tbuckley/cabot-search huggingface dataset:
Feasibility of continuing docetaxel-based therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC) that experience hypersensitivity reactions (HSR).
Authors: Anna Couvillon, Melony A. Beatson, Nancy Harold, Fatima H. Karzai, Ravi Amrit Madan, James L. Gulley, William L. Dahut
Journal: Journal of Clinical Oncology (2013)

132 Background: Patients that receive docetaxel are observed closely for HSRs. Severe HSRs have been reported in patients premedicated with corticosteroids. The rate of allergic reactions reported in the TAX 327 trial (n=332) was 8% (any grade) and 1% (grade 3/4). In TAX 327 treatment was stopped after a total of 10 cycles of docetaxel. A recent trial conducted at the NCI has included patients treated with docetaxel-based therapy until radiographic progression with no cap on total dose or cycle number. Most patients have had significantly more than 10 cycles (median greater than 16 with a range of 1 to 48; however, some cycles did not include docetaxel). Given the increased incidence of HSR to docetaxel on our protocols, we developed guidelines for the clinical management of HSRs to docetaxel. Methods: We reviewed the literature on taxane HSRs and developed a 4-step clinical management guideline for the prevention and treatment of HSRs to docetaxel. Our guidelines utilize increasing amounts of H1/H2 antihistamines, corticosteroids, slower infusion rates of docetaxel, and/or decreasing concentrations of docetaxel. Results: From August 2009 to present, 63 mCRPC patients have been treated with docetaxel-based therapy. Twenty-three patients (37%) have experienced a HSR to docetaxel. HSRs initially occurred at cycle 1 (17%), cycle 2 (48%), cycle 3 (17%), cycle 4 (n=2), cycle 14 (n=1), cycle 16 (n=1). All patients were re-challenged with docetaxel using our 4-step clinical management guideline approach. Ten patients continued docetaxel without further HSRs. The remaining 13 patients continued to experience HSRs but were able to safely complete each infusion of docetaxel. No patients required discontinuation of therapy. Of the 23 patients with HSRs, 21 received more than 10 cycles of therapy with a median of 17 and a range of 1 to 38. Conclusions: Patients with mCRPC disease that is taxane sensitive and who experience HSR to docetaxel can continue to receive docetaxel safely. Most of these patients demonstrated a continued PSA, clinical, and radiographic response to therapy.
Distant failure remains a major concern in treating locally advanced rectal cancer: Results of preoperative hyperfractionated accelerated radiotherapy (HART) and concomitant CPT-11
Authors: V. Voelter, A. Zouhair, C. Thuerig, H. Vuilleumier, M. Matter, H. Bouzourene, S. Leyvraz, R. Stupp
Journal: Journal of Clinical Oncology (2005)

3709 Background: Patients with locally advanced rectal carcinoma are at high risk for both local recurrence and distant metastases. We previously reported the feasibility of HART with CPT-11 (Voelter et al, IJROBP 2003). The recommended dose level (RDL) of weekly CPT-11 and HART was determined at 90 mg/m2. Here, we report on an expanded patient population and analyze the primary site of failure. Methods: 44 patients (30 males; median age 61, range 28–75) with advanced rectal carcinoma (cT2: 1, cT3: 38, cT4: 5, cN+: 21, M+: 5 [during phase I]) were included. Overall, 27 patients were treated at the RDL. Surgery was to be performed within one week after the end of radiochemotherapy. 4 cycles of postoperative (adjuvant) CPT-11 were planned. Results: 41 patients completed radiochemotherapy and surgery as scheduled and 3 patients needed minor dose reductions. 64% of patients had sphincter sparing surgery. Postoperative complications ≥ grade 3 were observed in 25% with an anastomotic leakage rate of 18% and a mortality rate of 2%. T-downstaging was achieved in 35% and the resection margins were tumor free (R0) in 72%. Adjuvant chemotherapy was administered to 74% of the patients. At a median follow-up of 3 years, the estimated overall survival is 76% and the local recurrence rate is 13%. For the 39 patients who were initially M0, the estimated disease free survival is 65%. Distant metastases were very common and occurred in 35% of the M0 patients. Conclusions: HART and CPT-11 induces considerable tumor downstaging. Local control and the rate of tumor free resection margins are comparable to 5-FU based radiochemotherapy. However, distant metastases occur in 35% of the patients. Despite the association of CPT-11 to preoperative radiotherapy at a cumulative dose of 270 mg/m2, distant failure remains an unresolved problem. This finding is confirmed throughout most of the phase II and III trials. To improve the control of micrometastatic disease, efforts should be made to reinforce pre- & postoperative chemotherapy and to integrate targeted therapies (eg EGF-R antagonists, COX-2 inhibitiors). GI ASCO 2005 10.12.2004 No significant financial relationships to disclose.
Heterogeneity of Kras status in primary colorectal cancer and corresponding liver metastases.
Authors: Y. Kaneko, H. Kuramochi, G. Nakajima, A. Nakamura, Y. Inoue, K. Hayashi, M. Yamamoto
Journal: Journal of Clinical Oncology (2011)

