tbuckley/cabot-search huggingface dataset:
Suppressed caspase-3 expression compensates for bcl-2 inhibition by antisense oligonuclotides in LNCaP cells.
Authors: M. Rubenstein, M. Bjurlin, C. M. Hollowell, P. Guinan
Journal: Journal of Clinical Oncology (2011)

e13510 Background: Mono- and bispecific oligos containing sequences directed towards bcl-2 were added to LNCaP cells and evaluated for expression of bcl-2 and caspase-3 (a non-sequence related protein promoting apoptosis). The purpose was to determine whether additional effects were produced in other proteins which would once again allow tumors to diminish apoptosis following specific suppression of bcl-2 (an inhibitor). Methods: RT-PCR was used to evaluate extracted RNA for gene expression of apoptosis regulating proteins bcl-2 (targeted) and caspase-3 (not targeted). Results: All oligos produced significant inhibition of LNCaP cell growth. Bcl-2 expression was suppressed by both mono- and bispecific oligos and caspase-3 was significantly (p < 0.006) suppressed by both mono- and two bispecific types: 35.8%, 40.3% and 43.5% respectively. Conclusions: While gene therapy is often aimed at suppressing bcl-2, for re-establishment of apoptosis you should at least maintain essential caspase-3 expression. These experiments identify a compensatory mechanism for tumors to select variants which once again evade apoptosis by diminished expression of an apoptosis promoter; and identify genes for potential replacement therapy.
Superior outcomes associated with earlier use: Experience with tositumomab and iodine I 131 tositumomab in 1,177 patients (pts) with low-grade, follicular, and transformed non-Hodgkin’s lymphoma (NHL)
Authors: S. A. Gregory, J. P. Leonard, J. M. Vose, A. D. Zelenetz, S. J. Horning, S. J. Knox, T. A. Lister, J. A. Radford, O. W. Press, M. S. Kaminski
Journal: Journal of Clinical Oncology (2005)

6561 Background: Tositumomab and Iodine I 131 Tositumomab (the BEXXAR Therapeutic Regimen) has been studied in clinical trials of pts with previously untreated, relapsed, and refractory NHL. The relationship of treatment history to efficacy of Tositumomab and Iodine I 131 Tositumomab was examined. Methods: Investigator-assessed efficacy of Tositumomab and Iodine I 131 Tositumomab was available for 10 studies including 1,177 pts. Responses were confirmed by a subsequent response at least 4 weeks later in 9 studies (best response was used for data from an Expanded Access Program). Line of therapy included single agent regimens, combination regimens, and rituximab-containing regimens. Radiotherapies were excluded. Median follow-up was 33 mo (range, 0–128 mo). Results: Median age: 57 (range, 21–90); % male/female: 54/46; median time from NHL dx: 40 mo; stage III/IV: 90%; tumor diameter ≥5 cm: 47%; bone marrow involvement: 44%. Efficacy is summarized by line of therapy. All differences are highly statistically significant (P < .001). Conclusions: Response rates, complete response rates and associated durations of response following Tositumomab and Iodine I 131 Tositumomab all increase significantly as number of prior therapies decreases. Durable complete responses were observed across the spectrum of treatment sequences, but with significantly higher frequency when Tositumomab and Iodine I 131 Tositumomab were used earlier in the course of disease. Tositumomab and Iodine I 131 Tositumomab Use by Treatment Sequence 1st line (n=141) 2nd line (n=226) 3rd line (n=228) 4th line+ (n=540) Response rate, % 95 73 58 46 (95% Cl) (90, 98) (67, 78) (51, 64) (42, 51) Median duration of response, mo NR 35 16 12 (95% Cl) (65, NR) (22, NR) (14, 22) (9, 16) Complete response (CR), % 78 46 32 23 (95% Cl) (71, 85) (40, 52) (26, 38) (19, 27) Median duration of CR, mo (95% CI) NR (72, NR) NR (NR, NR) 35 (22, NR) 59 (27, NR) PFS > 1 year, % 82 59 42 27 CI = Confidence Interval; NR = Not reached; CR = Complete response; PFS = Progression-free survival Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
The analysis of status and clinical implication of KIT and PDGFRa mutations in gastrointestinal stromal tumor (GIST)
Authors: C. Du Sr., Y. Zhou, Y. Shi, H. Fu, G. Zhao
Journal: Journal of Clinical Oncology (2008)

