tbuckley/cabot-search huggingface dataset:
Modifying tumor associated macrophage function through cannabinoid receptor 2
Authors: Taxiarhia Arabatzis, Taylor Littlefield, Jordan Watson, Jason Thole, Elizabeth McAndrew, Katherine E Hanlon
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts In human breast cancers, tumor infiltration by tumor associated macrophages (TAMs) correlates with multiple markers of poor prognosis: higher tumor macrophage counts are associated with higher tumor grade, higher tumor vascular density, and reduced overall survival[[1][1]]. TAMs
Validation study of direct sequencing and PCR-invader for detecting EGFR mutations in non-small cell lung cancer (NSCLC)
Authors: Y. Naito, K. Goto, H. Kenmotsu, Y. Nishiwaki, K. Kubota, H. Ohmatsu, S. Niho, K. Yoh, K. Nagai, N. Saijo
Journal: Journal of Clinical Oncology (2009)

8094 Background: EGFR mutation is both a predictive and prognostic factor for NSCLC treated with EGFR-TKI. Although new, highly sensitive methods for detecting EGFR mutations are currently available, these methods have not been validated. Methods: To validate direct sequencing and PCR-invader for detecting EGFR mutation, we analyzed 124 NSCLC by both methods concomitantly. Tumor tissues were obtained by surgical resection. Formalin-fixed paraffin-embedded specimens were prepared to analyze EGFR mutation. In direct sequencing, Exon 18, 19, and 21 of the EGFR gene were amplified, and PCR amplification products were sequenced directly (Mitsubishi Chemical Medience Corporation). PCR-invader was performed using the invasive cleavage of probe oligonucleotides to detect 10 mutations including Exon 18, 19, 20, 21 (BML incorporation). Results: EGFR mutations were detected in 51 patients (41%) by direct sequencing and 56 (45%) by PCR-invader. Discordance between two methods was found in 12 patients (10%). Exon 19 deletion was detected in 18 and 22 patients respectively. Exon 21 L858R was detected in 30 and 32 patients respectively. Each mutation in exon 19 deletions or L858R detected by direct sequencing could also be identified by PCR-invader. Overall 45 mutations were concordant by both methods. In two patients who received gefitinib, one patient with wild type by both methods did not respond to gefitinib. On the other hand, the other patient expressing Exon 19 deletion by PCR-invader but regarded as wild type by direct sequencing responded to gefitinib monotherapy. Conclusions: Discrepancy between two methods for detecting EGFR mutation was demonstrated and PCR-invader seems to be more sensitive. Further investigation including other highly sensitive methods is currently underway. No significant financial relationships to disclose.
Calculating carboplatin doses using the 4-variable modification of diet in renal disease (4-v MDRD) estimate of glomerular filtration rate (GFR) in the Calvert formula
Authors: S. G. Poole, M. J. Dooley, D. Rischin
Journal: Journal of Clinical Oncology (2007)

2521 Background: The dose of carboplatin is usually calculated using the Calvert formula, with various bedside estimates utilized rather than directly measured GFR. The 4-v MDRD equation (Levey AS, et al. Ann Intern Med 2006; 145: 247–254) is now advocated as the routine method of estimating renal function from serum creatinine in all patients. Adoption in clinical practice is occurring despite lack of validation in oncology patients. The aim of this study was to compare carboplatin doses derived from the Calvert formula using measured GFR and the estimates of the 4-v MDRD equation and other established estimates. Methods: GFR was determined using technetium-99m diethyl triamine penta-acetic acid (Tc 99m DTPA) clearance. Serum creatinine (Jaffe method) was measured and GFR estimates calculated using 4-v MDRD, Cockcroft and Gault formula (CGF), Wright, Martin, and Jelliffe (JF) formulae. Carboplatin doses were calculated using the Calvert formula, targeting an area under the curve of 7mg.ml - 1 .min -1 . Results: GFR was measured in 510 adult oncology patients (323 male, 187 female, mean age 63 years, range 17–87 years, mean GFR 84 mL/min, range 16–205 mL/min). The mean (range) carboplatin dose was 765 mg (287–1,610 mg), 681 mg (237–1,306 mg), 674 mg (249–2,044 mg), 721 mg (261–1,536mg), 741 mg (261–2,128mg), 620 mg (244- 1,329 mg) for measured GFR, 4-v MDRD, CGF, Wright, Martin, and JF formulas respectively. The accuracy (% within 20% of ‘true’ dose) was 58%, 63%, 73%, 72% and 49% for 4-v MDRD, CGF, Wright, Martin, and JF formulas respectively. Carboplatin doses derived using the 4-v MDRD estimate of GFR become increasingly less accurate with increasing GFR (see table ). All other formulas performed similarly. Conclusions: The 4-v MDRD equation resulted in an imprecise estimation of carboplatin doses with the degree of variability dependant on the level of renal function. [Table: see text] No significant financial relationships to disclose.
EGFR, PTEN, and survivin expression in pre- and posttherapeutic specimens does not predict a clinical benefit from preoperative chemoradiation with cetuximab in patients (pts) with locally advanced rectal cancer (LARC).
Authors: K. Dellas, F. Roedel, D. Arnold, M. Kappler, M. Hipp, F. Bataille, D. Vordermark, C. Roedel, A. Hartmann
Journal: Journal of Clinical Oncology (2010)

