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Immune checkpoint inhibitors (ICIs) can cause a variety of immune-related adverse events (irAEs). The coronavirus disease 2019 (COVID-19) is associated with increased amounts of pro-inflammatory cytokines, which may affect the outcome of irAEs. Data are limited regarding the impact of COVID-19 on irAEs in ICI-treated cancer patients. Hence, in this study, we retrospectively analyzed ICI-treated adult patients with malignant solid tumors at a single institution between August 2020 and August 2021. Patients who had the most recent ICI treatment over 1-month before or after the positive COVID-19 test were excluded from the study. For the COVID-19 positive group, only the irAEs that developed after COVID-19 infection were considered as events. A total of 579 patients were included in our study, with 46 (7.9%) in the COVID-19 positive group and 533 (92.1%) in the COVID-19 negative group. The baseline characteristics of patients in the 2 groups were similar. With a median follow-up of 331 days (range: 21-2226), we noticed a nonsignificant higher incidence of all-grade irAEs in the COVID-19 positive group (30.4% vs. 19.9%, P =0.18). The incidence of grade 3 and 4 irAEs was significantly higher in the COVID-19 positive group (10.9% vs. 3.2%, P =0.02). Multivariate analysis confirmed the association between COVID-19 infection and increased risk of severe irAE development (odds ratio: 1.08, 95% confidence interval: 1.02-1.14, P =0.01). Our study suggested that COVID-19 may pose a risk of severe irAEs in cancer patients receiving ICIs. Close monitoring and possibly delaying ICI administration could be considered when cancer patients are infected with COVID-19.

Background Immune checkpoint inhibitors (ICIs) have shown modest antitumor activity in unselected advanced sarcomas. Histology driven approach to patient selection is the current standard for off-label anti-programmed cell death 1 (PD1) immunotherapy use. Methods We retrospectively reviewed the clinical characteristics and outcomes of patients with advanced sarcoma who were treated with off label anti-PD1 immunotherapy at our center. Results A total of 84 patients with 25 histological subtypes were included. Nineteen patients (23%) had a cutaneous primary tumor site. Eighteen patients (21%) were classified as having clinical benefit, including 1 patient with complete response, 14 with partial response, and 3 with stable disease lasting over 6 months with previously progressive disease. Cutaneous primary site location was associated with higher clinical benefit rate (58% vs. 11%, p . 2.5 months, p = 0.003) and OS (19.0 vs. 9.2 months, p = 0.011), compared to non-cutaneous primary. Patients with histological subtypes that pembrolizumab is indicated per current National Comprehensive Cancer Network guidelines had modestly higher rate of clinical benefit versus other histologies, however, the difference was statistically insignificant (29% vs. 15%, p = 0.182) and no statistically significant difference in PFS or OS was observed between these groups. Immune-related adverse events were more frequently seen among patients with clinical benefit (72% vs. 35%, p = 0.007). Conclusions Anti-PD1-based immunotherapy is highly efficacious in advanced sarcomas of cutaneous primary site. Cutaneous primary site location is a stronger predictor of ICI response than histologic subtype and should be accounted for in treatment guidelines and clinical trial design.

Background The prognostic value of different KRAS (Kirsten rat sarcoma viral oncogene) mutation subtypes and their association with programmed death ligand 1 (PD-L1) expression in lung adenocarcinoma (LADC) remain unclear. We examined the association of KRAS mutation subtypes with clinical outcomes and PD-L1 expression status. Patients and Methods Patients diagnosed with KRAS-mutated LADC were evaluated for PD-L1 expression, cancer staging, overall survival (OS), and relapse-free survival. Results A cohort of 254 KRAS-mutated LADC patients (median follow-up, 17 months) was studied. The 3 major subtypes of KRAS mutations were G12C (46.1%), G12V (21.7%), and G12D (15.7%). We found that all these subtypes had no impact on cancer stages, brain metastasis at diagnosis, OS, and relapse-free survival. Among this cohort, 33% of 94 patients who had PD-L1 staining data available had PD-L1–positive disease (≥ 1% of tumor cells). PD-L1 expression status was not significantly different among the 3 major mutation subtypes. Of interest, among patients with G12C mutation, positive PD-L1 expression was associated with significantly shorter OS (median survival, 5.7 vs. 12.8 months, P = .007). In multivariable analysis, PD-L1 positivity remained as an adverse factor for OS, with hazard ratio of 4.44 (P = .0007). PD-L1 status did not affect OS in other subtypes of mutations. Conclusion KRAS mutation subtype is not associated with patient clinical outcomes or PD-L1 expression status. However, PD-L1 positivity appears to negatively affect OS in LADC patients with G12C mutation. Further study is needed to confirm our observation and to determine if programmed cell death 1/PD-L1 antagonist may affect the clinical outcome of patients with different KRAS mutation subtypes.

188 Background: Our previous phase I/Ib study revealed modest clinical efficacy of rego/nivo in refractory MSS-CRC, implying benefits in selected populations. This has prompted us to investigate predictive biomarkers. Methods: Pre-treatment tumor samples from the previous phase Ib rego/nivo study were obtained and assessed for mRNA sequencing (RNAseq). Response-associated transcripts were identified using DESeq2 method and annotated using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Results: A total of 19 pretreatment tumor samples were analyzed including 14 patients (pts) with disease control (DC) (2 partial response and 12 stable disease) and 5 pts with progression disease (PD). We observed significant upregulation of 89 genes including SFTPB ( P

228 Background: We previously conducted a phase I/Ib study with regorafenib and nivolumab in patients with refractory metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). This study aimed to investigate the biomarkers that predict the treatment response. Methods: Out of the 51 patients who received regorafenib and nivolumab, 22 archival pretreatment tumor samples were subjected to the Xerna TME Panel, a machine learning-based RNA-sequencing biomarker assay and were classified into one of four TME biomarker subtypes: Angiogenesis (A), Immune Active (IA), Immune Desert (ID), or Immune Suppressed (IS). Potential predictive biomarkers including the TME subtypes, KRAS (wild type vs mutant), PD-L1 (negative vs. positive, samples with > 1% tumor cells for PD-L1 were considered positive), CD8 expression (low vs. high), and Treg cells (low vs. high) in tumor microenvironment were evaluated for correlation with overall survival (OS), progression free survival (PFS) and disease control rate (DCR, defined as complete response + partial response + stable disease). Results: Among the 22 patients, 16 (72.7%) had liver metastasis and 15 (68.2%) had lung metastasis. KRAS mutation was found in 16 (68.2%) patients. 11/21 (52.4%) were positive for PD-L1. 12 (54.5%) had high CD8 expression, whereas 9/21 (42.9%) had high Treg cells in tumor microenvironment. Ten (45.5%) patients were classified as biomarker-positive (IA + IS subtypes) and 12 (54.5%) were biomarker-negative (A + ID) based on Xerna TME panel. Two (9.1%) patients achieved partial response, 12 (54.5%) had stable disease, and five (22.7%) developed progressive disease. The median PFS was 5.6 months and median OS was 13.1 months. No significant correlation was observed between RAS mutation (p = 0.664, p = 0.609), PD-L1 expression (p = 0.287, p = 0.173), CD8 (p = 0.152, p = 0.456) and PFS or OS. Low Treg was found to be associated with prolonged PFS (median: 9.8 vs. 1.9 months, p = 0.011) but not OS (p = 0.280). Similarly, only low Treg level was related with DCR (83.3% vs. 33.3%, p = 0.032). While not reaching statistical significance, Xerna TME biomarker-positive patients showed trends for higher median PFS (7.9 months vs. 4.1 months, p = 0.254), median OS (15.75 months vs. 11.9 months, p = 0.378), and higher DCR (70% vs. 58%, p = 0.675) compared to biomarker-negative patients. Additionally, the two patients with partial responses were Xerna TME biomarker-positive. Conclusions: Our study demonstrated that low Treg in tumor microenvironment is correlated with better prognosis in patients with refractory metastatic pMMR CRC who were treated with regorafenib plus nivolumab. Xerna TME panel analysis of these patients also showed trends for predictive clinical benefit. Prospective and larger cohort studies are needed to better define predictive biomarkers for this combination in the future.

2525 Background: Immune checkpoint inhibitors (ICIs) can cause a variety of inflammatory autoimmune tissue damage, referred to as immune-related adverse events (irAEs). COVID-19 is associated with increased amounts of proinflammatory cytokines, which may synergistically affect the outcome of irAEs. Data are limited regarding the impact of COVID-19 on irAEs in ICI-treated cancer patients. Methods: We retrospectively analyzed adult patients with malignant solid tumors treated with ICIs at AdventHealth Orlando between August 2020 and August 2021. All COVID-19 infections were confirmed by PCR. Patients who had the most recent ICI treatment over one month before or after the positive COVID-19 test were excluded from the study. For COVID-19 positive group, only the irAEs that developed after COVID-19 infection were considered as events. Results: A total of 579 patients were included in our study, with 46 (7.9%) in COVID-19 positive group, and 533 (92.1%) in COVID-19 negative group. The baseline characteristics of patients in the two groups were similar in terms of age, ethnicity, ECOG, cancer histology, and type of ICI. With a median follow-up of 10 months (1-73 months), no differences in the time from ICI initiation to irAE onset, corticosteroid use, or additional immunosuppressant use were seen. A trend in higher incidence of all-grade diarrhea/colitis (8.7% vs. 3.0%, p=0.07) and grade 3 and 4 hepatitis (4.3% vs. 0.8%, p=0.08) was noted in the COVID-19 positive group, however the difference was not statistically significant. No significant difference in the incidence of pneumonitis (2.2% vs. 1.1%, p=0.44), nephritis (2.2% vs. 0.8%, p=0.34) or dermatitis (6.5% vs. 6.4%, p=1.00) were noted between COVID-19 positive and negative groups. We noticed a higher incidence of all-grade irAEs in the COVID-19 positive group (30.4% vs. 19.9%, p=0.18), but the difference was not statistically significant. The incidence of grade 3 and 4 irAEs was significantly higher in the COVID-19 positive group (10.9% vs. 3.2%, p=0.02). Nine COVID-19 related death occurred while no irAE-related death was noted in the entire cohort. Conclusions: Our study suggested that COVID-19 may pose a risk of severe irAEs in cancer patients receiving ICIs. Close monitoring and possible delaying ICI administration could be considered when cancer patients were infected with COVID-19. [Table: see text]

Chordoma is a rare malignant tumor of bone with high morbidity and mortality. Recently, aggressive pediatric poorly differentiated chordoma with SMARCB1 loss has been described. This study summarizes the clinicopathologic features of poorly differentiated chordoma with SMARCB1 loss in the largest series to date. A search of records between 1990-2017 at MGH identified 19 patients with poorly differentiated chordoma. Immunohistochemical stains were evaluated. Kaplan-Meier survival statistics and log-rank (Mantel Cox) tests compared survival with other subtypes. The patients (n = 19) were diagnosed at a median age of 11 years (range: 1-29). Tumors arose in the skull base and clivus (n = 10/19; 53%); cervical spine (n = 6/19; 32%); and sacrum or coccyx (n = 3/19; 16%). The clinical stage of these patients (AJCC 7e) was stage 2A (n = 7/16; 44%); stage 2B (n = 6/16; 38%); stage 4A (n = 1/16; 6%); and stage 4B (n = 2/16; 13%). The tumors were composed of sheets of epithelioid cells with nuclear pleomorphism, abundant eosinophilic cytoplasm, and increased mitoses. Tumors were positive for cytokeratin (n = 18/18; 100%) and brachyury (n = 18/18; 100%). Patients were treated with a combination of excision, radiation therapy, and chemotherapy. No difference in overall survival, progression free survival, local control time, and metastasis free survival was identified between poorly differentiated chordoma of the skull base and of the spine. Compared to other chordoma subtypes, poorly differentiated chordoma has a significantly decreased mean overall survival after stratification by site (p = 0.037). Pediatric poorly differentiated chordoma has a distinct clinical and immunohistochemical profile, with characteristic SMARCB1 loss and decreased survival compared to conventional/chondroid chordoma. Recognition of this subtype is important because these malignancies should be treated aggressively with multimodality therapy.

Monopolar spindle1 (Mps1, also known as TTK) is the core component of the spindle assembly checkpoint, which functions to ensure proper distribution of chromosomes to daughter cells. Mps1 is hardly detectable in normal organs except the testis and placenta. However, high levels of Mps1 are found in many types of human malignancies, including glioblastoma, thyroid carcinoma, breast cancer, and other cancers. Several Mps1 inhibitors can inhibit the proliferation of cancer cells and exhibit demonstrable survival benefits. Mps1 can be utilized as a new immunogenic epitope, which is able to induce potent cytotoxic T lymphocyte activity against cancer cells while sparing normal cells. Some clinical trials have validated its safety, immunogenicity and clinical response. Thus, Mps1 may be a novel target for cancer therapy. Mps1 is differentially expressed between normal and malignant tissues, indicating its potential as a molecular biomarker for diagnosis. Meanwhile, the discovery that it clearly correlates with recurrence and survival time suggests it may serve as an independent prognostic biomarker as well.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, which can be explained at least in part by its propensity towards metastasis and the limited efficacy of adjuvant therapy. MetastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, and their functional status is significantly correlated with HCC prognosis. Unlike targeted therapy, metastamiRs have the potential to target multiple genes and signaling pathways and dramatically suppress cancer metastasis. In this review, we discuss the regulatory role of metastamiRs in the HCC invasion-metastasis cascade. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis has shown that many extensively studied metastamiRs target several critical signaling pathways and these have remarkable therapeutic potential in HCC. The information reviewed here may assist in further anti-HCC miRNA drug screening and development.

Ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare form of Cushing disease (CD) with over-secretion of ACTH from nonpituitary tumor outside the adrenal or pituitary glands. Its diagnosis relies on both biochemical tests (high-dose dexamethasone suppression test, ACTH level, corticotropin-releasing hormone test) to confirm ACTH-dependent CD and image studies (CT or MRI of chest, abdomen, and/or pelvis) for source localization. We present a rare case of ectopic ACTH syndrome from a pancreatic neuroendocrine tumor (NET).

e23511 Background: Conditional survival provides a dynamic prediction of prognosis for patients surviving a defined period of time after diagnosis. This study aimed to determine the conditional survival and prognostic factors over time among patients with non-metastatic bone osteosarcoma. Methods: We reviewed 714 bone osteosarcoma patients treated from 1985 to 2016. Patients with metastatic disease at diagnosis or limited follow up were excluded, resulting in 587 cases for analysis. Clinical and pathological variables were recorded. Predictive variables included age at diagnosis, gender, previous radiation history, tumor site, tumor size, histologic subtype, histologic grade, resection margin, chemotherapy, and radiation therapy. The multivariate Cox proportional hazards regression was used to analyze prognostic factors of conditional overall survival and progression-free survival at baseline and 5 years after diagnosis. Results: The estimated 5-year conditional overall survival increased from 71.0% (95% CI: 67.5%-75.0%) at baseline to 86.9% (95% CI: 82.6%-90.5%) at 5 years, which means if a patient with non-metastatic bone osteosarcoma survived 5 years, the chance of surviving another 5 years was 86.9%. If the patient was progression-free for 5 years, the 5-year conditional overall survival was even higher, 93.2% (95% CI: 89.5%-96.4%), and the 5-year conditional progression-free survival improved from 57.1% (95% CI: 53.3%-61.0%) at baseline to 91.2% (95% CI: 87.5%-94.6%) at 5 years. Prognostic factors for mortality and disease progression change as survival time increases. At baseline, age (p < 0.001 and p = 0.003), histologic subtype (p < 0.001 and p = 0.001), grade (p < 0.001 and p < 0.001), tumor size (p = 0.002 and p = 0.002), resection margin (p < 0.001 and p < 0.001) and chemotherapy (p = 0.001 and p = 0.001) were predictive of both overall survival and progression-free survival. However, only age (p < 0.001) and histologic subtype (p = 0.015) remained significant for mortality and resection margin (p = 0.001) for disease progression at 5 years. Conclusions: The survival probability of osteosarcoma improves as survival time increases. Estimates of conditional survival can provide useful information for individualized surveillance strategies, risk evaluation, patient counseling, and making clinical decisions.

e23505 Background: Chordomas are malignant tumors arising from remnant notochordal tissue. Despite improved local control with preoperative/postoperative RT, progression-free survival and OS remain poor in patients (pts) with high-risk features. Chordoma has been identified to express and activate platelet-derived growth factor receptor signaling. We conducted a phase 1 trial to identify the maximum tolerated dose (MTD), safety, and feasibility of nilotinib with RT as either preoperative or definitive treatment for patients with high-risk chordoma. Enclosed is an updated report on LC, MFS, and OS. Methods: We recruited 23 pts with nonmetastatic chordoma to the phase I and dose expansion arms of the study. High-risk was defined as the presence of any of the following: local recurrence after surgery, previous intralesional resection, unplanned incomplete resection, unresectable/marginally resectable disease, or declining surgery due to excessive morbidity. Pts were treated with nilotinib and concurrent RT to 50.4 Gy relative biological effectiveness (RBE) followed by surgery and postoperative RT to a cumulative dose up to 70.2 Gy RBE or definitively up to 77.4 Gy RBE without surgery. On completion of RT, pts were eligible to continue nilotinib until disease progression. Results: The dose escalation arm of the study identified nilotinib 200 mg daily as the maximum tolerated dose (MTD). Eighteen evaluable pts were treated with nilotinib plus RT at the MTD. The objective best response rate was 6% (1 of 18 pts). The 4 and 5-year LC rates were 94.3% (95% CI 83.2-100) and 70.7% (95% CI 20.8-100), respectively. The MFS rate was 74.3 at 4 and 5 years (95% CI 51.8-96.7). The 4 and 5-year OS rates were 70.2% (95% CI 44.4-95.9) and 54.6% (95% CI 20.5-88.6). Conclusions: In updated data from a cohort of high-risk chordoma pts nilotinib 200 mg/d with RT +/- surgery, with long-term follow-up, local control and distant metastasis free survival remains favorable. Clinical trial information: NCT01407198 . [Table: see text]

Background. Dedifferentiated chondrosarcomas (DDCSs) are highly malignant tumors with a dismal prognosis and present a significant challenge in clinical management. Methods. In an IRB approved retrospective protocol, we identified 72 patients with DDCS treated at our institution between 1993 and 2017 and reviewed clinicopathological characteristics, treatment modalities, and outcomes to analyze prognostic factors. Results. Femur (44.4%), pelvis (22.2%), and humerus (12.5%) were most commonly involved sites. Twenty-three patients (31.9%) presented with distant metastasis, and 3 (4.2%) of them also had regional lymph node involvement. The median overall survival (OS) was 13.9 months. On multivariate analysis, pathological fracture, larger tumor size, lymph node involvement, metastasis at diagnosis, extraosseous extension, and undifferentiated pleomorphic sarcoma component correlated with worse OS, whereas surgical resection and chemotherapy were associated with improved OS. For progression-free survival (PFS), pathological fracture and metastasis at diagnosis showed increased risk, while chemotherapy was associated with decreased risk. Among patients who received chemotherapy, doxorubicin and cisplatin were significantly associated with improved PFS but not OS. Among patients without metastasis at diagnosis, 17 (34.7%) developed local recurrence. Thirty-one (63.3%) developed distant metastases at a median interval of 18.1 months. On multivariate analysis, R1/R2 resection was related with local recurrence, while macroscopic dedifferentiated component was associated with distant metastasis. Conclusions. The prognosis of DDCS is poor. Complete resection remains a significant prognostic factor for local control. Chemotherapy with doxorubicin and cisplatin seems to have better PFS. More prognostic, multicenter trials are warranted to further explore the effectiveness of chemotherapy in selected DDCS patients.

