tbuckley/cabot-search huggingface dataset:
Nilotinib in patients with imatinib-resistant or -intolerant chronic myelogenous leukemia in chronic phase (CML-CP): Updated phase II results
Authors: H. M. Kantarjian, F. J. Giles, A. Hochhaus, K. N. Bhalla, G. J. Ossenkoppele, N. Gattermann, A. Haque, N. Gallagher, F. Castagnetti, P. le Coutre
Journal: Journal of Clinical Oncology (2008)

7010 Background: Nilotinib, a potent and highly selective BCR-ABL inhibitor, has been approved in both the US and Europe for the treatment of patients (pts) with CML-CP and accelerated phase CML (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. Methods: This phase 2, open-label study was designed to evaluate the efficacy and safety of nilotinib in pts with Philadelphia chromosome-positive (Ph+) imatinib-resistant or -intolerant CML-CP. Nilotinib was administered at 400 mg twice daily (BID), with the possibility to dose escalate to 600 mg BID for inadequate responses. The primary endpoint was the rate of major cytogenetic response (MCyR). Results: Included in this analysis were 321 pts (71% imatinib-resistant; 29% imatinib-intolerant). 72% of pts received prior imatinib doses > 600 mg. Of the 206 pts who did not have complete hematological remission (CHR) at baseline, 158 (77%) achieved CHR during nilotinib therapy. Overall, MCyR was observed in 184 pts (57%); 41% had complete CyR. MCyR was observed in 125 (55%) of the 227 imatinib-resistant pts and in 59 (63%) of the 94 imatinib-intolerant pts. The median time to CHR and MCyR was 1.0 and 2.8 months, respectively. The majority of pts (84%) maintained MCyR for at least 18 months. At 18 months, the estimated overall survival rate was 91%. Treatment with nilotinib is ongoing in more than half of pts enrolled. The most frequent grade 3/4 laboratory abnormalities were thrombocytopenia (28%), neutropenia (30%), and asymptomatic serum lipase elevation (15%). Grade 3/4 non-hematologic AEs were rare and included rash, headache, and diarrhea. A low incidence of QT prolongation (QTcF > 500 msec, < 1%) was observed overall. The safety profile of nilotinib has not changed with increased follow up. There was minimal cross-intolerance between nilotinib and imatinib in pts intolerant to prior imatinib treatment. Conclusions: The present study confirms that nilotinib induces significant and durable responses in CML- CP pts with imatinib-resistance or -intolerance. Nilotinib is well tolerated, with minimal occurrence of grade 3/4 AEs and minimal cross-intolerance to imatinib, and is a valuable new treatment option for this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Innovive, Merck, Novartis, Wyeth
Iron Overload Strongly Correlates with Acute Graft-Versus-Host-Disease of the Liver and Treatment Related Mortality after Allogeneic Hematopoetic Cell Transplantation (HCT).
Authors: Ann-Kathrin Eisfeld, Ralph Burkhardt, Daniel Teupser, Sabine Schroeder, Rainer Krahl, Andrea Junghans, Elvira Edel, Christa Doehring, Uwe G. Liebert, Dietger W. Niederwieser, Haifa K. Al-Ali
Journal: Blood (2005)
Combined modality therapy for patients with nodal metastases from melanoma
Authors: M. T. Ballo, M. I. Ross, J. N. Cormier, J. N. Myers, J. E. Gershenwald, J. E. Lee, G. K. Zagars
Journal: Journal of Clinical Oncology (2005)