3653 Background: Results of our phase II trial in pts with LARC treated with standard radiation plus capecitabine, oxaliplatin and cetuximab have shown that this regimen is feasible but without a significant improvement of pathohistological response (Rödel et al., 2008). Although a certain subgroup of pts might benefit, there is no effective method to predict treatment efficacy. To identify potential biomarkers we analyzed EGFR, PTEN, and survivin in order to investigate their predictive value in LARC pts treated with the mentioned regimen. Methods: Pre- and postherapeutic tumor specimens from 47 pts of the phase II trial were taken before treatment as biopsies and at the time of surgery. Correlation of pre- and posttherapeutic expression pattern of EGFR, PTEN and survivin was done with pathohistologic response (according to a modified classification by Dworak et al., 1997), progression free and overall survival (PFS/OS). Results: Posttherapeutically EGFR expression was significantly lower (p < 0.001) compared to prettreatment levels, in particular in pts with moderate (p = 0.033) and high (p = 0.013) regression grading. The proportion of pts with EGFR null-expression increased from pretherapeutic 45% to posttherapeutic 89%. However, initial EGFR expression did not significantly correlate with pathohistologic response (p = 0.12). Univariable logistic regression analysis revealed that loss of EGFR expression did not predict PFS or OS (p = 0.67 and p = 0.63). In contrast to EGFR, expression of PTEN was increased after treatment (p = 0.003) whereas expression of survivin was not altered (p = 0.092). Again, PTEN upregulation did not correlate with regression grading (p = 0.36) and did neither predict PFS nor OS (p = 0.90 and p = 0.59). Conclusions: Preoperative chemoradiotherapy with capecitabine, oxaliplatin and cetuximab resulted in downregulation of EGFR expression, upregulation of PTEN and no change in survivin. However, changes in expression pattern were not associated with clinical endpoints tumor regression grading, PFS or OS. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Lilly, Merck, Roche, sanofi-aventis Merck, Roche, sanofi-aventis
Quantification, self-renewal, and genetic tracing of FL1+ tumor-initiating cells in a large cohort of human gliomas
Authors: V. Clement-Schatlo, D. Marino, K. Burkhardt, P. Teta, F. Leyvraz, B. Schatlo, S. Frank, K. Schaller, V. Castella, I. Radovanovic
Journal: Neuro-Oncology (2014)
Phase II study of S-1 with pharmacogenomic response and toxicity analysis in advanced gastric cancer - Korean multi-institutional experience
Authors: S. Y. Rha, H. C. Chung, H. C. Jeung, H. K. Kim, S. Y. Kim, S. Y. Kim, H. Y. Lim, S. J. Gong, J. Saruta, Y. C. Kim, H. S. Choie
Journal: Journal of Clinical Oncology (2005)

4068 Background: We conducted a multi-institutional phase II trial of oral S-1 in Korean patients with advanced gastric cancer including pharmacokinetic and pharmacogenomic evaluation. Methods: Chemonaive advanced gastric cancer patients with measurable lesions were enrolled. S-1 was administered orally twice daily, 70 mg/m2/day for 28 days followed by 2-week rest. cDNA microarray based CGH analysis was performed using genomic DNA from periphral mononuclear cells. Results: Twenty-eight patients out of enrolled 31 patients were assessable. The relative dose intensity was 0.98 with a mean dose of 117 mg (90 - 150 mg). Toxicity profile was favorable with grade III anemia 3.7% and neutropenia 2.5% per cycle. There were no grade III/IV non-hematologic toxicities. Meanwhile, the response rate was 12.9% (1 CR) and the median time to progression was 118 days. Pharmacokinetic analysis of 3 patients revlealed that Cmax of CDHP and oxo was significantly low compared to Japanese (33 vs 129 ng/ml; 191.0 vs 276.0 ng/ml, respectively). Therefore, we escalated the dose uo to 80 mg/m2/day with the same schedule. As of 1st December 2004, 24 out of 31 patients were evaluable with ongoing 16 patients. The mean administered dose was 131 mg (100–150 mg) and the median relative dose intensity was 0.90. The grade III toxicity observed were diarrhea 4.3%, hyperbilirubinemia 4.3%, and anemia 13% per cycle. The confirmed cases of partial response are 4 (12.9%) and 6 more patients are in PR state waiting to be confirmed. We could identify the predictive gene sets related to response (20 genes, FDR 18.3%) and grade III anemia (31 genes, FDR 11.3%) of S-1 using array-CGH results. Conclusion: we confirmed that S-1 has a moderate activity for advanced gastric cancer. With the evidence of ethnic differences even in Asians, pharmacogenomic analysis might be helpful for predicting the efficacy and the toxicity of S-1. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Jeil,Taiho
The treatment of pregnant women with breast cancer and the outcomes of the children exposed to chemotherapy in utero
Authors: P. H. Johnson, K. Gwyn, N. Gordon, L. Middleton, H. Kuerer, P. George, W. Yang, G. Hortobagyi, R. Theriault
Journal: Journal of Clinical Oncology (2005)

540 Background: Our study of pregnant breast cancer patients treated with chemotherapy is the largest prospective series described thus far. Methods: 54 pregnant breast cancer patients consented to treatment with standard neoadjuvant or adjuvant FAC chemotherapy (5-flurouracil, doxorubicin, and cyclophosphamide). After delivery patients could be exposed to other chemotherapeutic agents, tamoxifen and/or radiation therapy. Parents/guardians of the children exposed to chemotherapy in utero were mailed a survey regarding the health of their children (those who did not respond were contacted by telephone). Results: Treatment: 43% of patients underwent neoadjuvant chemotherapy (23/54). 85% percent of patients received at least three cycles of FAC while pregnant (41/48). Mean gestational age at initiation of chemotherapy was 22.8 weeks (range 10.9–34.4 weeks). 56% of patients underwent surgery during pregnancy (30/54). Outcomes: Of those neoadjuvant patients who went to surgery, 63% (10/16) were down-staged. As of 12/04, 76% percent of the cohort patients are alive (38/50). Of those with follow-up in the past 24 months, most are disease-free (33/34). Mean gestational age at delivery was 37 weeks (range of 29–42 weeks). Mean birth weight was 2964.5 g, (range of 1389–4167 g). 27 of 30 patients/guardians (90%) responded to a survey inquiring about the health and development of their child exposed to chemotherapy in utero. All considered their child to be healthy, and all but two children were described as having “normal” development. One child was found to have a sub-arachnoid hemorrhage at age two days and has residual right leg weakness. One was born with Down’s Syndrome. Conclusion: FAC in the second and third trimesters appears to be relatively safe for pregnant breast cancer patients who wish to continue their pregnancy. Follow-up thus far (age range 2–176 months) indicates that most children have not suffered significantly adverse health effects as a result of in utero exposure to FAC. Potential long-term effects of such exposure are not known, further studies of these issues are planned. We continue to treat pregnant women with breast cancer and follow their children. No significant financial relationships to disclose.
In <i>situ</i> proteomics of biomarker expression in epithelial ovarian cancer
Authors: M. Kassar, Z. Yu, A. Bamias, S. Markakis, D. Kowalski, E. Efstathiou, R. L. Camp, D. L. Rimm, D. Psyrri, M. Dimopoulos
Journal: Journal of Clinical Oncology (2005)

5041 Background: Despite advances in treatment, 50% of women with advanced ovarian cancer still die of the disease. The poor clinical outcome underscores the need to develop novel strategies in the management of patients with advanced disease. Methods: A tissue array composed of 151 cases of advanced stage (stages III and IV) epithelial ovarian cancer treated postoperatively with paclitaxel and platinum-based chemotherapy was constructed. For protein analysis, a novel molecular-based quantitative method (AQUA) was used. Survival analysis was performed using X-tile. Primary end points were disease-free survival (DFS) and overall survival (OS). Correlation of protein expression levels with clinical-pathological variables was performed by chi-square test. Results: The following proteins were analyzed: Cell cycle regulators (p53, p21, pRb, p16), anti-apoptotic protein bcl-2, Epidermal Growth Factor Receptor (EGFR), phosphorylated Akt (p-Akt), phosphatase PTEN, cox-2 and β-catenin. High p53 expression was associated with improved DFS (p=0.0080) and OS (p=0.0003). High pRb expression was associated with improved DFS (p=0.009). High EGFR tumor expression was associated with inferior DFS (p=0.0046) and OS (p=0.0025). High tumor PTEN expression was associated with improved DFS (p=0.039) and OS (p=0.0025). High bcl-2 expression was associated with serous histology (p=0.014) and inferior DFS (p=0.0026). In multivariate analysis adjusting for known prognostic variables, the aforementioned markers retained their prognostic value. There was no association between p21, p16, p-Akt, cox-2 and β-catenin levels with survival times. Conclusion: AQUA is a promising molecular method for the identification of prognostic markers and targets for therapy in epithelial ovarian cancer. No significant financial relationships to disclose.
In vitro analysis of suicide gene expression and function in human T lymphocytes transduced to express a tumor-targeted chimeric antigen receptor.
Authors: J. H. Park, R. Yeh, I. Riviere, M. Sadelain, R. J. Brentjens
Journal: Journal of Clinical Oncology (2010)

e13124 Background: Adoptive infusion of T cells genetically modified to express chimeric antigen receptors (CARs) targeted to tumor- associated antigens (TAAs) is a promising novel approach to cancer therapy. However, since TAAs are often expressed by normal tissues and given limited clinical experience with this technology, safeguards are needed in the form of additional expression of transduced suicide genes to allow for the efficient in vivo abrogation of infused T cells in the setting of unanticipated adverse events which may develop in the context of planned clinical trials. Methods: We tested the in vitro function of two different suicide genes each initially inserted distal to a CAR gene targeted against CD19 (1928z) and an IRES (internal ribosome entry site) element cloned into the SFG retroviral vector. Subsequently, we tested whether increased gene expression led to improved function of these suicide genes by replacing the IRES element with a 2A linker peptide. Two suicide gene-prodrug combinations evaluated in this study are herpes simplex virus thymidine kinase (HSV-TK SR39)/ganciclovir and E.coli derived nitroreductase (NTR)/metronidazole. Results: Cell growth of PG13 fibroblasts transduced with SFG 1928z.IRES.NTR was inhibited by 40% at 5mM of metronidazole but by 90% when transduced with SFG 1928z.2A.NTR. Similarly, PG13 (1928z.IRES.HSV-TK) fibroblasts exhibited 60% inhibition at 1μM of ganciclovir compared to 85% inhibition of PG13 (1928z.2A.HSV-TK) fibroblasts. Consistent with these findings, we found that human T cells transduced with either 1928z.2A.NTR or 1928z.2A.HSV-TK demonstrated 90% and 88% inhibition, respectively, at similar substrate concentrations. Conclusions: This study demonstrates highly effective suicide genes for human T lymphocytes transduced with a tumor-targeted CAR that can potentially serve as a reliable safety mechanism for adoptive T-cell immunotherapy. Ultimately we anticipate that these studies will allow us to rationally select the optimal suicide gene-prodrug combination to be incorporated into future clinical trials utilizing gene modified tumor-targeted T cells. No significant financial relationships to disclose.
Comparison of axillary nodal ratios and absolute number of involved nodes as prognostic factors for stage II/III breast cancer treated with neoadjuvant chemotherapy
Authors: B. Keam, S. Im, J. Lim, D. Kim, D. Oh, J. Kim, T. Kim, I. A. Park, D. Noh, Y. Bang
Journal: Journal of Clinical Oncology (2008)

