Development Of Liver Metastases Research Articles

Yttrium-90 Glass Microsphere Transarterial Radioembolization for Patients with Unresectable Liver-Dominant Breast Cancer Metastasis

Transarterial radioembolization (TARE) using Yttrium-90 (Y90) microspheres is a potential therapeutic option for treatment-refractory, unresectable, liver-dominant breast cancer metastases (LdBM). We hypothesized that Y90 TARE is an effective and safe treatment for delaying progression in patients with LdBM. In this IRB approved (MCC 18294) study, we retrospectively analyzed institutional database to identify patients with unresectable and chemotherapy-refractory LdBM who underwent Y90 TARE. We extracted patient demographics, systemic therapy details and imaging studies for response assessment. Liver function tests, CA15-3 level, Albumin-Bilirubin (ALBI) and Model for end-stage liver disease (MELD) score were assessed at baseline, 1- and 3-months post TARE to evaluate for hepatotoxicity. Hepatic progression-free (hPFS) and overall survival (OS) were estimated using Kaplan-Meier analysis, and compared using log-rank test. Cox regression was performed to evaluate the effect of predictors on defined outcomes. Maximum toxicity grade was reported using Common Terminology Criteria for Adverse Events version 5. Between 2010-2019, 32 patients with LdBM underwent 51 TARE sessions with Y90 glass microsphere. All patients progressed through systemic therapy. Median age was 61 years (range 27-81). Interval to develop liver metastasis from initial breast cancer diagnosis was 5-years (median). Median follow-up duration after TARE was 11 months (range, 1-44). 18 patients had sequential bilobar treatment, 1 sequential segmental, 9 unilobar right, 1 unilobar left, 2 segmental and 1 whole-liver single session TARE. Median hPFS and OS after TARE were 7-months (95% CI 5.0–9.1) and 13 months (95% CI 9.2–16.8), respectively. The 6-months and 1-year actuarial hPFS were 52% and 21%; and 1-year and 2-year OS were 58.5%, and 35.7%, respectively. Factors independently predicting worse hPFS were age <60 years (6-month hPFS 41.3% vs 62.5%, p = 0.04) and bilobar disease (33.3% vs. 68.8%, p = 0.005). On multivariate analysis, bilobar disease (p = 0.01) and high baseline CA 15-3 (p = 0.05) were predictors of longer OS. No significant change was noted in ALBI, MELD, total bilirubin, albumin and alkaline phosphatase levels at 1- and 3-months post-TARE. Grade 3 toxicity was noted in 3-patients (9.4%), all received sequential bilobar treatment, necessitating hospitalization for pain (2-patients), and worsening liver function (1-patient). The 30-day mortality was 3.1%; 1 patient died from radioembolization-induced liver disease. For patients with therapy-refractory unresectable LdBM, Y90 TARE is effective and relatively safe. TARE can potentially delay progression allowing patients with LdBM to continue systemic therapy longer.

Frequency, prognosis and treatment modalities of newly diagnosed small bowel cancer with liver metastases

BackgroundPopulation-based analysis for the liver metastases of small bowel cancer is currently lacking. This study aimed to analyze the frequency, prognosis and treatment modalities for newly diagnosed small bowel cancer patients with liver metastases.MethodsPatients with small bowel cancer diagnosed from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Binary logistic regression analysis was performed to determine predictors for the presence of liver metastases at diagnosis. Kaplan–Meier method and Cox regression analyses were performed for survival analyses.ResultsA total of 1461 small bowel cancer patients with liver metastases at initial diagnosis were identified, representing 16.5% of the entire set and 63.9% of the subset with metastatic disease to any distant site. Primary tumor with poorer histological type, larger tumor size, later N staging, more extrahepatic metastatic sites, and tumor on lower part of small intestine had increased propensity of developing liver metastases. The combined diagnostic model exhibited acceptable diagnostic efficiency with AUC value equal to 0.749. Patients with liver metastases had significant poorer survival (P < 0.001) than those without liver metastases. In addition, combination of surgery and chemotherapy (HR = 0.27, P < 0.001) conferred the optimal survival for patients with adenocarcinoma, while the optimal treatment options for NEC and GIST seemed to be surgery alone (HR = 0.24, P < 0.001) and chemotherapy alone (HR = 0.08, P = 0.022), respectively.ConclusionsThe combined predictor had a good ability to predict the presence of liver metastases. In addition, those patients with different histologic types should be treated with distinct therapeutic strategy for obtaining optimal survival.