7518 Background: Patients treated for regional nodal metastases from melanoma are at risk of distant metastases, regional failure, and long-term toxicity. Present treatment algorithms do not account adequately for these competing risks. Methods: Between 1983 and 2003, 466 patients with melanoma nodal metastases were managed with lymphadenectomy and radiation, with or without systemic therapy. For this retrospective review, actuarial outcomes were calculated using the Kaplan-Meier method and multivariate analysis was done with the proportional hazards model. Results: Of the 466 patients, surgery was a therapeutic procedure for clinically apparent nodal disease in 434. Adjuvant radiation was delivered to all patients, generally using a hypofractionated regimen, and systemic therapy was delivered to 154 patients. With a median follow-up of 4.2 years, 252 patients relapsed and 203 patients died of progressive disease. The 5-year DSS, DFS, and DMFS rates were 49%, 42%, and 44%, respectively. By multivariate analysis, increasing number of involved lymph nodes and primary ulceration were associated with an inferior 5-year disease-specific and distant metastasis-free survival. For patients with more than 10 involved LN the 2-year rate of brain failure approached 45%. The 5-year regional (in basin) control rate for all patients was 89% and on multivariate analysis there were no patient or disease characteristics associated with inferior regional control. The 5- and 10-year rates of symptomatic lymphedema were 9% and 11%, respectively, and varied according to nodal region. For patients with cervical, axillary or groin LN disease the corresponding rates of symptomatic lymphedema were 1%, 20%, and 27%, respectively (p <0.0001). Conclusions: Although regional nodal disease can be satisfactorily controlled with lymphadenectomy and radiation, the risk of death from melanoma remains high and patients requiring groin irradiation are at risk of chronic lymphedema. The data indicate that the threshold for recommending aggressive regional therapy should account for the site of nodal disease and certain clinical-pathologic factors. Also, clinical investigation must focus on the high rate of brain failure in some of these patients. No significant financial relationships to disclose.
The expression levels of microRNAs that have the androgen receptor in localized prostate cancer as a target.
Authors: Katia Ramos Moreira Leite, Manuel Garcia Florez, Sabrina Thalita Reis, Nayara Viana, Betina S. Katz, Nelson Dip, Iran Amorin Silva, Jose Pontes Jr, Miguel Srougi
Journal: Journal of Clinical Oncology (2014)

206 Background: Prostate cancer (PC) depends on the androgen activity being the androgen blockage the main treatment in the setting of metastatic disease. Mechanisms of resistance in metastatic tumors are not completely known. MicroRNAs (miRNA) are small non-coding molecules that have as canonical mechanism the negative control of gene expression promoting messenger RNA (mRNA) degradation or impairing protein translation. The role of miRNAs that have as target the AR are still unknown. Our objective is to study the expression profile of miRNAs that have AR as target in localized prostate cancer. Methods: The expression levels of miRNAs that have as target AR (miR9, 34a, 34c, 185, 130a, 299, 421, 371, 541) were studied using qRT-PCR in the surgical specimens of 83 patients that underwent radical prostatectomy to treat localized prostate cancer. The expression levels of miRNAs were correlated to Gleason score (GS), pre-operatory PSA, pathological stage and biochemical recurrence (PSA&gt;0.2 ng/mL) in a mean follow up of 45.9 months. The mean age was 62.9, mean GS was 7.2, mean PSA was 7.93 ng/mL, and 42 (50.6%) patients were staged pT2. Twenty-four (28.9%) patients presented biochemical recurrence. Specimens of six patients submitted to open surgery to treat benign prostate hyperplasia (BPH) composed the control group. Results: The mean expression of AR was 1.63, being overexpressed in 59% of the cases. The mean expression levels of the nine studied miRNAs was miR9=3.06, miR34a=0.76, miR34c=1.14, miR185=1.65, miR130a=1.9, miR299=6.23, miR421=2.84, miR371=1.41, and miR541=0.93. The univariate analysis showed that pT2 tumors have higher expression of miR371(p=0.009). Conclusions: In localized PC the higher expression of miR371 is related with organ-confined disease. This miRNA could be important in the control of AR and the comprehension of its role in PC might bring alternatives to treat metastatic disease. Funded by FAPESP – 2012/50163-0.
A Host Cell Reactivation Assay for DNA Repair System Analysis in Primary Hematopoietic Cells.
Authors: Joerg Baesecke, Kai Thoms, Tina Roedling, Birgit Aut, Volker Viereck, Frank Griesinger, Detlef Haase, Christine Neumann, Lorenz Truemper, Steffen Emmert
Journal: Blood (2004)
KRAS tests utilizations, biologics uptakes, and disparities in access by demographic groups among metastatic colon cancer patients.
Authors: Daisuke Goto, C. Daniel Mullins, Kaloyan A. Bikov, Brian S. Seal, Nader Hanna
Journal: Journal of Clinical Oncology (2015)

