tbuckley/cabot-search huggingface dataset:
Use of gene expression signatures to identify origin of primary and therapeutic strategies for patients with advanced solid tumors.
Authors: S. D. Hsu, M. K. Kim, A. Foye, A. Silvestri, H. K. Lyerly, M. Morse, E. Petricoin, P. G. Febbo
Journal: Journal of Clinical Oncology (2010)

10504 Background: An improved understanding of biological interactions between site of primary and the metastatic process can improve diagnostic accuracy and better design treatments for patients with metastatic cancer. Methods: 96 metastatic solid tumors were analyzed using global gene expression to determine genes and pathways associated with colon, lung, breast, prostate and ovarian cancer. Site of origin (SOO) gene expression signatures were developed using binary regression and validated on 1,217 independent samples (GSE2109 and GSE12630). Targetable pathways associated with colorectal cancer (CRC) were validated using reverse phase proteomic arrays and in vitro synergy experiments. Results: Unsupervised hierarchical clustering of samples demonstrated that SOO maintains dominant influence on solid tumor gene expression. Gene-expression-based SOO signatures were developed with predictive accuracy ranging between 88%-99.8% in 1,104 primary tumors (GSE2109) and 84.2%-99.1% in 113 moderately to poorly differentiated metastatic tumors (GSE12630). Gene Set Enrichment Analysis identified 108 gene sets, including MYC, beta-catenin, IGFR1 and SRC, with increased coordinated expression in CRC compared to all other metastatic samples (normalized p < 0.05). Reverse phase protein arrays confirmed increase of MYC (Mann Whitney p = 0.0074), beta-catenin (p = 0.0032), and SRC (p = 0.0078) protein levels in metastatic CRC (n = 22) versus non CRC metastases (n = 12). Strong positive correlation between SRC protein expression and predicted oxaliplatin sensitivity was identified in these pathways (Spearman p = 0.0016), whereas no correlation was found with irinotecan. In 3 oxaliplatin sensitive CRC cell lines (HT29, WiDr and SKCO-1), the combination of dasatinib (SRC inhibitor) with oxaliplatin was found to be synergistic with mean combination indices (± stdev) of 0.71 ± 0.04, 0.76 ± 0.10, and 0.22 ± 0.01, respectively. Conclusions: Our findings suggest that the complex alterations required for metastasis do not obscure the impact of a cancer cell's origin and SOO signatures have the potential to be highly accurate diagnostic tools to identify novel therapeutic targets for advanced cancers. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Theranostics Health Theranostics Health
Influence of histologic subtype on metastatic pattern in colorectal cancer.
Authors: Niek Hugen, Cornelis J. H. Van De Velde, Johannes H. W. de Wilt, Iris D. Nagtegaal
Journal: Journal of Clinical Oncology (2014)

395 Background: In colorectal cancer (CRC) mucinous adenocarcinoma (MC) and signet-ring cell carcinoma (SRCC) have been associated with differences in metastatic patterns compared to the more common adenocarcinoma (AC). This study systematically evaluates metastatic patterns of different histological subtypes and analyses metastatic disease based upon primary tumor localization. Methods: A nationwide retrospective review of pathological records of 5,813 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch Pathology Registry (PALGA). To validate metastatic patterns in rectal cancer patients, data was compared to the prospective randomized multicentre TME-trial that investigated efficacy of preoperative radiotherapy. Results: In the autopsy study 1,675 patients with CRC had metastatic disease. Metastatic disease was more frequently found in MC and SRCC than in AC (33.9%, 61.2% and 27.5%; P&lt; 0.0001) and more often had metastases at multiple sites (58.6% and 70.7% versus 49.9%; P=0.001). AC more commonly metastasized to the liver compared with MC and SRCC, 73.0% versus 52.2% and 31.7% (P&lt;0.0001). The occurrence of metastases exclusively to the liver was less common in MC and SRCC patients. In SRCC patients, liver metastases were almost always observed in combination with other metastases. MC and SRCC metastasized to the peritoneal surface frequently, 48.2% and 51.2%, compared with 20.1% in AC (P&lt;0.0001). Colon cancer patients presented more frequently with intra-abdominal metastases, than rectal cancer patients. Rectal cancer patients presented more often with extra-abdominal metastases. Results from the TME-trial confirmed findings in rectal cancer patients from the autopsy study. Conclusions: There are profound differences in metastatic patterns between different histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take histological subtype into account during pre-operative examination for metastases and during follow-up. Results also indicate that these factors should be considered a stratification factor in future research initiatives focusing on advanced disease.
The impact of bevacizumab on liver regeneration following hepatectomy in rats.
Authors: H. Mori, M. Shimada, T. Utsunomiya, S. Imura, Y. Morine, T. Ikemoto, J. Hanaoka, S. Iwahashi, Y. Saito, S. Yamada
Journal: Journal of Clinical Oncology (2011)