10562 Background: To investigate the status of KIT and PDGFRA mutations in the gastrointestinal stromal tumors (GIST) and its clinical implication in China. Methods: 141 GISTs were evaluated for the presence of KIT and PDGFRA mutations. Exon 9, 11, 13, 17 of KIT and exon 12, 18 of PDGFRA were analyzed by PCR amplification and direct sequencing. The clinical features, prognostic factors, mutational status and their relationships were analyzed with statistical tools in this study. Results: Generally, KIT mutations were identified in 76.6% (108/141) in all our 141 GISTs: 70.2% (99/141) involving exon 11, 5.7% (8/141) involving exon 9, 0.7% (1 /141) involving exon 13 and no mutation detected in exon 17. The gene mutations were mostly heterogeneous. The KIT exon 11 mutational format included deletion (65.7%), point mutation (24.2%) and insert duplications (10.1%). The mutations clustered in the classic “hot spot” at the 5|o:end of the exon mostly heterogeneous and the second “hot spot” were internal tandem duplications (ITD) at the 3’end of the exon. PDGFRA mutations were totally identified in 12.1% (4/33) of no-KIT-mutation GISTs and 40% (4/10) of CD117- negative GISTs: all involving exon 18 with the mutations D842V. With the analysis between clinical features and mutation status, we found the significant difference of gene mutation rate in the different primary tumor organs (x2=7.229, p=0.027; x2=7.000, p=0.03).The overall mutation rate in the GIST originated from colorectum or extra-gastrointestinal tract was lower than that from stomach and small intestinal and the difference is significant (x2=6.728, p=0.009; x2=4.059, p=0.044). The ckit exon11 mutation rate in the gastric stromal tumors is higher than that in the other sites and the difference is significant (x2=5.713, p=0.017; x2=4.341, p=0.037). The mutation rates, whatever overall mutation rate or ckit exon11 mutation rate, were no significant differences between the groups of age, gender, tumor size, mitotic rate, grade of malignant potential and liver metastasis or not. Conclusions: Most GIST had the KIT or PDGFRA gene mutation. There was significant difference between gene mutation rate and primary tumor organ in China. No significant financial relationships to disclose.
Effectiveness of percutaneous radiofrequency ablation for metachronous liver metastases of gastric cancer.
Authors: Jun-Eul Hwang, Dae-Eun Kim, Hyun-Jeong Shim, Woo Kyun Bae, Sang-Hee Cho, Ik-Joo Chung
Journal: Journal of Clinical Oncology (2013)