Living donor liver transplantation for colorectal liver metastasis: a narrative review

: Colorectal cancer (CRC) is a spread disease worldwide. Most of the patients with CRC will develop liver metastases along the time and more than 75% of them are unresectable (uCRLM). In this case, despite the actual modern chemotherapy, the 5-year overall survival (OS) is lower than 10%. In the recent ten years liver transplantation (LT) for uCRLM experienced a “comeback” with excellent results in terms of OS at 5 years ranging from 60% to 100% according to different selection criteria, notwithstanding high recurrence rates (mainly extrahepatic). These promising results are based on a global population of almost 50 patients who underwent a DDLT. In times of organ paucity and still critical indication, standard DDLT will not find any place outside of studies. Additionally, the use of extended criteria donors (ECD) showed recently poor results in this context. Therefore, one way out of this dilemma may be represented by the use of Living-Donor liver transplantation (LDLT). In this review, we report about LDLT for uCRLM. In addition to a report of initial experience (i.e., global amount of 25 cases), we mainly focused on ethical, technical and oncological aspects of the procedure and proposed future applications as well. In summary, in times of scarcity of organs, LDLT for uCRLM may represent a valid alternative to DDLT with minimal donor risk and maximal recipient benefit in selected cases.

504P Primary tumour location impacts oncological outcome of patients with resected colorectal liver metastases

Primary tumour location has emerged as a prognostic factor for colorectal cancer. Approximately 38% of patients will develop liver metastases, yet evidence on the impact of sidedness after resection is lacking.

Primary congenital choledochal cyst with squamous cell carcinoma: a case report

Cases of extrahepatic bile duct carcinoma are mostly adenocarcinomas and extrahepatic bile duct squamous cell carcinomas are rare. We report here a case of choledochal squamous cell carcinoma in a young woman who underwent surgery and chemotherapy. The woman presented with abdominal discomfort. A physical examination showed tenderness in the upper abdomen. Laboratory tests showed elevated direct bilirubin, total bilirubin, and C-reactive protein levels. Abdominal computed tomography and magnetic resonance imaging showed a cystic-solid mixed soft tissue mass in the common bile duct. Pain symptoms in the patient were not relieved and surgical treatment was performed. Postoperative pathological results showed a choledochal cyst complicated by squamous cell carcinoma. The patient was treated by biliary intestinal anastomosis followed by chemotherapy. However, the patient developed liver metastasis and recurrence at a 6-month follow-up. Primary congenital bile duct cysts with squamous cell carcinoma are extremely rare. Surgical resection is the main treatment option for choledochal squamous cell carcinoma. Postoperative chemoradiotherapy can be used, but the efficacy is poor and chemotherapy does not significantly prolong the patient’s survival.

Abstract 6406: FAK and MEK co-targeting: A new multimodal precision therapy for GNAQ-driven uveal melanoma

Abstract Uveal melanoma (UM) is characterized by gain-of-function mutations in GNAQ or GNA11, encoding Gα proteins from the Gq/11 family. UM is the most common eye malignancy in adults. Approximately 50% of UM patients develop liver metastasis (mUM) within 5-10 years after diagnosis, independently of the successful treatment of the primary lesions. mUM is refractory to cytotoxic, targeted, and immunotherapies, with most mUM patients dying within a year. Recent information suggests that GNAQ-oncogenic signaling involves a non-canonical pathway distinct from the activation of PLCβ and PKC-MEK-ERK, which may explain the failure of MEK inhibitors (MEKi) in increasing mUM patient survival. Instead, we found that GNAQ promotes the activation of YAP1, a key oncogenic driver, by a mechanism involving the activation of RhoA by the direct association of Gαq to TRIO, a Rho-GEF (Cancer Cell, 2014). In turn, YAP1 is essential for uveal melanoma cell growth, however no effective and safe YAP1 inhibitors are currently available. Using a novel bioinformatics pipeline, we recently found that PTK2, encoding Focal Adhesion Kinase (FAK), is a synthetic lethal gene with GNAQ activation, and uncovered that GNAQ controls YAP1 through FAK (Cancer Cell, 2019). This study identified FAK as a druggable signaling hub downstream from GNAQ in UM. However, activation of compensatory pathways often results in resistance to targeted agents. Here, we combined the use of CRISPR-Cas9 sgRNA screens with a recently described Cancer Signaling Toolkit approach to identify synthetic lethal interactions enhancing the response to FAKi and signaling networks mediating drug resistance, respectively. Remarkably, both approaches converged to reveal that co-targeting FAK and the MEK-ERK pathway would be a promising combination for treatment of UM. Indeed, MEK-ERK pathway inhibition by multiple approved MEKis (e.g., trametinib), combined with FAK inhibition (VS-4718 or defactinib), showed remarkable synergistic growth inhibitory effects in UM cells. Additionally, the novel RAF/MEK inhibitor RO5126766 also showed synergistic anti-proliferative effects with defactinib. Accordingly, FAKi combination with MEKi exerted cytotoxic effects (apoptotic death) leading to rapid tumor shrinkage in UM xenografts, whereas single drugs were primarily cytostatic. Furthermore, the FAKi/MEKi combination was successful at reducing tumor burden in recently developed liver metastasis UM models. By coupling the unique genetic landscape of UM with the power of unbiased computational pipelines and systems biology genetic screens, our studies revealed that FAK and MEK-ERK co-targeting may provide a new network-based precision therapeutic strategy for mUM treatment. Indeed, the combination of defactinib and RO5126766 is currently being evaluated in patients with various solid tumors (NCT03875820), and could be explored in mUM based on these preclinical findings. Citation Format: Justine S. Paradis, Monica Acosta, Nadia Arang, Robert Saddawi-Konefka, Ayush Kishore, Takahito Sugase, Xiaodong Feng, Kris C. Wood, Silvia Coma, Mizue Terai, Takami Sato, Jonathan A. Pachter, J. Silvio Gutkind. FAK and MEK co-targeting: A new multimodal precision therapy for GNAQ-driven uveal melanoma [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 6406.

Abstract 3331: Role of innate immune cells in the development of vessel co-opting CRC liver metastases

Abstract Approximatively 50 % of patients who undergo resection for primary colorectal cancer will develop liver metastases. Liver metastases present as two major histopathological growth patterns (HGP) the desmoplastic and the replacement HGP. In the desmoplastic HGP, the cancer cells are surrounded by a desmoplastic stromal ring preventing their contact with the normal liver. In the replacement HGP, the cancer cells infiltrate the normal liver and replace hepatocytes near the tumour periphery. We have found that the desmoplastic HGP tumors derive their blood supply through angiogenesis while the replacement HGP tumors are non-angiogenic and co-opt the blood vessel of the liver they invade. Furthermore, we have published that patients under chemotherapy presenting with a vessel co-opting phenotype have a worse pathological response and five-year overall survival compared to patients presenting with angiogenic liver metastases. Their prognosis is worse when treated with bevacizumab an anti-VEGF antibody used alongside chemotherapy. CRCLM are considered immunologically cold lesions, with low numbers of infiltrating T-cells, and thought to be unlikely to benefit from immunotherapies. We have recently found that neutrophils and macrophages but not lymphocytes infiltrate vessel co-opting lesions to a greater extent than angiogenic lesions. Using flow cytometry and the Nanostring GeoMx spatial protein profiling platform capable of detecting up to 96 proteins simultaneously on FFPE tissue slices, we established the immunoprofile of immune cells recruited to angiogenic or vessel co-opting CRCLM lesions in chemonaive and treated patients. Many studies have demonstrated that neutrophils and macrophages play an important role in tumor progression, modification of the ECM, angiogenesis, and immunosuppression. We hypothesize that innate immune cells can facilitate blood vessel co-option of CRCLM lesions and contribute to an immunosupressive environment favorable to tumor growth. Fully understanding the role of the innate immune system in the developmend of vessel co-opting CRCLM tumors could allow for the development of immunotherapies capable of converting vessel co-opting lesions into angiogenic lesions that are more successfully treated with chemotherapy and anti-angiogenic therapies. Citation Format: Thomas Z. Mayer, Diane H. Kim, Miran Rada, Stephanie Petrillo, Anthoula Lazaris, Peter Metrakos. Role of innate immune cells in the development of vessel co-opting CRC liver metastases [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 3331.

Abstract 6470: Possibility of digital cytology of intraoperative ascites and lavage fluid in patients with colorectal cancer

Abstract Introduction: In patients with colorectal cancer, the results of intraoperative peritoneal cytology do not affect the prognosis. One of the reasons is the low sensitivity of peritoneal cytology. Thus, improving the sensitivity of peritoneal cytology may improve the accuracy of prognostic prediction. Digital cytology (dCytology), which detects genetic mutations in ascites or abdominal lavage fluid using digital polymerase chain reaction (PCR), is a new method by which to evaluate peritoneal cytology. In this study, we evaluated the sensitivity and clinical significance of dCytology. Methods: We included patients with clinical T3-T4 colorectal cancer who underwent surgery from November 2018 to November 2019 in our department. In patients with ascites, ascitic fluid was collected at the start of surgery. In patients without ascites, lavage fluid was collected using 50 mL of physiological saline. Half of the liquid was used for conventional cytology, and the other half was used for dCytology. DNA was extracted from the supernatant and intraperitoneal free cells and from the cancer tissue. Circulating tumor DNA was extracted from the preoperative plasma. Digital PCR was performed on cancer tissue, supernatant DNA, intraperitoneal free cell DNA, and circulating free DNA (cfDNA) using a KRAS multi-probe. Results: This study included 150 patients, 75 of whom had KRAS mutation in their tissues. Among them, dCytology was positive in 45 patients (60%, pStage I/II/III/IV/recurrence/unresectable: 6/22/23/16/4/4). Thirty patients had right-sided colon cancer, 20 had left-sided colon or upper rectal cancer, 7 had lower rectal cancer, and 4 had recurrent disease. Conventional cytology was positive in 11 of the 45 patients (24%), and dCytology was positive in 7 of the 11 patients. cfDNA was positive in 19 patients, and dCytology was positive in 10 of the 19. Four patients, including two patients with positive dCytology but negative conventional cytology, developed recurrence disease. Two of the four patients developed liver metastasis but no peritoneal dissemination. Discussion: The sensitivity of dCytology was higher than that of conventional cytology. Our results suggest that tumor cells can exist in the abdominal cavity of patients with colorectal cancer. Interestingly, dCytology was positive even for patients in whom the tumor was not exposed on the outside of the colon wall (T3) and in whom the tumor was not located in the abdominal cavity (Rb). Citation Format: Koji Ueda, Takeshi Yamada, Michihiro Koizumi, Seiichi Shinji, Akihisa Matsuda, Ryo Ohta, Goro Takahashi, Masahiro Hotta, Kohki Takeda, Keisuke Hara, Sho Kuriyama. Possibility of digital cytology of intraoperative ascites and lavage fluid in patients with colorectal 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 6470.

Abstract A20: Gαq controls the Hippo pathway through MOB1 tyrosine phosphorylation by FAK

Abstract YAP overactivation is an essential molecular event for cancer initiation and growth of most solid tumors, but pharmacologic targeting of the YAP or Hippo pathway has been proven to be challenging. In this regard, YAP activity is also required for stem and progenitor cell maintenance and function in multiple tissues, and as such, YAP is necessary for normal tissue homeostasis and regeneration. Thus, targeting YAP directly may result in normal cell growth arrest and tissue damage. The elucidation of the signaling networks sustaining YAP pervasive activation in each cancer type may afford the opportunity to identify novel suitable precision therapeutic targets for cancer treatment. GNAQ and GNA11 activate mutations (encoding GTPase deficient and constitutively active Gαq proteins) occurs in ~90% of uveal melanoma (UM) and 4% of skin cutaneous melanoma (SKCM), respectively, firmly established UM, and a subset of SKCM as Gαq-driven human malignancies. Approximately 50% of UM patients develop liver metastasis within 5-10 years after diagnosis, independently of the successful treatment of the primary lesions. To date, there are no effective treatment options for metastatic UM disease. Through the bioinformatics analysis of the TCGA UM dataset (n=80) using skin melanoma samples that do not harbor Gαq genomic alteration (n=209) as control, (1) we first identified the genes that are highly overexpressed in UM. (2) We then filtered the genes for those whose reduced expression leads to better patient survival in UM. (3) We finally used large datasets of gene essentiality and drug response screenings in cancer cells to identify genes that are predicted to reduce cell viability when targeted in Gαq-gain cells. (4) Finally, 7 top predicted drug targets were found from a set of genes that can be targeted by approved and experimental drugs (n=756). The top predicted gene target was PTK2, which encodes the nonreceptor tyrosine kinase FAK (focal adhesion kinase). We found that Gαq activates pY379-FAK (reflecting FAK activation) though a Trio-RhoA signaling pathway, independent of PLC-β regulated second messenger activation. Interestingly, genome-wide transcriptional analysis (RNA-seq) of UM cells treated with a FAK inhibitor (VS-4718) revealed that YAP signatures were highly inhibited by FAK blockade. This suggested that FAK signaling actives YAP downstream of Gαq in UM, in addition to our previously found Trio/Rho GTPase/F-actin polymerization regulation of YAP activation mechanism. Further signaling analysis uncovered that FAK stimulates YAP through direct YAP tyrosine phosphorylation (enhancing YAP protein stability) and, unexpectedly, MOB1 tyrosine phosphorylation on Y26. The latter disrupts MOB1/LATS interaction, causing Hippo signaling inhibition and YAP activation. Interestingly, FAK inhibitors are already under clinical evaluation, and showed strong inhibition of YAP activity and UM growth in vitro and in vivo, thus representing a potential precision therapeutic option for UM treatment. Citation Format: Xiaodong Feng, Nadia Arang, Damiano Cosimo Rigiracciolo, Joo Sang Lee, Huwate Yeerna, Zhiyong Wang, Simone Lubrano, Ayush Kishore, Jonathan A. Pachter, Gabriele M. König, Marcello Maggiolini, Evi Kostenis, David D. Schlaepfer, Pablo Tamayo, Qianming Chen, Eytan Ruppin, J. Silvio Gutkind. Gαq controls the Hippo pathway through MOB1 tyrosine phosphorylation by FAK [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A20.

Increase in CD4+FOXP3+ regulatory T cell number and upregulation of the HGF/c-Met signaling pathway during the liver metastasis of colorectal cancer.

Colorectal cancer (CRC) is the third and second most common type of cancer diagnosed in males and females, respectively, and is the fourth leading cause of cancer-associated mortality worldwide. Liver metastasis is the primary cause of mortality in patients with CRC, and therefore requires therapeutic focus. Regulatory T cells (Tregs) and hepatic stellate cells (HSCs) are potentially involved in regulating the immune response during liver metastasis. The aim of the present study was to evaluate the influence of CD4+ forkhead box p3 (Foxp3)+ Tregs and the HGF/c-Met signaling pathway in the liver metastasis of CRC. A model of the latter was established using Balb/c mice via splenic injection of human CRC cells (CT-26 line). The mice were monitored for 3 weeks after being injected, and the spleens and livers were removed on day 22 for further analysis. Moreover, the single-cell suspensions were labeled with CD4 and Foxp3 antibodies, and were analyzed using flow cytometry. Expression levels of α-smooth muscle actin (SMA), hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (c-Met) were analyzed using immunohistochemistry. Mice injected with CT-26 cells exhibited signs of illness and significant weight loss, compared with the control mice (P=0.013), and they also developed liver metastases, at an average of 20.5 tumors per mouse. Pathological evaluation using hematoxylin and eosin staining confirmed the tumors as liver metastases of CRC. The numbers of CD4+ T cells were significantly decreased in the spleen (P<0.001) and liver (P=0.003) of tumor-bearing mice, while the proportions of CD4+FOXP3+ Tregs increased significantly in the spleen (P<0.001) and liver (P=0.026) compared with that in the controls. Additionally, α-SMA, HGF and c-Met levels increased significantly during metastatic growth in the liver. In conclusion, CD4+FOXP3+ Treg levels increased and the HGF/c-Met pathway was upregulated during the liver metastasis of CRC in mice, indicating the presence of potential therapeutic targets.

The prognostic biomarkers of the patients treated with platinum-based chemotherapy in treatment emergent or related neuroendocrine prostate cancer.

e17576 Background: Treatment emergent or related neuroendocrine prostate cancer (tNEPC) is an aggressive subtype of prostate cancer in patients previously treated with androgen receptor pathway inhibitor (ARPI) as a mechanism of resistance. These patients are typically treated platinum-based chemotherapy using small cell lung cancer (SCLC). The clinical features of tNEPC are poorly defined. The aim of the present study was to investigate the prognostic biomarkers of the patients treated with platinum-based chemotherapy in tNEPC. Methods: We reviewed baseline, treatment and outcome data of 41 patients with tNEPC. Clinicopathological factors and laboratory data before administering the first cycle of platinum-based chemotherapy were collected to assess the prognostic factors for overall survival (OS). Definition of tNEPC were based on NEPC morphology on the basis of any current or prior tissue sample, development of liver metastases in the absent of PSA progression, or elevated serum neuron specific enolase (NSE). Results: Median PSA and NSE were 119.8 ng/ml and 18.2 ng/ml, respectively. Twenty-four patients had pathologic features of NEPC. NSE were elevated above the 32 patients. The median OS from the start of platinum-based chemotherapy treatment was 10 months. Univariate analysis revealed that LDH (p = 0.003), absolute monocyte count &lt; 280 (p = 0.022), visceral metastasis (p = 0.014) prior to platinum-based chemotherapy were significantly associated with shorter OS. Multivariate analysis revealed that LDH (p = 0.047), absolute monocyte count &lt; 280, (p = 0.012), visceral metastasis (p = 0.005) prior to platinum-based chemotherapy treatment were independent prognostic indicators for OS. Based on the relative risk of death, NEPC patients before platinum-based chemotherapy were divided into 3 risk groups: low, intermediate and high ( p&lt; 0.001). Conclusions: Our findings provide new insights into the practical implication of NEPC. Our results might be to tailor the management of NEPC treated with platinum-based chemotherapy.

An analysis of clinicopathological characteristics and prognosis on hepatoid adenocarcinoma of stomach.

e16558 Background: Hepatoid adenocarcinoma of the stomach(HAS) is a rare type of gastric adenocarcinoma(GAC). At present, histopathology is the gold standard for the diagnosis of HAS, however, HAS is easy to be missed diagnosis, and lack of a perfect diagnosis system and effective treatment strategy. In this research, clinical pathological features will be analyzed to improve the diagnostic system, judge prognosis and provide clues for exploration of pathogenesis and targeted therapy of HAS. Methods: 576 cases including 5 confirmed patients with HAS were enrolled onto this study from 1320 patients with GAC. 10 cases of HAS were diagnosed by the second histopathological examination from the other 571 enrolled cases. 30 cases from the remaining 561 enrolled patients were randomly selected as the control group. The information of the two group cases were completed by collecting the existing case data, detecting the missed immunohistochemical indicators and telephone follow-up. The clinicopathological features of the two group cases were compared, and the treatment and prognosis of 15 HAS cases were analyzed. Results: In this study, 15 cases of HAS were found in 576 patients with GAC, including 5 cases from the 1st pathological diagnosis and 10 cases from the 2nd pathological diagnosis. There was no significant difference in age, gender, HP positive rate, serum CEA or CA19-9 level, tumor size, TNM stage, tumor invasion depth, lymph node invasion, distant metastasis rate, differentiation degree, nerve/vascular invasion, and Ki-67 expression level between the two groups( P&gt; 0.05). Compared with the control group, the serum AFP level, and the expression level of GPC3, AFP, EGFR and VEGF protein of patients in HAS group were significantly high, as well as the patients in the HAS group were more likely to develop liver metastasis( P&lt; 0.05). The mOS was 12 mo vs 42 mo for HAS group vs control group( P&lt; 0.05). Multivariate analysis showed immunohistochemical AFP staining intensity was an independent risk factor for prognosis of HAS. Conclusions: As a special type of GAC, HAS is prone to developing liver metastasis with poor prognosis. Based on the higher missed diagnosis rate of HAS, it is suggested to make 2nd cancer histopathological diagnosis including immunohistochemical detection of AFP and GPC3 for GAC patients with significantly increased serum AFP level. The intensity of immunohistochemical AFP staining is an independent risk factor for the prognosis of patients with HAS. VEGF, EGFR and PD-1 / PDL-1 may be potential therapeutic targets of HAS, which is worth further study.

LM02-trial perioperative treatment with panitumumab and FOLFIRI in patients with wild-type RAS, potentially resectable colorectal cancer liver metastases.

e16046 Background: Nearly half of patients with colorectal cancer develop liver metastases and only 20% are initially resectable. Surgical resection of liver metastases results in five-year survival rates of 24-48%. Perioperative FOLFOX therapy increases progression free survival. In advanced disease the addition of targeting therapies to chemotherapy results in an overall survival advantage. In this study the efficacy and safety of perioperative panitumumab and FOLFIRI therapy were investigated. Methods: Patients with previously untreated, wild-type RAS, potentially resectable colorectal cancer liver metastases were included. Chemotherapy consisted of irinotecan 180mg/m2 intravenously over 120 minutes and fluorouracil bolus 400mg/m2 intravenously, followed by a 46 h infusion of fluorouracil 2400mg/m2 repeated every 2 weeks. Panitumumab was given as an intravenous dose of 6mg/kg every 2 weeks. Preoperative 4 cycles and postoperative 8 cycles were administered. Primary objectives were the evaluation of efficacy and safety. Results: We enrolled 36 patients in 7 centers in Austria. ITT-analyses included 35 patients. There were 28 men and 7 women, the median age was 66 years. 91.4% completed the planned 4 cycles of preoperative therapy and 82.9% underwent liver resection. R0 resection rate was 82.7%. 20 patients started postoperative chemotherapy and 12 patients completed the planned 8 cycles. Objective response rate after preoperative therapy was 65.7% with one radiological complete remission and 22 partial remissions. In 20% and 5.7% of patients stable disease and progressive disease were documented, respectively. Three patients discontinued preoperative treatment due to adverse events without response evaluation. The most common grade 3 adverse events were diarrhea (n = 4), rash (n = 3) and leukopenia (n = 3) during preoperative therapy. One patient died due to sepsis and one had a pulmonary embolism grade 4. After surgery two patients died due to hepatic failure and one patient had a suture related complication grade 3. Most common grade 3/4 adverse events during postoperative therapy were rash (n = 2), stroke (n = 1) and intestinal obstruction (n = 1). Conclusions: Panitumumab in combination with FOLFIRI as preoperative therapy for operable colorectal liver metastases in RAS wild-type patients results in a radiological objective response rate in 65.7% of patients with a manageable grade 3 diarrhea rate of 14.3%. Progression-free survival and overall survival are still monitored. Clinical trial information: 2012_000265-20 .

Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities consistent with exacerbated cachexia.

Advanced colorectal cancer (CRC) is often accompanied by development of liver metastases (LMs) and skeletal muscle wasting (i.e., cachexia). Despite plaguing the majority of CRC patients, cachexia remains unresolved. By using mice injected with Colon-26 mouse tumors, either subcutaneously (s.c.; C26) or intrasplenically to mimic hepatic dissemination of cancer cells (mC26), here we aimed to further characterize functional, molecular, and metabolic effects on skeletal muscle and examine whether LMs exacerbate CRC-induced cachexia. C26-derived LMs were associated with progressive loss of body weight, as well as with significant reductions in skeletal muscle size and strength, in line with reduced phosphorylation of markers of protein anabolism and enhanced protein catabolism. mC26 hosts showed prevalence of fibers with glycolytic metabolism and enhanced lipid accumulation, consistent with abnormalities of mitochondrial homeostasis and energy metabolism. In a comparison with mice bearing s.c. C26, cachexia appeared exacerbated in the mC26 hosts, as also supported by differentially expressed pathways within skeletal muscle. Overall, our model recapitulates the cachectic phenotype of metastatic CRC and reveals that formation of LMs resulting from CRC exacerbate cancer-induced skeletal muscle wasting by promoting differential gene expression signatures.