533 Background: Mutant KRAS oncogenes are observed in approximately 35%-45% of colorectal cancer patients. Cetuximab (CET) and panitumumab (PAN) are epidermal growth factor receptor (EGFR) inhibitors that are used in the treatment of metastatic colon cancer (mCC). KRAS mutations decrease the treatment response of these biologic agents. Reports of this decreased treatment response in CET and PAN surfaced in 2006. In 2009, the FDA changed the label on CET and PAN to state that these agents were “not recommended” for the treatment of colon cancer in patients with KRAS mutations. This label change encouraged prescribers to perform KRAS tests. The objective of this study is to examine the utilization of KRAS tests for mCC treatment in real-world practice. Methods: We examined 6,044 mCC patients in the SEER-Medicare database who were diagnosed between 2006 and 2009 (their median age at diagnosis was 78). Using recorded procedure codes, we identified whether each patient received a KRAS test or not and whether CET and/or PAN were given. We further identified demographic characteristics of patients. Results: Among the 6,044 patients, 15% patients were tested for KRAS mutations. This frequency increased from 7% for those diagnosed in 2006 to 24% for those diagnosed in 2009. Following KRAS testing, CET or PAN were administered to 29% of patients. On average for 2006-2009, 5% of patients who were not tested received CET or PAN (or 15% if patients who did not receive any treatment are excluded). This frequency dropped from 7% for those diagnosed in 2006 to 2% for those diagnosed in 2009 (19% and 7% respectively if patients without any treatment are excluded). We found disparities in receipt of KRAS testing: the test was administered to 12% of black patients, 16% of white patients, 17% of males, and 14% of females. These differences were found statistically significant (p &lt; 0.05). Conclusions: KRAS testing rates increased over time. Moreover, as time passed fewer patients were administered CET and/or PAN without being tested for KRAS mutations. Black patients and women were less likely to receive a KRAS test, which could impact access to treatment.
NRG Oncology/RTOG 9601, a phase III trial in prostate cancer patients: Anti-androgen therapy (AAT) with bicalutamide during and after salvage radiation therapy (RT) following radical prostatectomy (RP) and an elevated PSA.
Authors: William U. Shipley, Stephanie L. Pugh, Himu R. Lukka, Pierre Major, Niall M. Heney, David A. Grignon, Oliver Sartor, Malti Patel, Jean-Paul Bahary, Anthony L. Zietman, Thomas Michael Pisansky, Kenneth Lee Zeitzer, Colleen Anne Lawton, Felix Yi-Chung Feng, Richard Dana Lovett, Alexander G. Balogh, Luis Souhami, Seth A. Rosenthal, Kevin Kerlin, Howard M. Sandler
Journal: Journal of Clinical Oncology (2016)

3 Background: Previous reports suggested that AAT when combined with salvage RT following RP in patients may improve prostate cancer control outcomes. Methods: Post-RP patients with pT3pN0 or with pT2pN0 and positive margins who had or developed elevated PSA levels from 0.2 to 4.0 ng/ml were randomized on a phase III, double-blind, trial of RT + placebo (64.8 Gy in 36 fractions of 1.8 Gy) vs. RT + AAT (24 months bicalutamide, 150 mg daily) during and after RT. The primary end-point was overall survival. Trial design required 725 patients and provided 80% power to detect a reduction in death rate by at least 28.5% and a 1-sided significance level of 0.046. Results: From 3/98 to 3/03, 761 eligible patients (median age 65) were randomized to RT + AAT (384) or RT + placebo (377). 248 patients (33%) were pT2pN0 and 513 (67%) were pT3pN0. 671 (88%) had a PSA nadir after RP of &lt; 0.5 ng/ml. 649 (85%) had an entry PSA value of &lt;1.6, 112 patients (15%) had an entry PSA of 1.6-4. Median follow up was 12.6 years. Actuarial overall survival at 10 years was 82% for RT plus AAT and 78% for RT + placebo and a hazard ratio of 0.75 (95% CI: 0.58-0.98) with a 1-sided p value of 0.018 (2-sided p = 0.036). The 12-year incidence of PC central-reviewed deaths were 2.3% for RT + AAT and 7.5% for RT + placebo ( p&lt; 0.001).The cumulative incidence of metastatic PC at 12 years was less in the RT + AAT arm, 14% (51 patients), vs. 23% (83 patients) in the RT + placebo arm (p &lt; 0.001). Subgroup analyses of the relative benefits of the addition of AAT to RT are planned and will be presented. Late grade III and IV toxicity were similar in the AAT and placebo arms. The combined grade III and IV toxicities for RT + AAT and RT + placebo were: bladder 7.0% vs. 6.7%, bowel 2.7% vs. 1.6%. Gynecomastia differed significantly by treatment arm, 70% vs. 11%. Conclusions: 24 months of AAT using 150mg bicalutamide daily during and after salvage RT significantly improved long term overall survival and reduced the incidence of metastatic PC and PC death. Support: NCI grants U10CA21661, U10CA180868, U10CA180822, and U10CA37422 and AstraZeneca. Clinical trial information: NCT00002874.
Cetuximab in refractory metastatic colorectal cancer: Analysis of efficacy and response by patient and disease variables
Authors: B. Mirtsching, J. Cichon, S. Beasley, C. Teel, D. Jackson, C. Headlee
Journal: Journal of Clinical Oncology (2005)