e14037 Background: It is well known that Kras mutation status is a definitive marker for the treatment of colorectal cancer when anti-EGFR antibody agents are used. Several previous reports demonstrated that the Kras status in primary tumor and paired metastases were well concordant, although some samples showed mismatch status between them. Recent report assumed that the one of the reasons of this mismatch was due to intratumoral heterogeneity of Kras mutation status. Methods: Ninety colorectal cancer patients with primary tumor and liver metastases (76 were synchronous metastases and 14 were metachronous) were evaluated. Cancer cells of primary tumor and paired liver metastases were selectively dissected from formalin-fixed paraffin embedded samples with using Laser-captured microdissection. The Kras sequences of codon 12, 13 were analyzed by direct sequencing. Results: The concordance rate of Kras mutation status between primary tumor and paired liver metastases were 88.2% in synchronous metastases, and 100% in metachronous. Nine patients showed different Kras status between primary and metastases. Twelve patients had received liver resection for twice, 2 patients (17%) showed different Kras status between the samples from first liver resection and second resection. We assumed this discrepancy was due to intratumoral heterogeneity, four different areas of primary tumor were dissected; two from invasion front areas and other two from surface areas of each tumor in 9 patients who showed different Kras status between primary and metastases, and Kras status were compared. Seven out of 9 patients showed at least one area of mismatched Kras status, suggesting the existence of intratumoral heterogeneities. Conclusions: The Kras status was matched between primary and paired liver metastases in most of the patients, although some patients showed mismatch status. Intratumoral heterogeneity is assumed to be one of the reasons of this mismatch.
Effect of PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, on proliferation in renal cell carcinoma at nanomolar concentrations and prediction of sensitivity by molecular markers.
Authors: Joshua E. Logan, Nikayeh Mostofizadeh, Amrita J. Desai, Erika Maria Von Euw, Dylan Conklin, Veerauo Konkatkit, Habib Hamidi, Mark A. Eckardt, Lee Anderson, Hsiao-Wang Cheng, Charles Ginther, Eileen Taschereau, James G. Christensen, Arie S. Belldegrun, Dennis J. Slamon, Fairooz F. Kabbinavar
Journal: Journal of Clinical Oncology (2013)

413 Background: Cell cycle dysregulation is prevalent in renal cell carcinoma (RCC). PD-0332991 is an orally active, potent, and selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6, blocking retinoblastoma (Rb) phosphorylation at nanomolar concentrations. Methods: 28 RCC and immortalized kidney cell lines were used to examine the effects of PD-0332991 on proliferation to determine the half maximal inhibitory concentration (IC 50 ). Effects of PD-0332991 on cell-cycle, apoptosis, and Rb phosphorylation were assessed with flow cytometry and western blot analysis for five of the cell lines: RCC-HB and SW 156 (sensitive/malignant), R444 and Hs 891.T (resistant/malignant), and CCD 1103 (resistant/immortalized non-malignant). Molecular markers for response prediction were studied using array CGH and gene expression profiling. Results: Concentration-dependent inhibition of proliferation was identified in response to PD-0332991, with IC 50 values ranging from 25.0nM up to 700nM; five cell lines were identified as completely resistant at 1000nM. PD-0332991 induced G0/G1 cell cycle arrest, as well as induction of late apoptosis in SW 156, and Rb phosphorylation was blocked in a time-dependent fashion in both sensitive cell lines, while resistant lines were unaffected. Genotype and expression data of CDKN2A and CDKN2B were combined and a consensus was made regarding p16 and p15 status; significant association between loss and sensitivity to PD-0332991 was identified for p16 (p = 0.027). For CCND1, CCNE1, E2F1, Rb, CDK4, and CDK6 no amplifications or homozygous deletions were identified by array CGH; cell lines were then classified as having high or low expression for each of these markers. E2F1 had low expression levels significantly associated with response to PD-0332991 (p = 0.041). Conclusions: PD-0332991 shows anti-proliferative activity in RCC through blockade of the cell cycle. The decreased expression of molecular markers p16 and E2F1 predict for sensitivity to PD-0332991 in RCC.
Effect of CF102 on growth suppression and apoptosis in an orthotopic model of hepatocellular carcinoma
Authors: S. Bar Yehuda, S. M. Stemmer, L. Madi, D. Castel, A. Ochaion, S. Cohen, F. Barer, G. Perez-Liz, L. Del Valle, P. Fishman
Journal: Journal of Clinical Oncology (2008)

22113 Background: The A3 adenosine receptor (A3AR), a Gi protein associated cell surface receptor was suggested as a target for cancer treatment. In this study the expression and functionality of the A3AR in Hepatocellular carcinoma (HCC) was examined Methods: RT-PCR, western blot analysis and Immuno-histochemistry were used to evaluate the level of A3AR and cell growth regulatory proteins in tissues and peripheral blood mononuclear cells (PBMCs). A rat orthotopic model of N1S1 HCC tumor cells was used. Results: A3AR was found to be highly expressed in tumor tissues derived from patients and rats with HCC. A3AR over-expression was also found in the PBMCs, reflecting receptor status in the remote organ. The high expression level of the receptor was directly correlated to over expression of NF-ΚB, known as a transcription factor of A3AR. CF102, a synthetic highly selective agonist at the A3AR, induced growth suppression of rat HCC in an orthotropic model when given orally. Analysis of tumor lesions excised from CF102-treated animals demonstrated: a) de-regulation of the NF-κB and the Wnt signal transduction pathways; b) up-regulation of BAD, BAX and Caspase-3 resulting in apoptosis. Conclusions: A3AR is highly expressed in tumors and PBMCs of HCC patients and tumor bearing rats. Oral administration of CF102 induced tumor growth suppression and apoptosis of HCC. These data suggest A3AR as a novel targeted therapy to treat HCC. No significant financial relationships to disclose.
Measurements of total DNA and methylated tumor suppressor genes in the plasma of patients with metastatic non-small cell lung cancer (NSCLC) before, and after chemotherapy, as potential biomarkers for response to treatment
Authors: C. G. Azzoli, S. Park, J. Gomez, L. Krug, V. Miller, N. Rizvi, L. Ben-Porat, K. Danenberg, P. Danenberg, M. Kris
Journal: Journal of Clinical Oncology (2005)

7203 Background: Measuring DNA in plasma using quantitative RT-PCR is a promising method for the detection and surveillance of NSCLC. Detection of methylated genes may be more specific than total DNA for the presence of cancer. Methods: We undertook a prospective trial measuring total DNA, and the levels of 5 commonly methylated tumor suppressor genes in the plasma of a planned 200 patients with metastatic NSCLC before, and up to 3 times during chemotherapy. Blood samples are coincident with radiologic response assessments by RECIST. Blood is collected in Na citrate, gel density gradient tubes spun at 1800 RCF for 20 min, plasma removed without disturbing the mononuclear layer, and frozen at -80°C. DNA is extracted from a fixed volume of plasma, and measured using quantitative PCR of the β-Actin gene. DNA is treated with sodium metabisulfite solution which converts unmethylated cytosines to uracil. For methylation-specific RT-PCR, primers and probes have been designed to amplify bisulfite-converted DNA in the promoter region of the methylated version of the gene of interest, assuming the DNA sequence is fully methylated, and values normalized to the level of β-Actin in modified DNA. Results: Data from the first 43 patients are available. In the initial experiment, methylated APC was detectable in 7 patients (16%, C.I. 7–31%), p16 in 6 (14%, 5–28%), and MGMT, DAPK, GSTP1 only rarely (1–2%). Total DNA was detectable in all patients at baseline (median 11.1, range 0.6 - 2030 ng/2ml). To date there are 33 patients with both DNA and radiologic response data (8 POD, 21 SD, 4 PR). To facilitate analysis, the RECIST category SD was subdivided into SD vs. MR (14 patients with ≥ 10% reduction in measurable disease). The median change in DNA concentration was -5 ng/2ml for PR/MR, + 45 for POD/SD (p= 0.04 by Krukal-Wallis test). Conclusions: Initial results find methylated tumor suppressor genes in plasma in the minority of patients. Total DNA was detectable in all patients, and changes appear to correlate with radiologic response. Enrollment in this trial is ongoing, with survival analysis planned. Supported by RO1-CA092315. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics (CEO), Response Genetics Response Genetics
Impact of angiotensin system inhibitors (ASI) on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.
Authors: Rana R. McKay, Gustavo Enrique Rodriguez, Xun Lin, Ronit Simantov, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2014)

437 Background: Increasing evidence suggests that angiotensin II modulates angiogenesis and tumorigenesis. In this study, we utilized a clinical trials database to evaluate the role of ASIs (angiotensin-converting enzyme inhibitors and angiotension-receptor blockers) on survival outcomes in pts with mRCC. Methods: We conducted an analysis of pts with mRCC treated from 2003-2013 on phase III (NCT00083889, NCT00065468, NCT00678392, NCT00474786, NCT00631371, NCT00920816) and II clinical trials (NCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423, NCT00835978). We evaluated pts treated with ASIs at baseline or within the first 30 days of study. Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: We identified 4,736 pts treated with sunitinib (n=1,059), sorafenib (n=772), axitinib (n=896), temsirolimus (TEM) (n=457), TEM + interferon-alfa (IFN-α) (n=208), bevacizumab (BEV) + TEM (n=393), BEV + IFN-α (n=391), or IFN-α (n=560). Most pts were &lt; 65 years of age (69%), male (71%), with clear-cell histology (89%) and prior nephrectomy (70%). With regard to International mRCC Database Consortium risk groups, 14%, 42%, and 24% had favorable, intermediate, and poor-risk disease, respectively. 1383 (29%) pts received treatment with an ASI. Baseline hypertension was present in 84% of ASI users and 33% of ASI non-users. ASI use was associated with improved progression-free survival (PFS) and overall survival (OS) when compared to pts who did not receive an ASI (Table). This association was retained in multivariable analysis adjusted for age, gender, presence of bone metastases, and risk groups. Conclusions: This is the largest retrospective study to date evaluating the role of ASIs on outcomes in cancer pts. In this analysis, we demonstrate that concomitant use of ASIs may improve survival outcomes in pts with mRCC treated in the era of targeted therapy. [Table: see text]
Heart failure and mortality risk in patients undergoing high-dose chemotherapy with autologous stem cell transplant for breast cancer after radiotherapy.
Authors: Aditi Singhvi, Kiran Garikapati, Dania Khoulani, Syed Hassan, Waqas Qureshi
Journal: Journal of Clinical Oncology (2013)

135 Background: High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplant (HSCT) has been used as part of the treatment of metastatic breast cancer. However, the evidence behind this approach continues to be controversial. We hypothesize that previous radiation therapy (RT) may increase the risk of cardiomyopathy and mortality in these patients. Methods: Patients who underwent HSCT after HDCT for breast cancer treatment during 1988-2012 were included. The patients that underwent HSCT for indications other than breast cancer were matched 1:2 based on age and gender. The data was analyzed using the cox proportional hazard model, looking at time-to-survival with adjustments made for cardiotoxic chemotherapeutics, histology of cancer, ER/PR status, EGFR mutation status, number of RT sessions, age, and functional status. Results: Sixty-six patients with metastatic breast cancer underwent HSCT. Patients with breast cancer were more likely to develop systolic heart failure (10% vs. 6.1%, p=0.002). There were 29 (43.9%) patients who underwent whole breast RT (WBRT). Prior WBRT was an independent predictor of developing post-transplant systolic heart failure (HR 3.77; 95% CI 1.29–10.75, p=0.007). The Kaplan–Meier curve shows a better survival for patients without a previous WBRT (Log rank p=0.009). Patients with prior WBRT were found to have decreased survival (HR 1.59; 95% CI 1.16–2.17, p=0.004). Conclusions: Patients with a history of WBRT who underwent HSCT were more likely to develop new onset systolic heart failure than patients without WBRT. This might be due to the effects of RT on the coronary arteries and the cardiac myocytes, leading to worse outcomes. Future studies are needed to evaluate outcomes of HSCT in patients with metastatic breast cancer without prior WBRT.
Erratum for the Research Article: “The HMGB1-RAGE axis mediates traumatic brain injury–induced pulmonary dysfunction in lung transplantation” by D. J. Weber, A. S. A. Gracon, M. S. Ripsch, A. J. Fisher, B. M. Cheon, P. H. Pandya, R. Vittal, M. L. Capitano, Y. Kim, Y. M. Allette, A. A. Riley, B. P. McCarthy, P. R. Territo, G. D. Hutchins, H. E. Broxmeyer, G. E. Sandusky, F. A. White, D. S. Wilkes
Journal: Science Translational Medicine (2014)
Factors associated with membrane carbonic anhydrase IX (mCAIX) immunohistochemistry (IHC) in non-small cell lung cancer (NSCLC).
Authors: D. J. Stewart, M. Nunez, C. Behrens, S. Swisher, J. A. Roth, J. Heymach, I. I. Wistuba
Journal: Journal of Clinical Oncology (2011)

e21125 Background: CAIX reduces cell acidity, is upregulated by HIF1a, and correlates with HIF1a and with poor prognosis in some cancers but not others. We found in multivariate analysis that mCAIX but not cytoplasmic (c) CAIX (cCAIX) correlated with relapse in stage I-II NSCLC (Proc AACR, 2010). Methods: In 308 resected NSCLCs (stage I, II, III, IV in 188, 61, 46 and 9 patients) we used IHC to assess CAIX and other markers of hypoxia, proliferation, etc. IHC scores (0-300) were calculated by multiplying stain intensity (0-3) by % cells staining. We used nonparametric statistics to assess factors correlating with mCAIX scores. Results: Median mCAIX scores were lower in adeno vs squamous NSCLC (5 vs 65, p<0.0001) and correlated inversely with % papillary adeno present (r -0.17, p 0.02). mCAIX correlated with tumor diameter (r 0.19, p 0.0008) but not with node stage (N0 vs N1-2, 30 vs 20, p 0.93). mCAIX correlated with nuclear (n) Ki67 (r 0.20, p 0.0005), mitoses (r 0.18, p 0.001) and necrosis (r 0.20, p 0.0006) but not apoptosis (r 0.05, p 0.38). mCAIX did not correlate with nHIF1a (r -0.01, p 0.84) and paradoxically correlated inversely with cHIF1a (r -0.14, p 0.02) and cVEGF (r -0.13, p 0.03), but did correlate with the hypoxia-induced transcription factor cSHARP2 (r 0.18, p 0.002). cCAIX did correlate with cHIF1a, but only in tumors < 5 cm (r 0.14, p 0.04) and N0 patients (r 0.17, p 0.01). mCAIX was higher with EGFR wild type vs mutant (20 vs 0, p 0.006) and Notch amplified vs not (120 vs 21.25, p 0.0006), and did not vary with KRAS mutation (5 vs 15.83, p 0.76). There was a trend to lower mCAIX in well vs moderately/poorly differentiated tumor (5 vs 30, p 0.06). mCAIX correlated negatively with the tumor suppressors cRB (r -0.13, p 0.03), cP16 (r -0.12, p 0.03), nP16 (r -0.13, p 0.03) and nP14 (-0.12, p 0.04). Conclusions: In NSCLC mCAIX expression correlates with tumor type, subtype, size, proliferation and necrosis, and varies inversely with tumor suppressor genes. mCAIX did not correlate with HIF1a. cCAIX only correlated with cHIF1a in small and N0 tumors. Variable findings between studies with respect to CAIX importance may depend on tumor type, size and stage, and on whether mCAIX is assessed separately from cCAIX. Support: DoD # W81XWH-07-1-0306.
Ultrasound morphologic classification criteria for the presence of melanoma metastases in the sentinel lymph node
Authors: C. A. Voit, A. C. van Akkooi, G. Schaefer-Hesterberg, A. Schoengen, W. Sterry, A. M. Eggermont
Journal: Journal of Clinical Oncology (2008)

9014 Background: We have previously shown that ultrasound (US) guided FNAC can very accurately identify the sentinel node (SN). Another recent study from our center, presented at ECCO 14, demonstrated that US guided FNAC prior to final SN surgery could identify up to 65% of all SN-positive patients, as defined by definitive histopathology workup. The aim of the present study was to analyze in detail the different US-characteristics of SN metastases. Thus preoperative US can avoid many surgical SN-procedures. Methods: All patients underwent preoperative lymphoscintigraphy followed by an US-exam. The US pictures were evaluated for several morphologic items; presence or absence of central echoes, a hump structure, echo-poor islands, balloon shape, cap-like structure, central and/or peripheral perfusion. In case of suspicious or clearly malignant US patterns a FNAC was performed. All patients proceeded to undergo a standard surgical SN procedure. The final histology was considered the golden standard. Sensitivity and Specificity of the different US patterns were calculated. Results: From 2001 a total of 650 consecutive patients have been included into the prospective database so far. We report here on the first 400 AJCC stage I/II melanoma patients with sufficient follow-up. The median Breslow thickness was 1.8 mm, median follow-up was 28 months. The sensitivity of different patterns was; absence of central echoes 82% (p<0.001), presence of a hump structure 55% (p<0.001), the presence of echo-poor islands 59% (p<0.001), balloon shape 96% (p<0.001) and presence of peripheral perfusion 52% (p<0.001). Presence or absence of a cap-like structure or central perfusion could not identify SN metastases (p>0.05). Conclusions: US-guided FNAC prior to SN staging can accurately identify SN metastases in melanoma patients and reduce the need for surgical procedures. Balloon shape and absence of central echoes are the most sensitive US morphology patterns to identify SN metastases. A more detailed overview of all characteristics will be presented. No significant financial relationships to disclose.