228 Background: In our clinical data, we had the interesting findings that the pathologic sinusoidal obstruction syndrome and serum hyaluronic acid after neoadjuvant oxaliplatin-associated chemotherapy for liver metastatic colorectal cancer with bevacitumab (Bev) was ameliorated compared to those without Bev. The purpose of this study was to investigate the influence of bevacizumab administration on regenerating liver in rat 70% and 90% hepatectomy (Hx) model as a surrogate model of human massive hepatectomy for liver metastatic colorectal cancer. Methods: Male Wister rats weighing 180-230g were divided into the following four groups: 70%Hx, 70%Hx + Bev, 90%Hx and 90%Hx+Bev group. The rats were pretreated with intraperitoneal administration of bevacizumab (5mg/kg) 7 days before hepatectomy. The remnant liver and blood samples were taken one day after hepatectomy, and the following parameters were evaluated: blood analysis (AST, ALT, LDH, T- Bil, and hyaluronic acid), liver weight to body weight (Lw/Bw) ratio, and postoperative survival rate for three days. Results: In the 70%Hx model, there was no significant difference between the 70%Hx group and 70%Hx + Bev group in blood analysis one day after hepatectomy; AST (1928 vs. 923 IU/L), ALT (1282 vs. 670 IU/L), T-Bil (0.17 vs. 0.19 mg/dl), LDH (3822 vs. 2967 U/L) and hyaluronic acid (995.7 vs. 1026.6 ng/ml) and in Lw/Bw ratio (1.78 vs. 1.84). In 90%Hx model, AST and ALT of blood analysis in 90%Hx+Bev group significantly decreased compared to those in 90%Hx group; AST (3428 vs. 4995 IU/L, P&lt;0.05), ALT (1471 vs. 2287 IU/L, P&lt;0.05), T-Bil (1.94 vs. 2.57 mg/dl), LDH (3229 vs. 5351 U/L) and hyaluronic acid (3865.7 vs. 7862.2 ng/ml). The Lw/Bw ratio in 90%Hx+Bev group significantly increased compared to that in 90%Hx group (0.80 vs. 0.67, P&lt;0.05). The postoperative survival rate in 90%Hx+Bev group showed tendency to improve compared to that in 90%Hx group (75% vs. 50%, P=0.19). Conclusions: The administration of bevacizumab seven days before hepatectomy did not significantly affect the liver functions and liver regeneration rate. These findings suggest that hepatectomy might be safe and feasible after the use of bevacizumab. No significant financial relationships to disclose.
Phase II study of cladribine (2CDA) followed by rituximab for eradication of minimal residual disease (MRD) in hairy cell leukemia (HCL)
Authors: F. Ravandi-Kashani, H. Kantarjian, S. Verstovsek, C. Koller, S. Faderl, D. Thomas, D. Jones, J. Jorgensen, S. O’Brien
Journal: Journal of Clinical Oncology (2005)

6620 Background: HCL is an indolent lymphoproliferative malignancy characterized by infiltration of the bone marrow, liver, and spleen by neoplastic B-cells with cytoplasmic hair-like projections. Despite the success of the nucleoside analogs 2CDA and pentostatin in achieving long-term remissions in HCL, some patients (pts) continue to relapse and the relapse-free survival curve does not appear to achieve a plateau. Rituximab has been used effectively to treat pts with relapsed HCL. We investigated whether the prolonged administration of rituximab one month after therapy with 2CDA can effectively eradicate MRD in pts with newly diagnosed HCL or those who have relapsed after one prior therapy. Methods: 2CDA 5.6 mg/m2 is administered over 2 hours daily for 5 days. One month later, rituximab 375 mg/m2 is administered weekly for 8 weeks. MRD is assessed by flow cytometry as well as by IgH polymerase chain reaction (PCR) assay using framework-1, -2 and -3 primer sets. MRD is evaluated at one month following 2CDA and after completion of rituximab. Results: To date, ten pts have been enrolled onto the study. Eight pts had received no prior therapy, one pt had relapsed after prior 2CDA therapy 9 years ago and one pt had received chlorambucil only. Two pts had the variant form of HCL. Six pts have completed all therapy, 3 are receiving rituximab, and 1 pt has completed 2CDA only. So far, six (100%) of the evaluable pts have achieved a complete remission (CR) with no evidence of MRD by flow in 6 and by PCR in 3. PCR remained positive in 1 pt and was not evaluable in 2 pts. Eight of 9 pts with evaluable flow studies one month after completing 2CDA remained positive; 1 pt was negative after 2CDA only and 6 became negative after completing rituximab. Five of 6 pts with evaluable PCR studies one month after completing 2CDA remained positive; 1 pt was negative after 2CDA only and 3 became negative after rituximab. Conclusions: We conclude that assessment and eradication of MRD by flow and PCR in HCL is feasible. Longer follow-up is necessary to determine whether MRD status at completion of therapy can predict relapse. This may allow design of regimens that may further improve long-term disease-free survival in HCL. No significant financial relationships to disclose.
Hemorrhagic complications of robot-assisted laparoscopic partial nephrectomy for renal masses.
Authors: Andrew Franklin, Jack Campbell, Naveen Pokala
Journal: Journal of Clinical Oncology (2016)

621 Background: Partial nephrectomy is the current standard of care for T1a tumors. With advances in laparoscopy and robotic-assisted surgery, RPNx is increasingly being performed for complex renal tumors. However, significant hemorrhagic complications can occur. We review hemorrhagic complications following RPNx. Methods: At our institution 111 RPNx were performed on 110 patients (2011-2015). Demographic data and Nephrometry scores were determined. Total operating time, intraoperative blood loss, postoperative blood transfusion rate, gross hematuria, need for further procedures and mortality were collected. Pathology, including histologic diagnosis, and margin status was recorded. Results: Of 111 RPNx, 110 were done for renal masses and 112 masses were removed. Of these, 77% were malignant and most common commonly Renal Cell Carcinoma, Clear Cell pT1a (51%). Mean operative time was 245 minutes (SD 68), mean blood loss was 297 mL (SD 68), and average length of stay was 2.8 days. Hemorrhagic complications occurred in 21 patients (19%). Five had hematuria and 16 received a transfusion. Four patients required interventional radiology (IR) for angioembolization. Two patients died, one from hemorrhagic complications, and the other from septic shock related to a bowel injury. The most common Nephrometery score was 4a followed by 5a. Of those with hemorrhagic complications the most common Nephrometery score was 8, with 60% being 7 or higher. Among patients needing IR, 75% were 6 or higher and the one patient who died had a score of 11a in the setting of bilateral renal masses. Patients with hemorrhagic complications had a change in hemoglobin and hematocrit from per- to post-operation of 3.06 g/dL and 9.07% respectively compared to 2.34 g/dL and 6.28% for patients with no hemorrhagic complications. Conclusions: RPNx is a safe and nephron-sparing surgery for patients with appropriate renal masses. Significant hemorrhagic complications can occur, commonly managed with blood transfusions or angioembolization. However, catastrophic bleeding can occur in patients with high Nephrometry scores and monitoring in the ICU setting is recommended in high-risk patients.
The critical role of dysregulated FOXM1–PLAUR signaling in human colon cancer progression and metastasis.
Authors: Dawei Li, Ping Wei, Zhihai Peng, Chen Huang, Huamei Tang, Zhiliang Jia, Jiujie Cui, Xiangdong Le, Suyun Huang, Keping Xie
Journal: Journal of Clinical Oncology (2013)