3671 38 metastatic CRC patients refractory to oxaliplatin- and irinotecan-regimens were treated with single-agent cetuximab in two research studies, an open-label phase II investigation and an Expanded Access Program. Entry criteria were similar and analysis of participating patients revealed no differences between the groups. Methods: A pooled analysis was performed to compare outcomes of our patients with outcomes of cetuximab monotherapy published (Cunningham PASCO 2003 22:252a Abstract 1012). 38 EGFR+, >=third-line patients (28 M,10 F; median age 61; PS 0–2) were treated with cetuximab 400 mg/m2 IV week 1, 250 mg/m2 on subsequent weeks until toxicity or disease progression. Disease Characteristics: 31 colon, 7 rectal primaries. Time from last chemotherapy: <30 d in 8, 31–90 d in 24, >90d in 8. Median number of metastatic organ sites: 2.5. 3 sites: 32%, >=4 sites: 18%. Sites (%): liver 89, lung 61, LN 24, bone 16, soft tissue 11, adrenal 11, peritoneal, pelvic floor 5, resected brain 5, pleural 3. Results: ORR 8% (5% PR, 3% CR) with 42% SD for overall clinical benefit rate of 50%. The CR patient had lung-only disease and maximal response was not achieved until week 16, ongoing CR >52 weeks. PR patients had maximal response at week 6–8. The fraction of patients with disease control by week of study was maximal at week 8, but remained substantial (>25%) through week 16. The median PFS was 49 d (1.6 mo), (95% CI 31–67 d, 1–2.2 mo) and the median OS as 211 d (7 mo) (95%CI 175–247 d, 5.8–8.2, mo). Grade 3 rash was only 3% (1 pt). Statistical results are summarized in the table below. Rash intensity did not correlate with EGFR staining intensity. PFS and OS were significantly longer in patients with >rash intensity and <number of metastatic sites, but was not influenced colon v rectal primaries, EGFR staining intensity, or interval from prior chemotherapy. Conclusions: Patients with limited disease burdens are more likely to achieve benefit. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Aventis, Bristol-Myers Squibb, ImClone Amgen, Bristol-Myers Squibb, ImClone Amgen, Bristol-Myers Squibb, Genentech, Genta, GlaxoSmithKline, Novartis, Sanofi, Threshold, Wyeth
SOCS3 immunohistochemical expression to support the 2005 International Society of Urological Pathology (ISUP) modified Gleason grading system.
Authors: Gian Luigi Petrone, Francesco Pierconti, Maurizio Martini, Tonia Cenci, Luigi Maria Larocca
Journal: Journal of Clinical Oncology (2016)

216 Background: In the 2005 International Society of Urological Pathology (ISUP) Consensus Conference, a modified Gleason grading system for prostate cancer was proposed. (Epstein JI et al. Am J Surg Pathol 2005; 29:1228-1242) Afterwards an interobserver study among experts in genitourinary pathology proposed some modifications and refinements to the 2005 ISUP modified grading system concerning the cribriform pattern carcinoma that it should never be diagnosed as Gleason pattern 3, assigning Gleason pattern 4 to cribriform glands (Latour M et al. Am J Surg Pathol 2008; 32: 1532-1539; Epstein J I Journal of Urology 2010: 183:433-440). Methods: The study population consisted of 80 patients undergoing biopsies at the Institute of Urology of our hospital, between February 2012 and January 2013 stratified into 3 different categories on the basis of histologic pattern: 1) 20 patients with classical and modified Gleason score 3+3 = 6; 2) 30 patients with classical Gleason score 3+3 = 6 upgraded to Gleason score 7 according to the ISUP modified grading system; and 3) 30 patients with classical and modified Gleason score 3+4 = 7. We evaluate the immunohistochemical protein expression of the suppressor of cytokine signaling (SOCS) proteins 3 (SOCS3) in these three different group of prostatic cancer biopsies. Results: We found that the SOCS3 pattern staining negative (-) or with SOCS3 negative staining with weak intensity staining in less than 50% of neoplastic glands (+/-) increases progressively in concomitance with the rise of Gleason score and SOCS3 positivity (+), correlates with classical or modified Gleason score 6 (P = 0,0004 Fisher’s exact tests) and with classical Gleason score 3+3 = 6 upgraded to Gleason score 7 (P = 0,0010 Fisher’s exact tests). Conclusions: In conclusion our data seem to support from a molecular point of view the modified criteria by 2005 International Society of Urological Pathology (ISUP) Consensus Conference as well as the hypothesis that the diagnosis of Gleason cribriform pattern 3 virtually does not exist and cribriform glands-regardless of their size-are nearly always considered pattern 4.
Relationship of HER2 overexpression to brain metastasis (BM) in esophageal cancer (EC) patients.
Authors: T. Abu Hejleh, B. DeYoung, E. S. Engelman, J. Deutsch, M. B. Zimmerman, T. R. Halfdanarson, D. J. Berg, K. Parekh, W. Lynch, M. Iannettoni, S. Bhatia, G. H. Clamon
Journal: Journal of Clinical Oncology (2011)