622 Background: Pathologic axillary nodal status in breast cancer treated with neoadjuvant chemotherapy differs from those of early breast cancer treated upfront surgery. Neoadjuvant chemotherapy might have modified the yield of involved axillary lymph nodes. The purpose of this study was to identify the clinical significance of the involved nodal ratios (INR) in stage II/III breast cancer treated with neoadjuvant chemotherapy. Methods: From March 2002 to January 2007, a total of 205 stage II and III breast cancer patients (median age: 45) received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this prospective study. The patients received three cycles of neoadjuvant chemotherapy followed by curative surgery either breast conserving surgery or mastectomy with level II/III axillary lymph node dissection and received three more cycles of docetaxel/doxorubicin chemotherapy as adjuvant. Results: The median follow-up duration was 19.3 months. The overall response rate (RR) for neoadjuvant chemotherapy was 77.6%. The distributions of absolute number of involved nodes (ANIN) were follows: pN0= 61 (29.8%), pN1= 65 (31.7%), pN2= 49 (23.9%), pN3= 30 (14.6%). The mean INR was 29.3% (range 0–100.0%, INR≤30%: 126 (61.5%) vs. >30%: 79 (38.5%)). RR was associated with lower INR (p= 0.031). Relapse-free survival (RFS) of the patients who showed more than 30% of INR was significantly shorter (Hazard Ratio [HR]= 2.602, p= 0.002). The INR of more than 30% was also associated with shorter overall survival (OS) (HR= 3.301, p= 0.047). However, RFS and OS did not differ according to absolute number of involve nodes ANIN (p= 0.2420, p= 0.3186, respectively). In multivariate analysis, INR was independent prognostic factor for RFS and OS (HR= 3.757, p<0.001; HR= 6.487, p= 0.003). Conclusions: Axillary nodal ratios have better prognostic value than ANIN in stage II/III breast cancer treated with neoadjuvant chemotherapy. Nodal ratio may be used to identify the patients at high risks of recurrence in neoadjuvant setting. Our results suggest that the patients with high nodal ratio should be candidates for additional post operative treatment with chemotherapeutic or targeted agents which has different mechanism of action. No significant financial relationships to disclose.
Clinical characterization of first cycle reactions in patients with chronic lymphocytic leukemia treated with oblimersen
Authors: K. S. Kolibaba, A. A. Chanan-Khan, G. Bociek, T. Boyd, J. Moore, S. O’brien
Journal: Journal of Clinical Oncology (2006)

16514 Background: Serious adverse reactions during the first treatment cycle characterize many drugs used for chronic lymphocytic leukemia (CLL), including rituximab, alemtuzumab, flavopiridol, lenalidomide, and oblimersen. Termed cytokine release reactions (CRRs), these events have occurred more commonly in pts with bulky disease and elevated leukocyte counts, and some have been fatal. Rapid increases in serum levels of tumor necrosis factor-α, interleukin-6, interleukin-2, interferon-γ, and other cytokines may result in symptoms including fever, chills, nausea, vomiting, hypotension, and dyspnea. Ex vivo treatment of CLL cells with oblimersen induce release of vasoactive interleukin-8. First cycle reactions, including tumor lysis syndrome (TLS), proved dose-limiting in a phase 1–2 trial of oblimersen in pts with relapsed or refractory CLL. To characterize these reactions, we evaluated data from this single-agent study and from a phase 3 randomized clinical trial of oblimersen with fludarabine and cyclophosphamide (Flu/Cy). Methods: Data on investigator assessment of CRR and TLS were obtained from both studies, which included 155 pts; 40 were treated with oblimersen alone (3–7mg/kg/d by CIV for 5–7 days) and 115 with oblimersen (3 mg/kg/d × 7 days) in combination with Flu/Cy. Results: Of 145 pts treated with oblimersen 3mg/kg/d, either alone or with Flu/Cy, 2 pts (1.3%) experienced CRR and TLS, respectively. Two CRRs occurred in 10 pts treated with 4–7mg/kg/d. Reactions typically began 24–48 hours after starting treatment. CCR was usually associated with spiking fever, nausea, dehydration, rigors, and back pain. Rarely pts developed hypotension, acidosis, or reversible renal insufficiency, usually with a reduction in WBC. Symptoms lasted 1 day to several weeks (1 pt). In most cases, reactions were reversible with intensive supportive care, including IV fluids, pressors, and antibiotics; 1 death from TLS and 1 from CCR occurred during cycle 1. There was no definitive correlation with baseline measures of disease burden. Conclusion: First cycle oblimersen reactions are uncommon but represent a risk. Early symptoms (fever, nausea, and dehydration) require aggressive treatment, which may prevent progression of the reaction. [Table: see text]