Background Malignant peripheral nerve sheath tumors (MPNST) may be sporadic or associated with neurofibromatosis or prior radiation. MPNST may behave aggressively with a high rate of local recurrence and distant metastasis. Methods In an IRB approved protocol, we reviewed the clinical characteristics, treatment, and outcomes of 280 patients treated for MPNST at Massachusetts General Hospital (MGH) between 1960 and 2016. Results There were 138 men and 142 women with a median age of 41 (range: 3–95) years. Tumors were classified as neurofibromatosis-associated (nfMPNST, n = 77), radiation-induced (rMPNST, n = 21), or sporadic (sMPNST, n = 182) MPNST. The median time to development of rMPNST from prior radiation was 15 years. With a median follow-up of 43.1 months, the median overall survival (OS) was 65.3 months. Older age, nfMPNST, rMPNST, increased tumor size, lymph node involvement, metastatic disease, intermediate to high grade, radiotherapy alone, and R2 resection were related to worse OS, whereas surgery with radiotherapy was associated with improved OS. Among the 251 patients without metastasis, nfMPNST, rMPNST, and increased tumor size were correlated with worse metastasis-free survival; nfMPNST, radiotherapy alone, and R1/R2 resection were associated with local recurrence, whereas surgery with adjuvant radiotherapy was related to improved local control in patients with R1/R2 resection. Conclusions Both radiation-induced and neurofibromatosis-associated MPNSTs have poorer prognosis than sporadic MPNSTs. Complete resection of the tumor is a significant prognostic factor for MPNST. The addition of radiotherapy after surgery should be considered especially when the surgical margins are positive.

Background and Aim Inflammatory myofibroblastic tumor of the liver (IMTL) is a very rare benign disease with a good prognosis. The study aims to determine the clinical, radiological, and pathological characteristics of IMTL. The diagnosis and treatment strategies were discussed. Methods A total of 11 patients with pathologically confirmed IMTL receiving treatment over a 15-year period were reviewed retrospectively. The analysis included demographics information and pertinent clinical data. Results obtained from patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (IHCC), and metastatic liver cancer (MLC) receiving surgical resection were compared. Results In comparison to HCC, IHCC, and MLC, IMTL has an earlier onset (P

Background & aims The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy. Methods A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patients with multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to contrast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174). Results The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual-specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort. Conclusions Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

Meta-analyses on coffee and cancer incidence mainly restricted to limited cancers. We carried out a more comprehensive meta-analysis of cohort studies to explore association between coffee and most cancer types. We conducted comprehensive search and summarized relative risk (RR) and 95% confidence intervals for the highest versus lowest coffee intake and cancer using STATA12. We conducted dose-analysis if result suggested significant association. The publication bias was evaluated with begg’s and egger’s test. Finally, 105 individual prospective studies were included. Inverse associations were observed on oral, pharyngeal, colon, liver, prostate, endometrial cancer and melanoma, with RR 0.69 (95% CI = 0.48–0.99, I2 = 73.4%, P = 0.044), 0.87 (95% CI = 0.78–0.96, I2 = 28.4%, P = 0.007), 0.46 (95% CI = 0.37–0.57, I2 = 0%, P = 0), 0.89 (95% CI = 0.84–0.93, I2 = 30.3%, P = 0.003), 0.73 (95% CI = 0.67–0.80, I2 = 0%, P = 0) and 0.89 (95% CI = 0.80–0.99, I2 = 0%, P = 0.031) respectively. However, the relative risk for lung cancer is 2.18 (95% CI = 1.26–3.75, I2 = 63.3%, P = 0.005). The summary relative risk for increment of 2 cups of coffee were RR = 0.73, 95% CI = 0.67–0.79 for liver cancer, RR = 0.97, 95% CI = 0.96–0.98 for prostate cancer and RR = 0.88, 95% CI = 0.85–0.92 for endometrial cancer. Accordingly, coffee intake was associated with reduced risk of oral, pharynx, liver, colon, prostate, endometrial cancer and melanoma and increased lung cancer risk.

Therapies for primary liver cancer, the third leading cause of cancer-related death worldwide, remain limited. Following multi-omics analysis (including whole genome and transcriptome sequencing), we were able to identify the dual-specific protein kinase TTK as a putative new prognostic biomarker for liver cancer. Herein, we show that levels of TTK protein are significantly elevated in neoplastic tissues from a cohort of liver cancer patients, when compared with adjacent hepatic tissues. We also tested the utility of TTK targeted inhibition and have demonstrated therapeutic potential in an experimental model of liver cancer in vivo. Following lentiviral shRNA knockdown in several human liver cancer cell lines, we demonstrated that TTK boosts cell growth and promotes cell spreading; as well as protects against senescence and decreases autophagy. In an experimental animal model, we show that in vitro knockdown of TTK effectively blocks intrahepatic growth of human HCC xenografts. Furthermore, we note that, in vivo silencing of TTK, by systemically delivering TTK siRNAs to already tumor-bearing liver, limits intrahepatic spread of liver cancer cells. This intervention is associated with decreased tumor aggressiveness, as well as increased senescence and autophagy. Taken together, our data suggest that targeted TTK inhibition might have clinical utility as an adjunct therapy in management of liver cancer.

Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Department of Liver Transplantation and Hepatobilliary Surgery, Provincial Hospital Affilliated to Shandong University, Jinan 250021, China; Bioinformatics Research Group, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China

Background This study aimed to clarify the risk factors for survival and recurrence of hepatocellular carcinoma (HCC) in a cohort of Chinese HCC patients after hepatectomy and to compare 6 developed staging systems. Methods A retrospective analysis was performed on 165 consecutive patients. The Kaplan–Meier method was used to calculate survival. Postoperative prognostic factors were evaluated using univariate and multivariate analyses. The overall predictive power of each staging system was evaluated by the area under the receiver operating characteristic curve. Results The overall survival rates of 1, 3, and 5 years were 81.2%, 58.6%, and 56.7%, respectively, and the corresponding disease-free survival rates were 52.9%, 23.3%, and 15.5%, respectively. α-fetoprotein level and blood transfusion were correlated significantly with patients' overall survival, and portal vein thrombosis and tumor size (>5 cm) were correlated significantly with poor disease-free survival. Conclusions The French staging system is better for predicting the prognosis of HCC patients receiving surgical treatment.

Background and Objectives: Primary liver cancer (PLC) presenting as pyogenic liver abscess (PLA) is potentially life-threatening, but has been occasionally reported, especially for cholangiocarcinoma. Methods: Medical records of nine patients who presented as PLA, but were eventually confirmed as hepatocellular carcinoma (HCC; n ¼ 5) or intrahepatic cholangiocarcinoma (IHCC; n ¼ 4), from September 1997 through April 2011, were retrospectively reviewed. Results: Presenting symptoms included fever, chills, right-upper-quadrant abdominal pain, nausea, vomiting, weight loss, and diarrhea. Physical signs included tenderness in the right-upper-quadrant abdomen, jaundice, and ascites. With the exception of elevated alpha-fetoprotein (AFP) in HCC patients and elevated carbohydrate antigen 19-9 (CA19-9) in IHCC patients, lab results were not significantly different between these nine patients and PLA patients. All the nine patients underwent invasive treatment in addition to antibiotics. Conclusions: Elevated AFP and CA19-9 could suggest HCC and IHCC in patients with symptoms/signs typical of PLA. Contrast-enhanced computed tomography could be helpful in patients with normal AFP and CA19-9. Making an accurate and early diagnosis and seizing the opportunity of surgery are essential to improve the management strategies of patients with PLC mimicking PLA. J. Surg. Oncol. 2011 Wiley Periodicals, Inc.

e23562Background: Retroperitoneal sarcomas (RPS) can cause local, intraperitoneal, and distant failures. Treatment requires a tailored, multidisciplinary strategy. Methods: In an IRB approved proto...

11567Background: Synovial, Clear cell, Angiosarcoma, adult Rhabdomyosarcoma and Epithelioid sarcoma is often referred to by the mnemonic SCARE as soft tissue sarcoma subtypes with higher risk of ly...