e14572 Background: BM is historically an uncommon relapse pattern of EC. HER2 is a membrane tyrosine kinase that is overexpressed in various cancers as EC and breast cancer (BC). BM in BC patients has been linked to HER2 overexpression, but HER2 status was not explored in EC patients who experience BM. Methods: We retrospectively reviewed the medical records of EC patients who underwent esophagectomy at University of Iowa Hospitals and Clinics between 2000 and 2010. Data analyzed consisted of demographic and clinical variables including tumor stage, grade, histology, neoadjuvant chemoradiation (NCR), tumor response to NCR and first site of cancer relapse. We stained the brain metastasis tissue for HER2 overexpression using Dako Hercept immunohistochemistry (IHC) test per the FDA approved kit guidelines Results: 142 patients were reviewed; 124 males and 18 females. Median age: 64 years (36-86). 88 patients (62%) received NCR. In the NCR group, complete and partial responses (CR and PR) were achieved in 17 (19%) and 71 (81%) patients, respectively. Median follow-up for relapse was 9.2 months and median survival was 32.9 months (95% CI: 24.2-41.6 months). Thirty two percent (28/88) patients had cancer relapse. The brain was the first site of relapse in 7/28 patients (25%; 95% CI: 10.7%-44.9%). Patients with BM had the following characteristics: cancer stage was T3N1 (7/7), NCR (7/7), CR (1/7), PR (6/7), adenocarcinoma (5/7), Squamous cell carcinoma (2/7), poor differentiation (5/7). IHC staining for HER2 was done on 6/7 BM specimens. 3/6 (50%) specimens showed 3+ staining. The rest of the specimens (3/6) were negative (0 staining). Conclusions: HER2 overexpression might be associated with increased risk of BM in EC patients following esophagectomy. This finding is consistent with the BC literature showing increased risk of BM in patients who overexpress HER2. A larger cohort of EC patients will be required to validate this observation.
Do cytokines improve survival in patients with metastatic renal cell carcinoma (MRCC) of intermediate prognosis? Results of the prospective randomized PERCY Quattro trial
Authors: S. Negrier, D. Perol, A. Ravaud, C. Chevreau, J. O. Bay, R. Delva, E. Sevin, A. Caty, N. Tubiana-Mathieu, B. Escudier
Journal: Journal of Clinical Oncology (2005)

LBA4511 Background: Interleukin-2 (IL2), used to treat MRCC, is not known to improve survival. To assess this potential benefit, the French Immunotherapy Intergroup designed a multicenter trial for patients (pts) with intermediate prognosis for response to cytokine treatment (Negrier et al NEJM 1998). Methods: Untreated pts with more than one metastatic site and Karnofsky score ≥80 were randomized to medroxyprogesterone (MPA: control group), α-Interferon (IFN), sc IL2 or IFN+sc IL2 in a 2x2 factorial design. Patients were evaluated after 3 months; pts without progression continued treatment for up to 6 months. The primary endpoint was overall survival (OS). The planned sample size was 456 pts based on a minimum expected difference of 10% in OS at 2 years with 5% α error and 80% power. Intent-to-treat analysis was planned 6 months after last enrollment. OS analysis (1 interaction check test and 2 log-rank tests) will be performed after α-level adjustment to maintain overall α risk at 0.05. Results: From January 00 to July 04, 492 pts were randomized: 123 to MPA, 122 to IFN, 125 to IL2 and 122 to IFN+IL2. Patient characteristics were well balanced between the groups. Median age was 61 years, 75% were males, Karnofsky score was ≥ 90 in 61%, 96% had nephrectomy, time from initial diagnosis to metastases was > 1 year in 34%. A total of 11 vs. 60 vs. 127 vs. 181 grade 3/4 toxic events were observed in the MPA, IFN, IL2 and IFN+IL2 groups, respectively; no toxic death occurred. Response rates (WHO criteria) at 3 months in the 4 groups were 2.6, 4.4, 5.1 and 10.4% respectively. Current median follow up is 28 months. OS will be analyzed in January 05. Conclusions: This study will establish whether cytokines improve OS in MRCC pts with intermediate prognosis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche