tbuckley/cabot-search huggingface dataset:
Identification of a molecular signature of radiographic response to cetuximab in patients (pts) with advanced colorectal cancer
Authors: C. Garrett, C. Takimoto, M. Wojtowicz, H. Burris, M. Hidalgo, B. Tan, S. Krishnamurthi, M. Basik, J. Baselga, D. Mauro
Journal: Journal of Clinical Oncology (2005)

3626 Background: Although clinical activity of cetuximab in patients (pts) with colorectal cancer is well established, radiographic responses rates to monotherapy are low. EGFR protein expression and EGFR mutation analyses have failed to predict pts most likely to respond. Preclinical investigation utilizing affymetric gene expression profiling across sensitive and resistant colorectal cancer cell lines, xenografts and clinical tumor samples has identified a set of genes including Mucins 2 & 3, Cystic Fibrosis Transmembrane Receptor, SERPIN B5, CEACAM 6, Galectin, S100P, Talin, Spondin and 3-hydoxy-3 methyl-Coenzyme A Synthase, Cadherin 17, that are predictive of response. A pharmacogenomics (PGx) study of cetuximab monotherapy in pts with metastatic colorectal carcinoma was undertaken to explore whether the expression of this marker set could predict response to cetuximab. Methods: Pts with metastatic colorectal cancer were enrolled in a study of cetuximab monotherapy. A standard cetuximab dosing regimen was followed for the first 3 weeks of therapy, thereafter pts were eligible for dose escalation every 3 weeks to a maximum dose of 400 mg/m2 provided they had not experienced a ≥ Grade 2 skin rash. During the pretreatment phase all pts underwent a single biopsy procedure involving three passes with a 18 gauge needle of a single metastatic lesion. Tumor samples were placed immediatley in RNALater and shipped overnight at room temperature for RNA extraction. Additional PGx samples were collected which included blood and serum for genotyping and proteomics, respectively, as well as FFPET tumor tissue samples for immunohistochemistry and transcriptional profiling Results: Currently 55 pts have been enrolled to this study. The preliminary response rate is approximately 11%, consistent with historical data. 73% of the pts have been dose escalated without a single patient discontinuing due to skin toxicity. 80% of the tumor biopsy samples collected contain in excess of 2 μg of RNA. Conclusions: Analyses of transcriptional profiling, proteomic and genotyping data and its correlation to response will be made available at the meeting for the total enrollment of 80 pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Clinical impact of PET/CT on management of colorectal liver metastases (CLM): Prospective study assessing complementary value of PET/CT in addition to multi-detector row CT (MDCT) and MRI
Authors: S. Takahashi, T. Kinoshita, Y. Kuroki, K. Nasu, M. Konishi, T. Nakagohri, N. Gotohda, N. Saito, M. Sugitoh
Journal: Journal of Clinical Oncology (2008)

15037 Background: The aim of this prospective study was to assess complementary value of PET/CT in addition to MDCT and MRI in candidates of resection for CLM. Methods: Pts were eligible as follows; potentially resectable CLM with no prior chemotherapy, histologically proven colorectal carcinoma and no history of diabetes mellitus. First, MDCT of chest, abdomen and pelvis and MRI (with diffusion-weighted sensitivity encoding) of abdomen were performed and then a preliminary management decision was made. Next, PET/CT was performed within 4 wks, and a definitive management decision was made by taking information of PET/CT into account. Findings of the imagings were compared with the pathology as the diagnostic standard. When the lesion was not resected, follow up imaging of MDCT was considered as the reference. The primary endpoint was the rate of true upstaging by PET/CT. With 40 pts, this study had power to demonstrate 35% of true upstaging with 95% CI of 15%. Results: Between May 2005 and March 2007, 40 pts were enrolled. In 18 pts, the result of PET/CT differed from those of MDCT and MRI. However, management decision by MDCT and MRI was given a priority in 15 pts when definitive management decision was made because of small tumor-size or possibility of inflammatory tumor. In the rest of the 3 pts, decisions changed from preliminary ones. Extent of hepatic resection was enlarged in 2, and a peritoneal metastasectomy was needed in one. In the 3 pts, definitive decision was true upstaging in 1 (2.5%) and false-upstaging in 2. The same treatment as the definitive decision was done in 36 pts (resection in 29, chemotherapy in 5, observation in 2). No pt experienced unresectable CLM at laparotomy. Accuracy of each imaging according to lesion by lesion analyses is shown in Table 1. Conclusions: These results do not confirm complementary value of PET/CT in addition to MDCT and MRI. Therapeutic management by MDCT and MRI demonstrates efficacy in CLM. The accuracy of MDCT, MRI and PET/CT for detecting metastases in pts with CLM All lesions (130) Extrahepatic lesions (20) sensitivity (%) specificity (%) PPV (%) NPV (%) sensitivity (%) specificity (%) PPV (%) NPV (%) MDCT 90.16 57.14 97.35 23.53 100 100 100 100 MRI 97.17 57.14 97.17 50 100 100 100 100 PET/CT 71.31 57.14 96.67 10 52.6 0 90.9 0 PPV, positive predictive value; NPV, negative predictive value No significant financial relationships to disclose.
Growth patterns of liver metastases as compared to resected tumors of the same colorectal cancer patients.
Authors: Rikke Loevendahl Eefsen, Gert G. Van den Eynden, Pnina Brodt, Julia V. Burnier, Gunilla Hoyer-Hansen, Ib Jarle Christensen, Peter Metrakos, Ole Didrik Laerum, Birgitte Federspiel, Gro Willemoe, Kell Osterlind, Martin Illemann
Journal: Journal of Clinical Oncology (2012)

519 Background: Colorectal cancer (CRC) affects one million people a year. 25% of the patients have metastatic disease at the time of diagnosis. Metastatic disease is one of the major challenges in the treatment of cancer. Even though the TNM staging system is a good prognostic marker, tumours have a biological diversity that cannot be evaluated by the TNM system. Recently three different growth patterns of CRC liver metastases were identified. The aim of this study was to determine the growth patterns of CRC liver metastases from patients with more than one metastasis. Methods: A pilot study was conducted including 34 patients resected for CRC liver metastases, 28 patients selected from a database of 200 patients, operated in Copenhagen between 2007-2010 and 6 patients, operated in Montreal. From these 34 patients, 15 patients were resected for two or more liver metastases. All paraffin embedded tissue sections were stained for reticulin and haematoxylin and eosin at the Finsen Laboratory. Evaluation of the growth pattern was done by three different observers from Antwerp and Copenhagen. Reproducibility was &gt;90%. Results: In the fifteen patients, 9 from Copenhagen and 6 from Montreal, that had multiple hepatic metastases, there was uniformity in the growth pattern of the individual metastases. 40% had a desmoplastic, 33% a pushing and 20% a replacement growth pattern and 7% had a mix pattern. Of the 9 patients from Copenhagen 33% were synchronous and 67% metachronous metastases. Within patients, all patterns were identical. Conclusions: The uniformity of growth patterns seen in each patient suggests that these patterns are not random. The identical growth pattern may be determined by specific interactions between the tumor and the host microenvironment, as postulated by Paget’s seed and soil theory. This could represent three different stromal and cytokine responses or oncogenic pathway responses and could represent metastatic tumour growth in different microenvironments.
Gene Expression Profiling of Pulmonary Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Identifies New Diagnostic Markers, Biological Heterogeneity and Therapeutic Targets.
Authors: Wee J. Chng, Rafael Fonseca, Peter Leif Bergsagel, Julia A. Vrana, Paul J. Kurtin, Ellen Remstein, Ahmet Dogan
Journal: Blood (2007)
DEBIRI and capecitabine in refractory prevalently liver metastases of colorectal cancer: A phase II study.
Authors: Valentina Angela Marsico, Armando Orlandi, Eleonora Cerchiaro, Roberto Iezzi, Vincenzo Di Noia, Francesco Mannavola, Maria Alessandra Calegari, Salvatore Corallo, Alessandra Cassano, Carlo Barone
Journal: Journal of Clinical Oncology (2015)

724 Background: Treatment options for metastatic colorectal cancer (mCRC) patients refractory to chemotherapy are limited and clinical outcome is poor. In mCRC patients with liver-dominant disease hepatic locoregional therapy might be a treatment option. In this pilot study we evaluated the safety, tolerance, and efficacy of drug-eluting beads irinotecan (DEBIRI) in combination with capecitabine in the treatment of patients with mCRC with predominally liver disease. Methods: Twenty patients affected by liver metastasis of colorectal cancer were included in this study. All patients had progression of disease after two or more lines of chemotherapy and liver was the major or the predominant site of disease. DEBIRI, beads loaded with 100 mg irinotecan, was administered biweekly via hepatic artery. All patients assumed capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks, until disease progression. Primary endpoints were safety, tolerance and overall responce rate (ORR); secondary endpoints were progression free servival (PFS) and overall survival (OS). Results: Twenty patients underwent a total of 54 DEBIRI treatments of the 66 planned; the median number was 3 (range 2-4) administrated for patients. Grade 1-2 toxic effects included fatigue (70%), diarrhea (45 %), anemia (45%), elevated liver enzymes (45%), nausea (40%), neutropenia (35%) and thrombocytopenia (25%). One grade 3 diarrhea and a case of acute vasospastic angina were observed and required patient hospitalization, but no deaths at 30 days post occurred. Two partial responses were reported (10%) with ORR of 60%. PFS and OS were 4 and 7, 3 months respectively. Univariate analysis showed that patients with KRAS wild-type, good ECOG performance status and single lobe metastases have a better prognosis. Multivariate analysis confirmed that only the good clinical conditions represent an important positive prognostic factor (p=0.03). Conclusions: DEBIRI with capecitabine seem to be a safe, technically feasible and well-tolerated treatment in chemotherapy refractory mCRC with prevalently liver metastases. It has a moderate but not negligible activity in this heavily treated group of patients and deserves further studies in a larger series.
KAAD-cyclopamine sensitize malignant glioma cells to TRAIL-mediated apoptosis
Authors: M. Siegelin
Journal: Journal of Clinical Oncology (2009)

2025 Background: Malignant gliomas are the most aggressive human brain tumors without any curative treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic because TRAIL induces almost selectively apoptosis in cancer cells. The main obstacle in TRAIL-based therapy is that many glioblastoma cells are resistant. In the present study we found that the Hedgehog inhibitor, KAAD-cyclopamine, potently sensitized primary glioma cells to TRAIL-mediated apoptosis. Methods: Established cell lines and isolated primary tumor glioblastoma cells were treated with achievable plasma concentrations of TRAIL, KAAD-cyclopamine, or the combination of both. Apoptosis was assessed by Annexin V/Propidiumiodide staining and subsequent flow cytometric analysis. Activation of caspases and expression of apoptosis related proteins were determined by immunoblotting. For transfection experiments primary glioma cells were electroporated with plasmids encoding the cDNA of c-FLIP and bcl-2. Results: We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Single treatment with KAAD-cyclopamine or TRAIL does not induce cytotoxicity in malignant glioma cells. However, treatment with KAAD-cyclopamine in combination with TRAIL induces rapid apoptosis in TRAIL-resistant glioma cells. Notably, normal human astrocytes were not affected by the combination treatment consisting of KAAD-cyclopamine and TRAIL. KAAD-cyclopamine led to an upregulation of death receptor 4 and 5 and down-regulation of bcl-2 and c-FLIP. Furthermore, over-expression of both bcl-2 and c-FLIP attenuated KAAD-cyclopamine facilitated TRAIL-mediated apoptosis. Conclusion: The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by KAAD-cyclopamine cotreatment might, however, provide a powerful therapeutic option for glioma patients. No significant financial relationships to disclose.
Valproic Acid Signature Trial (VAST): A proof-of-principle study correlating pharmacology, pathology, and advanced imaging with genomic prediction of drug sensitivity in breast cancer.
Authors: A. L. Cohen, M. Schabel, A. Bild, T. L. Werner
Journal: Journal of Clinical Oncology (2011)

TPS148 Background: Valproic acid (VPA) is a histone deacetylase (HDAC) inhibitor that increases apoptosis and decreases proliferation of breast cancer in vitro and in vivo. VPA has been studied in breast cancer clinical trials in combination with anthracyclines but not as monotherapy. It is unknown whether drug levels or changes in peripheral blood mononuclear cell (PBMC) histone acetylation can or should be used to monitor the anticancer effects of HDAC inhibitors. Using our recently published MATCH algorithm, we have defined a gene expression signature that predicts response of breast cancer to valproic acid treatment in 2-dimensional culture, 3-dimensional culture, and mouse xenografts. Methods: VAST is a window of opportunity study occurring between diagnosis and the beginning of standard treatment. Women with untreated localized or metastatic breast cancer, a 1.5cm breast mass, and no contraindications to VPA treatment are eligible. At baseline, women undergo a dynamic contrast enhanced (DCE) MRI of the breast, a biopsy of the breast mass, and a blood draw for PBMC histone acetylation. Part of the biopsy is immediately preserved so RNA can be isolated for gene expression analysis; part is used for baseline measures of proliferation, apoptosis, and histone acetylation. Women take VPA for 7-10 days with intrapatient dose escalation starting at 30mg/kg/day and ending at 50mg/kg/day. Every 2-3 days a VPA level and PBMC histone acetylation are checked. At the end of the study, a DCE-MRI is repeated. The last day of the study is the day of lumpectomy or mastectomy. Post-treatment tissue is again used for RNA isolation and measures of proliferation, apoptosis, and histone acetylation. The primary analysis will correlate VPA levels, PBMC acetylation changes, and histone acetylation changes within the tumor. A sample size of 50 will give precise estimates of these correlations as well as of the sensitivity and specificity of the genomic predictions. Six women have enrolled so far. Novel aspects include the genomic signature of drug response, window of opportunity design, intrapatient dose escalation, and pharmacodynamic drug monitoring.
Assessment of single-institution HER2 testing patterns, rate of HER2+ disease, and utilization of trastuzumab in early breast cancer.
Authors: David D. Stenehjem, Minkyoung Yoo, Sudhir K. Unni, Mukul Singhal, Hillevi Bauer, Kim Saverno, Cheng Seok Quah, Anthony Masaquel, Diana I. Brixner
Journal: Journal of Clinical Oncology (2013)

124 Background: Improved outcomes with HER2-directed therapies highlight the importance of standardized testing for HER2 positivity. This study aimed to assess HER2 testing practices, rate of HER2+ disease, and trastuzumab use in early breast cancer (EBC) at the Huntsman Cancer Institute (HCI) a National Cancer Institute-Designated Center and member of the National Comprehensive Cancer Network. Methods: Included patients’ records from the HCI electronic data warehouse (EDW) and the HCI tumor registry were female, age ≥ 18 years, ≥ 2 visits in the EDW and a stage I to IIIa EBC diagnosis from 2005 to 2012. HER2 testing patterns were identified through chart review of pathology and clinical notes in the EDW. HER2+ was defined as either FISH+ or IHC3+. Patient characteristics, HER2+ rate, and trastuzumab use were evaluated descriptively. Discordance rate associated with reflex testing (IHC 2+ retested by FISH) was also evaluated. Results: A total of 1,459 women were included with stage I (49%, n=720), IIa (26%, n=374), IIb (14%, n=197), and IIIa (12%, n=168) EBC. Mean age was 57 years. HER2+ disease was identified in 243 (17%) tumors. Of HER2+ tumors, 104 (43%) were ER+/PR+, 33 (14%) ER+/PR-, 1 (&lt;1%) ER-/PR+, 79 (32%) ER-/PR-, and 26 (11%) unknown. Tumors were first tested for HER2 using: 1,192 (82%) IHC, 36 (3%) FISH, 227 (15%) unknown and 4 (&lt;1%) other tests. First IHC results were scored 0 (23%), 1+ (33%), 2+ (26%), 3+ (17%), and unknown (&lt;1%). Reflex testing within one month was performed in 301/308 (98%) of IHC 2+ tumors. The discordance rate of IHC/FISH was 10%. Trastuzumab was prescribed for 184/243 (76%) women whose tumors were considered HER2+ based on final interpretation and in 1 HER2 equivocal tumor. Documented reasons for lack of trastuzumab use in HER2+ patients (n=59) included low risk of recurrence based on stage or other treatments (n=18), loss to follow-up (n=13), unknown (n=11), not clinically appropriate due to age or comorbidity (n=10), and patient declined (n=7). Conclusions: This is one of few cancer registries assessing the rate of HER2+ disease in EBC. Reflex testing identified additional HER2+ tumors. The HER2+ rate was within range of previously published studies.
Immunohistochemical status of epidermal growth factor receptor (EGFR) in primary colorectal carcinoma and their related metastases
Authors: F. Bibeau, F. Boissière, S. Gourgou, J. C. Sabourin, F. Penault-Llorca, P. Rochaix, M. P. Bralet, D. Azria, M. Ychou, J. Savary
Journal: Journal of Clinical Oncology (2005)