405 Background: The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer (CRC) pathogenesis remains unknown. Methods: We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer. Results: We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by small interfering RNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis. Conclusions: Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis.
Use of serum CXCL16 to predict liver metastasis and prognosis in colorectal cancer patients.
Authors: K. Matsushita, Y. Toiyama, K. Tanaka, H. Yasuda, S. Saigusa, H. Fujikawa, Y. Inoue, C. Miki, S. Kageyama, M. Kusunoki
Journal: Journal of Clinical Oncology (2011)

424 Background: Colorectal cancer (CRC) is one of the major causes of cancer death worldwide. In CRC, serum levels of CEA have become well-established prognostic indicators. However, it is not generally accepted as optimal in its prognostic power. The aim of this study was to identify novel and reliable serum prognostic markers. Methods: We performed cytokine array to identify novel prognostic serum marker, and CXCL16 was selected. To investigate the relationships between sCXCL16 and clinicopathological findings including survival, the serum levels of CXCL16 in 237 CRC patients and 20 normal volunteers were assessed by enzyme-linked immunosorbent assay. Furthermore, we investigated proliferation, invasion and wound healing assay to investigate the biological role of CXCL16 to colon cancer cell by recombinant CXCL16 exposing to HT-29. Results: The mean sCXCL16 concentration in patients was significantly higher than that in normal volunteers (p&lt;0.0001). In addition, sCXCL16 levels increased significantly in accordance with the progression of UICC stage classification (p &lt; 0.05). In clinicopathologic findings, sCXCL16 was significantly associated with the presence of lymph node (p=0.019) and the presence of liver metastases (p=0.011). Elevated sCXCL16 level demonstrated a significant association with poor survival, and was an independent risk factor for poor survival. Furthermore, sCXCL16 was an independent marker for predicting liver metastasis (logistic analysis; p=0.0015). In vitro, recombinant CXCL16 promoted epithelial mesencymal transition (EMT) phenotype characterized by impaired E-cadherin and induction of Vimentin. In addition, CXCL16 promoted cell growth, migration and invasion. Conclusions: Our data demonstrate that preoperative sCXCL16 level increased in colorectal cancer patients, and that sCXCL16 correlated with liver metastasis, and is an independent prognostic factor for overall survival. Elevated CXCL16 has been proposed as a useful predictive marker for liver metastasis and overall survival in CRC. In vitro, CXCL16/CXCR6 axis might play an importance role in mediating cell survival, migration and invasion by EMT in CRC cell. No significant financial relationships to disclose.
Induction of CD33 Expression in B-Precursor ALL by E2A-HLF Fusion Transcription Factor Derived from t(17;19).
Authors: Koshi Akahane, Takeshi Inukai, Toshiya Inaba, Hidemitsu Kurosawa, Mikiya Endo, Hiroaki Goto, Nobutaka Kiyokawa, A. Thomas Look, Kumiko Goi, Kanji Sugita, Shinpei Nakazawa
Journal: Blood (2005)
Erratum to ‘Exploring and exploiting the systemic effects of deregulated replication licensing’ [Seminars in Cancer Biology 37–38C, (2016) 3–15]
Authors: Theodoros G. Petrakis, Eirini-Stavroula Komseli, Marilena Papaioannou, Kostas Vougas, Alexandros Polyzos, Vassilios Myrianthopoulos, Emmanuel Mikros, Ioannis P. Trougakos, Dimitris Thanos, Dana Branzei, Paul Townsend, Vassilis G. Gorgoulis
Journal: Seminars in Cancer Biology (2017)
The effect of varying doses of ABT-869 on biomarkers of angiogenesis and their correlation with pharmacodynamic outcome
Authors: R. A. Soo, E. McKeegan, C. S. Chen, C. H. Thng, T. S. Koh, D. Laird, K. Zhang, C. I. Wong, N. Gupta, B. C. Goh
Journal: Journal of Clinical Oncology (2008)