Liver transplantation for non-resectable colorectal liver metastasis: where we are and where we are going.

Almost 50% of patients diagnosed with colorectal cancer (CRC) will develop liver metastasis (LM). Although their only long-term curative treatment is surgery, less than half of these patients can be eventually resected. Therefore, palliative chemotherapy is offered as a definitive option, though with poor results. Recently, the University of Oslo group has published encouraging results in the treatment of these patients with liver transplantation (LT), whereby worldwide interest in this option has been renewed. A literature review of LT for patients with unresectable colorectal metastasis was performed. This included information regarding patient selection, complications, overall survival (OS) and disease-free survival (DFS), immunosuppression, chemotherapy, and description of the ongoing trials. Improvements in OS and DFS have been observed in consecutive published prospective trials, as patient selection has been refined. Papers reporting OS of patients who randomly presented similar selection criteria also exhibited good results. LT within the available therapeutic options in patients with CRC-LM seems to be a compelling alternative in carefully selected patients. The ongoing trials will provide valuable information regarding selection criteria, immunosuppressive therapy and different modalities of adjuvant chemotherapy, which are, to our knowledge, the vital platform of LT in CRC-LM. Although some of the developing techniques involve living donors, graft availability for these patients remains a matter of major concern.

Asian Case of Metastatic Melanoma in Which a Complete Response Was Maintained after Discontinuation of Dabrafenib and Trametinib

A 54-year-old man diagnosed with metastatic melanoma of the right inguinal node with occult primary developed liver and bone metastases. The combination of dabrafenib plus trametinib was initiated, and a complete response (CR) was achieved 24 months after starting treatment. One month later, the target therapy was discontinued at the patient’s decision, and he has remained free from progression for 21 months since discontinuation. To the extent of our knowledge, real-world data in Asian melanoma concerning the discontinuation of dabrafenib plus trametinib after achieving CR have not been published; therefore, our case is a meaningful one for considering to cease target drugs and to rescue their financial toxicity.

Outcomes of elderly patients with resectable liver metastases from colorectal cancer (CRLM): Single center experience.

34 Background: Half of patients with colorectal cancer develop liver metastases during the course of their disease. Surgery is the only potentially curative option for CRLM if resectable. Treatment of patients over 70 years old is challenging mainly because of comorbidities and other geriatric syndromes. Thus, we intended to report our experience with elderly patients with resectable CRLM. Methods: After approval by the Institutional Review Board (IRB), all records from a prospectively collected database at Centre Hospitalier de l’Université de Monréal (CHUM) were retrospectively analyzed. Clinicopathological characteristics, surgery and chemotherapy treatment modalities were reviewed. RFS and OS in patients ≥ 70y were calculated using the Kaplan Meier survival curve. Results: From 2010 to 2016, 101 patients older than 70 years were identified. Safety and surgical complications were previously reported. Median age was 75 years. CRLM were synchronous in 46.5% and metachronous in 53.5%. Relapse free survival (RFS) of patients ≥ 70 years was 33.7 months. Overall survival (OS) of patients ≥70 years was comparable to those of less than 65 years old (median OS: 56 vs 62 months; p = 0.15, respectively). Hepatic relapse showed worse survival when compared to extra-liver recurrence, mOS: 44 vs 33.2 vs 29.3 months for non-hepatic, hepatic only and hepatic with other sites respectively (trend p = 0.034). Although non-statistically significant, Patients with metachronous CRLM had superior mOS compared to those with synchronous disease (58.7 vs 44.7 months; p = 0.22). Conclusions: Survival Outcomes of patients with an age ≥ 70 years were comparable to those of younger patients and what is reported in literature. Age should not be a limiting factor in the management of elderly patients with resectable CRLM. Hepatic metastatectomies +/- chemotherapy should be offered with curative intents.

The Prevalence and associated Factors for Liver Metastases, Development and Prognosis in newly diagnosed Epithelial Ovarian Cancer: A large Population-Based Study from the SEER Database.