Background To determine more precisely time interval from resection to recurrence of hepatocellular carcinoma (HCC) and to identify the risk factors associated with postoperative recurrence. Methods From January 2004 to December 2007, 178 patients who underwent resection of HCC were followed prospectively for at least 12 months. Recurrence was identified by the digital subtraction angiography (DSA). Demographic, tumor, and disease characteristics were compared between patients with recurrence within 6 months and between 7 and 12 months, and those without recurrence to evaluate for their prognostic significance. Patients with intrahepatic recurrence were treated with trans-arterial chemoembolization (TACE) and re-assessed by CT scans, contrast-enhanced ultrasound, or MRI. Results Recurrence developed in 52 patients between 1 and 6 months, 11 patients between 7 and 12 months, and 115 patients remained disease free for at least 1 year. The recurrence rates of 6 months and 1 year were 29.2% and 35.4%, respectively. No statistically significant difference between was observed. Fourteen (22.2%) patients with recurrence and 11 (9.6%) patients without recurrence had previously presented as multifocal HCC, and the difference is of statistical significance (P = 0.025). The diagnostic accuracy of DSA as validated by other diagnostic methods was 81.8%. Conclusions Recurrences are more likely to develop within the first 6 months after resection for HCC. Multifocal HCC is an important risk factor associated with early recurrence of advanced HCC after hepatectomy. DSA may serve as an important surveillance for early detection of intrahepatic recurrence after surgery. J. Surg. Oncol. 2009;100:488–493. © 2009 Wiley-Liss, Inc.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, which can be explained at least in part by its propensity towards metastasis and the limited efficacy of adjuvant therapy. MetastamiRs are miRNAs that promote or suppress migration and metastasis of cancer cells, and their functional status is significantly correlated with HCC prognosis. Unlike targeted therapy, metastamiRs have the potential to target multiple genes and signaling pathways and dramatically suppress cancer metastasis. In this review, we discuss the regulatory role of metastamiRs in the HCC invasion-metastasis cascade. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis has shown that many extensively studied metastamiRs target several critical signaling pathways and these have remarkable therapeutic potential in HCC. The information reviewed here may assist in further anti-HCC miRNA drug screening and development.

Combined hepatocellular cholangiocarcinoma (CHC) accounts for 0.4%-14.2% of primary liver cancer cases and possesses pathological features of both hepatocellular carcinoma and cholangiocarcinoma. Since this disease was first described and classified in 1949, the classification of CHC has continuously evolved. The latest definition and classification of CHC by the World Health Organization is based on the speculation that CHC arises from hepatic progenitor cells. However, there is no evidence demonstrating the common origin of different components of CHC. Furthermore, the definition of CHC subtypes is still ambiguous and the identification of CHC subtype when a single tumor contains many components has remained unresolved. In addition, there is no summary on the newly recognized histopathology features or the contribution of CHC components to prognosis and outcome of this disease. Here we provide a review of the current literature to address these questions.

11020 Background: The multidisciplinary approach in treatment of osteosarcoma has been well established and well adopted nationwide. This study combined the clinical prognostic factors at initial presentation into a nomogram to predict local control (LC), metastasis free survival (MFS), and overall survival (OS) for patients with non-metastatic bone osteosarcoma. Methods: We reviewed 397 osteosarcoma patients treated from 1995 to 2014. Patients with metastatic disease at diagnosis or limited follow up were excluded, resulting in 283 cases for analysis. Clinical and pathologic variables were recorded. Predictive variables included age at diagnosis, gender, previous radiation history, site, tumor size, histologic subtype, histologic grade, extra-osseous extension (EOE), lymphovascular invasion (LVI), necrosis rate and margin. The multivariate Cox proportional hazards regression was used to analyze survival outcomes and risk variables. Results: At 10 years, LC was 70.4% (95% confidence interval, CI: 64.0%-76.7%), MFS was 64.7% (95% CI: 58.1%-71.3%), and OS was 61.5% (95% CI: 54.9%-68.1%). Multivariate Cox model identified age (p = 0.033), site (p = 0.020), EOE (p = 0.017), LVI (p = 0.011), and margin (p = 0.039) were correlated with LC; age (p = 0.028), tumor size (p < 0.001), histologic grade (p = 0.039), and LVI (p = 0.014) were correlated with MFS; whereas age (p < 0.001), prior radiation history (p = 0.010), tumor size (p = 0.002), histologic subtype (p = 0.012), EOE (p = 0.002), and LVI (p = 0.001) were associated with OS. The nomograms were drawn on the basis of the Cox regression model and were internally validated using bootstrapping, with predictive accuracy of ±7.2% for 10-year LC, ±7.4% for 10-year MFS, and ±7.5% for 10-year OS. Conclusions: Nomograms have been developed to predict the 10-year local-control failure, recurrence and death. We suggest that this tool at presentation may be useful for individualized risk evaluation, patient counseling, and making clinical decisions.