3711 Background: Treatment using monoclonal antibody targeting EGFR (Erbitux) has been recently approved in advanced colorectal cancer (CRC). It requires an immunohistochemical (IHC) assessment for patient eligibility. Controversial and limited data are available on the EGFR status in distant metastases. Because of clinical implications, we studied EGFR expression on primary CRC and their related metastases, to assess wether EGFR IHC status was similar on both sites. Methods: EGFR immunohistochemistry was evaluated from primary tumors and related synchronous metastatic sites in 32 CRC patients. The primary tumor was situated in the colon for 21 patients and in the rectum for 11 patients. The analyzed metastatic sites were the liver (n = 31) and the ovary (n = 1). An IHC standardized assay was used (EGFR pharm Dx, DakoCytomation) on paraffin embedded sections. EGFR positive status (EGFR +) was defined by a percentage of tumoral stained cells ≥1%, displaying a membranous pattern. For primary CRC, EGFR assessment was performed on tissue sections with the deepest tumoral areas, known to contain the strongest immunoreactivity. Results: 84% of the CRC cases (27/32) and 91% of the metastases (30/32) were EGFR +. Twenty five out of 27 EGFR + primary cases (93%) showed a metastatic positive status. Moreover, the number of EGFR + tumoral cells in the primary site was significantly correlated with those observed in the metastases (r2= 0.616, p= 0.0002). Two EGFR + primary sites had a negative metastatic EGFR expression and 5 EGFR + metastatic sites had a negative primary site expression. However, these discordant cases were not statistically significant (p= 0.453). Conclusions: Despite the limited number of cases, our results suggest that EGFR expression is frequent and similar on both primary and metastatic sites. These data may be of clinical interest because i) treatment decision is based on EGFR immunoreactivity and ii) tumoral material of both sites is not always concomitantly available. In order to precisely define a practical approach, assessment of EGFR expression on additional series, containing synchronous and metachronous metastatic sites of different origin, needs to be performed. No significant financial relationships to disclose.
Phase II study of recombinant adeno-viral human p53 (rAd-p53) gene therapy combined with surgery in treatment of melanomas of oral mucosa.
Authors: L. Li
Journal: Journal of Clinical Oncology (2011)

8533 Background: Oral mucosa melanomas has a poor prognosis. It is urgent to introduce new treatments to improve the survival rate of these patients. The aim of this study is to evaluate efficacy and safety of intratumoral injections before surgery and intravenous infusion after surgery of rAd-p53 in treatment of oral mucosa melanoma. Methods: Patients with a histopathologically diagnosed oral mucosa melenoma were randomly assigned in two groups: experimental group (EG) and control group (CG). EG received intratumoral injections of rAd-p53 at a dose of 2×109 virus particles (VP)/cm2 for 5 times with a interval of 3 days. Radical surgery was performed 24 to 48 hours after the last injection. The p53 protein expression in tumor tissue was examined using immunohistochemistry. After 7 days of surgery, the patient were given a 15-day cycle of rAd-p53 intravenous infusion, 2×1012 VP per infusion for 5 infusions. CG received radical surgery only. The patients were followed-up for evaluating long-term efficacy and adverse events. Results: A total 57 patients, 29 in EG and 28 in CG, were included in this study. After 24 months of follow-up, the 2 years survival rate of EG was 39.6%, significantly higher than 16.7% of CG. In EG, 13 patients experienced transient flu-like symptoms. High p53 protein expression was detected in in melanomas tissue of EG. Conclusions: The rAd-p53 gene therapy conbined surgery can increase survival rate and prolong survival time. Intratumoral injection can effectively increase p53 protein expression.
Renal cell carcinoma: A prognostic target for spectral pathology.
Authors: Caryn S. Hughes, Mick D. Brown, Peter Gardner, Johnathan H. Shanks, Noel W. Clarke, Melody Jimenez-Hernandez
Journal: Journal of Clinical Oncology (2013)

459 Background: In contrast to standard pathology, where stained cells and tissues are examined visually under a microscope, spectral pathology is the study of changes in cellular composition of unstained tissue using molecular fingerprint techniques, such as infrared and Raman spectroscopy. Hyperspectral images are collected which provide not only spatial information but also data of high dimensionality, probing the global biochemistry of the biological specimen in the mid-infrared range. Methods: 9 paraffin-embedded, formalin-fixed clear cell renal carcinoma tissue sections (8μm thick) of different grade, stage and with respective matched pairs, were floated onto infrared-transmitting substrates. After dewaxing, Fourier transform infrared imaging spectroscopy was performed on a Varian 670-IR spectrometer coupled with a Varian 620-IR imaging microscope (Agilent Technologies, CA) equipped with a 128×128 pixel Mercury-Cadmium-Telluride focal planar array detector. A hyperspectral image is obtained whereby each pixel records an infrared spectrum at a pixel resolution of ~5.5x5.5μm. Mosaic images were captured of full tissue specimens (one imaging tile equates to a tissue sampling area of ~700×700μm). Results: We have been able to detect the phenotype of ccRCC and observed a diminishing glycogen-rich signal during tumour progression towards high grade tissue. The spectral characteristics of ccRCC have been correlated with H and E, PAS, and CA-IX staining. Conclusions: Cancer metabolism can be tracked by lipid and glycogen infrared bands that carry a unique spectral signature, depending on tumour aggressiveness. The future focus is to generate a prognostic model for small renal masses.