using allele-specific copy number and somatic variants. PDXs retained their metastatic potential, with flank-implanted PDXs forming spontaneous metastases in multiple organs, including brain, and CM subsequent to intracardiac injection. PDXs also retained the histological and molecular profiles of the original patient tumors, including retention of genomic aberrations and signaling pathways. Novel modes of clonal evolution involving rapid expansion by a minor clone were identified in 2 PDXs, including CM13, which was highly aggressive in vivo forming multiple spontaneous metastases, including to brain. These PDXs had little molecular resemblance to the patient donor tumor, including reversion to a copy number neutral genome, no shared nonsynonymous mutations, and no correlation by gene expression. We generated a diverse and novel repertoire of PDXs that provides a new set of tools to enhance our knowledge of CM biology and improve preclinical testing. Furthermore, our study suggests that minor clone succession may confer tumor aggressiveness and potentiate brain metastasis.

Impact of sites versus number of metastases on survival of patients with organ metastasis from newly diagnosed cervical cancer.

ObjectiveThe aim of this study was to investigate the potential associations of the sites and the number of specific metastases with survival in patients newly diagnosed with cervical cancer.MethodsMedical records of patients with organ metastases of newly diagnosed cervical cancer at Zhejiang Cancer Hospital from October 2006 to December 2016 were reviewed retrospectively. Survival times were compared using the Kaplan-Meier method. Variables associated with survival were identified using univariate and multivariate Cox proportional hazards models.ResultsA total of 99 patients with newly diagnosed organ metastatic cervical cancer were identified. Median follow-up was 11.6 months (range, 0.5–114.7 months). Median overall survival (OS) time was 11.7 months from diagnosis, with 1, 2, and 5-year OS rates of 48.2%, 22.8%, and 12.6%, respectively. The most common site of organ metastasis was bone (36.8%), followed by lung (32.8%) and liver (24%). In univariate analysis, OS rates were better for bone metastasis than visceral metastasis (P=0.013), oligometastasis than non-oligometastasis (P=0.003) and single organ metastasis than multiple organ metastases (P=0.016), while that for liver metastasis was poorer than non-liver metastases (P<0.001). In multivariate analysis, liver metastasis (hazard ratio [HR] =4.02; 95% confidence interval [CI], 1.15-14.05, P=0.029) was significantly and independently related to poor overall survival.ConclusionOur data revealed the site of metastasis is associated with overall survival of patients with newly diagnosed organ metastatic cervical cancer, with liver metastasis signifying particularly poor overall survival. Individualized treatments should be administered to patients depending on the specific metastatic sites.

Analysis of Response Evaluation Criteria in Solid Tumors reduction ratio of primary chemotherapy in unresectable advanced or recurrent colorectal cancer.

Response Evaluation Criteria in Solid Tumors (RECIST) is used to assess the objective response of solid tumors to treatment. However, it remains unclear to what extent the response rate assessed by RECIST reflects a reduction of tumor size in multiple organs in patients with unresectable advanced or recurrent colorectal cancer (CRC) with multiple organ metastases. It is also unclear whether the management of liver metastases with systemic chemotherapy in CRC patients with multiple organ metastases improves their prognosis, although surgical resection has been shown to be the most effective treatment approach to CRC cases with liver metastases. A total of 38 CRC patients who underwent systemic chemotherapy in Kyushu Medical Center Hospital between January 2013 and April 2016 were examined. The patients had measurable lesions in multiple organs, including the liver, and did not undergo curative surgery for metastatic lesions after initiation of chemotherapy. The association between the total reduction ratio (TRR) of all lesions and liver lesion reduction ratio (LRR) was retrospectively analyzed. A total of 18 patients (47%) had H3 liver metastases, and the median liver lesion occupancy rate in the sum of the measured lesions with RECIST was 76%. TRR and LRR were strongly correlated, regardless of the volume of the liver metastases. Although a TRR of >30% was significantly associated with improved overall survival (OS), this improvement was not observed in patients with H3 liver metastases. TRR was correlated with LRR and was associated with a better OS. CRC patients with both multiple organ and H3 liver metastases exhibited poor survival, even with a high reduction ratio by chemotherapy.