14535 Background: ABT-869, an orally administered, potent small molecule inhibitor of VEGF receptors 1–3 and platelet derived growth factor, is active in solid malignancies. Consistent with similar anti-angiogenic agents, dose limiting toxicities of ABT-869 include proteinuria and hypertension (HPT). Development of serum biomarkers to measure the PD effect of ABT-869 may be useful in determining dose and predicting toxicity. Methods: Serum VEGF, placenta-derived growth factor (PlGF), soluble Flt-1 (sFlt-1) and circulating endothelial cells (CEC) were measured in a time sequence from patients with advanced solid tumors treated with ABT-869 in a Phase I study. Daily doses of ABT-869 were 0.1mg/kg (n=12), 10mg (n=6) (∼ 0.2mg/kg), 0.25mg/kg (n=12) and 0.3mg/kg (n=3). Correlation between biomarkers with dose, pharmacokinetics of ABT-869, tumor DCE-MRI tracer kinetics, proteinuria and HPT were performed with Pearson’s correlation coefficient. Results: Free sFlt-1 was reduced and PlGF was increased within 6 h of treatment and persisted throughout. By day 15, VEGF was significantly increased (p=0.02) and CECs reduced (p=0.03) compared to baseline levels. Comparison of these biomarkers between 0.1mg/kg and 0.25mg/kg dose groups demonstrated significantly higher PlGF (p=0.017), % apoptotic CECs (p=0.028) and lower sFlt-1 (p=0.023) and % activated CECs (p=0.027) on day 15 of treatment. The % increase in PlGF correlated positively with initial area under the curve (IAUC) (r= 0.57, p= 0.001) and Cmax (r=0.51, p = 0.004) while no correlation was seen between CECs and DCE-MRI parameters. IAUC correlated with proteinuria (p=0.023) but no correlation was seen between serum biomarkers and proteinuria or HPT. Conclusions: In this exploratory study, ABT869 induced dose-dependent changes in serum biomarkers consistent with anti-angiogenic activity. However, serum biomarkers had limited value in predicting safety i.e., proteinuria or HPT. The utility of tumor flow and permeability changes on DCE-MRI in predicting proteinuria should be further examined. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories
Quick screening of EGFR mutation using restriction fraction length polymorphism
Authors: I. Kawada, K. Soejima, H. Watanabe, I. Nakachi, K. Naoki, K. Eguchi, M. Kawamura, K. Kobayashi, A. Ishizaka
Journal: Journal of Clinical Oncology (2005)

7071 Background: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of non-small cell lung carcinomas (NSCLCs) to gefitinib (Iressa), kinase inhibitor. In-frame deletions/insertions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21) and less frequently in codon 718 (exon18). Currently, direct sequencing of corresponding region is the only way to verify the existence of these mutations. However, it is time and cost consuming. The aim of this study is to establish easy and cost-effective way to screen EGFR mutations. Methods: Thirty-eight frozen tumor specimens were obtained by surgery (n=24) or by computed tomography (n=10)- or ultrasonography (n=4)-guided lung biopsy from NSCLC patients according to a protocol approved by our institutional review board. For mutational analysis of the EGFR coding sequence of exon18, 19 and 21, RNA was extracted from specimens and cDNA was made by reverse transcription. PCR was performed on cDNA using 2 pairs of original primers designed for restriction fraction length polymorphism (RFLP) to detect mutations, then, half of the PCR products were digested with corresponding enzymes. The PCR products before and after digestion were run on 2% agarose gel and the existence of mutations was assessed. Simultaneously, all of the PCR products before digestion were sequenced directly to check mutations. Results: We found 7 deletion mutations in exon 19 and 3 point mutations in codon 858, but not in codon 718 by RFLP. The RFLP results completely matched to the sequencing Results: Among 38 patients, 13 were treated with gefitinib and 5 responded to the treatment. Four out of 5 responsive patients had deletion mutations in exon19, while one had no mutations. On the other hands, none of the non-responsive patients had any mutations. Conclusions: RFLP is a quick and cost-effective method for screening EGFR mutations and may be useful to predict sensitivity of NSCLC patients to gefitinib. No significant financial relationships to disclose.