Background: Primary Epithelial Ovarian Cancer (EOC), a malignant gynecologic disease, is considered one of the leading causes of mortality in women. The development of Liver Metastases (LM) in women with primary ovarian cancer commonly results in a poorer prognosis. This retrospective population-based study aims to measure the prevalence, prognostic factors, and associated risk factors for epithelial ovarian cancer patients with liver metastases (EOCLM).Materials and Methods: The current study cohort of patients based on the Surveillance, Epidemiology, and End Results (SEER) database identified with primary ovarian cancer between the years 2010 and 2016. A chi-square test was employed to compare Metastatic differences among demographic and clinical factors. Univariable and multivariable logistic regression analysis models were used to predict related prognostic factors for LM development. 7-year Kaplan-Meier curves were applied to compare the survival patterns of patients with and without LM. The Multivariable Cox regression model was used to estimate potential risk factors associated with LM related deaths.Results: 33895 eligible primary EOC patients were identified. Among them 2635 (7.77%) patients were initially diagnosed with de novo LM, and 31260 (92.23%) without metastases disease to any site. Non-serous histology type; Malignant Brenner Carcinoma, NOS (OR 1.94; CI: 1.39-2.71; P<0.001), T3/T1 stage (OR 5.65; CI: 3.87-8.24; P<0.001), N1/N0 stage (OR 1.67; CI: 1.43-4.95; P<0.001), grade; G3/G1 (OR 2.16; CI: 1.29-3.59, P<0.001), and cancer antigen-125; Elevated/Normal (OR 1.79; CI: 1.19-2.69, P<0.001) were significantly associated with LM occurrence. The median survival of EOC patients with LM was 12.0 (95% CI: 11.0-14.0; P<0.001) months. Multivariable cox regression showed being unmarried (HR 1.16; CI: 1.04-1.30; P=0.001), non-serous histology types, Mucinous (HR 2.38; CI: 1.82-3.12; P<0.001), Clear cell (HR 1.83; CI: 1.32-2.55; P<0.001), Malignant Brenner Carcinoma, NOS (HR 1.44; CI:1.23-1.66; P<0.001), Carcinosarcoma NOS, (HR 1.44; CI: 1.11-1.88; P<0.001) and radiotherapy (HR 1.52; CI: 1.12-2.06; P<0.001), were positively related to death. Chemotherapy (HR 0.30; CI: 1.12-2.06; P<0.001) and surgery (HR 0.34; CI: 0.29-0.39; P<0.001) were related with reduced rate of death.Conclusion: The retrospective cohort study showed that women with primary EOC had some high-risk factors associated with LM. LM can intensely decrease the survival of EOC patients. The findings of our research provided estimates for LM occurrence prediction and potential prognostic factors of EOC with de novo LM development. These findings can be useful for follow-up strategies, guidelines for screening, and treatment of EOCLM.

An Outcome Assessment of a Single Institution's Longitudinal Experience with Uveal Melanoma Patients with Liver Metastasis.

There is no FDA-approved treatment for metastatic uveal melanoma (UM) and overall outcomes are generally poor for those who develop liver metastasis. We performed a retrospective single-institution chart review on consecutive series of UM patients with liver metastasis who were treated at Thomas Jefferson University Hospital between 1971–1993 (Cohort 1, n = 80), 1998–2007 (Cohort 2, n = 198), and 2008–2017 (Cohort 3, n = 452). In total, 70% of patients in Cohort 1 received only systemic therapies as their treatment modality for liver metastasis, while 98% of patients in Cohort 2 and Cohort 3 received liver-directed treatment either alone or with systemic therapy. Median Mets-to-Death OS was shortest in Cohort 1 (5.3 months, 95% CI: 4.2–7.0), longer in Cohort 2 (13.6 months, 95% CI: 12.2–16.6) and longest in Cohort 3 (17.8 months, 95% CI: 16.6–19.4). Median Eye Tx-to-Death OS was shortest in Cohort 1 (40.8 months, 95% CI: 37.1–56.9), and similar in Cohort 2 (62.6 months, 95% CI: 54.6–71.5) and Cohort 3 (59.4 months, 95% CI: 56.2–64.7). It is speculated that this could be due to the shift of treatment modalities from DTIC-based chemotherapy to liver-directed therapies. Combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.

Blood Biomarkers of Uveal Melanoma: Current Perspectives.

The detection of metastases in patients with a diagnosis of uveal melanoma (UM) is a controversial issue. While only 1% of the patients have detectable metastases at the time of diagnosis, up to 30% of them will develop liver metastases within 5 years of treatment. UM spreads hematogenously, therefore, blood biomarkers may be helpful for prognosis and monitoring the disease progression. Despite the great progress achieved thanks to the genetic analysis of UM biopsies, this is an invasive technique and is limited by the heterogeneity of the tumor. The present review considers the current understanding in the field regarding biomarkers for the diagnosis and prognosis of UM and its metastasis, primarily to the liver. General covered topics include non-conventional markers such as proteins previously identified in cutaneous melanoma and UM cell lines, circulating tumor cells, microRNAs (miRNA), and circulating DNA, and how each may be critical in the development of novel blood biomarkers for UM.