136 Background: This study evaluated the efficacy of percutaneous radiofrequency ablation (RFA) for the treatment of metachronous liver metastases of gastric cancer. Methods: We enrolled a total of 44 patients who underwent RFA for the treatment of metachronous liver metastases after resection of a primary gastric adenocarcinoma from January 2002 to November 2011. The primary endpoint of this study was overall survival (OS) and recurrence-free survival (RFS) after RFA. Results: Systemic chemotherapy was combined with RFA in 40 patients.The OS and RFS after RFA for all patients were 14.7 (95% CI, 10.1-19.2) and 6.1 months (95%, CI 4.2-8.1). the OS and RFS of the patients with liver-only metastasis who underwent RFA and chemotherapy were 20.9 months (95% CI 18.4-23.4) and 9.8 months (95% CI 9.2-10.5), respectively. On multivariate analysis, the factors independently, negatively associated with RFS were bilobar intrahepatic distribution (HR 3.9, 95% CI 1.5-9.9, p=0.001), and extrahepatic metastatic lesions (HR 3.6, 95% CI 1.6-7.8, p=0.003). The factors independently, negatively associated with OS were extrahepatic metastatic lesions (HR 12.6, 95% CI 3.7-42.9, p=0.001), no chemotherapy (HR 43.3, 95% CI 7.4-251.3, p=0.001), and tumor number (≥ 2) (HR 2.6, 95% CI 1.2-5.9, p=0.015). Conclusions: The efficacy of RFA for metachronous liver metastases of gastric cancer is limited to patients with a single, unilobar metastasis without extrahepatic metastatic lesions. Combined systemic chemotherapy is very important for the prolongation of overall survival.
Phase II study of alternate-day oral therapy with S-1 for unresectable advanced pancreatic cancer: An updated report.
Authors: Sohei Satoi, Motoki Miyazawa, Masaji Tani, Manabu Kawai, Seiko Hirono, Ken-Ichi Okada, Hiroaki Yanagimoto, A-Hon Kwon, Takamasa Kanbe, Tomoyuki Mukouyama, Hiroaki Tsunoda, Kazuo Chijiiwa, Jiro Ohuchida, Jun Kato, Kazuki Ueda, Taketo Yamaguchi, Shinichi Egawa, Kazuhiko Hayashi, Tetsuhiko Shirasaka, Hiroki Yamaue
Journal: Journal of Clinical Oncology (2013)

252 Background: Based on the results of GEST, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended regimen of 4 weeks of administration interrupted by 2 weeks of drug withdrawal frequently causes adverse effect. Grade3/4 toxicities (%) in S-1 were neutropenia 8.8, anorexia 11.4, diarrhea 5.5. On the other hand, we experienced in clinical practice that the alternate-day administration of S-1 reduced adverse effects and was tolerable for unresectable advanced pancreatic cancer patients unwilling to continue the standard daily administration. We therefore conducted a multi-center cooperative prospective study to compare daily with alternate-day administration of S-1 for unresectable advanced pancreatic cancer. Methods: Patients with unresectable advanced pancreatic cancer (PS, 0 to 1; age, 20 to 80 years; no other therapy) were eligible for enrollment in this trial. S-1 was administered a dose of 40 to 60 mg twice daily, assigned according to body-surface area, on Monday, Wednesday, Friday, and Sunday (specified days). Each treatment cycle will be 42 days (6 weeks). The primary endpoint was overall survival (OS). Secondary endpoints were safety, response rate (RR), progression free survival (PFS), time to treatment failure (TTF). Results: A total of 50 patients were enrolled from Sep 2009 to Feb 2011. 48 patients were evaluable for response. Male/Female was 21/27, PS: 0/1 was 40/8. With a median follow-up time of 28.2 months, OS as primary endpoint was 8.4 months (95% CI, 5.4-10.8) with the 1 year survival rate 29.2%. PFS was 5.5 months, and TTF was 3.9 months. RR was 10.4% (95% CI: 3.5-19.1), and Disease Control rate was 79.2%. Grade 3/4 hematological and non-hematological toxicities were minor. All of those adverse reactions were tolerable and reversible. Conclusions: We will report the data from the final analysis at this meeting. The current data show mitigation of adverse effects with alternate-day administration of S-1, and it appears to be a more sustainable option for unresectable advanced pancreatic cancer. A randomized phase II trial comparing this regimen of S-1 with standard regimen of S-1 is ongoing. Clinical trial information: 000003453.
Breast conservation (BCT) for DCIS: A prospective study of how MRI impacts management (MGMT).
Authors: J. L. Marti, J. I. Goldberg, S. Patil, V. V. Barbashina, D. D. Giri, S. Brennan, C. Lee, C. Vallejo, E. A. Morris, K. J. Van Zee
Journal: Journal of Clinical Oncology (2010)

546 Background: The optimal role of MRI in the MGMT of patients (pts) with DCIS remains undefined. We undertook this prospective study to evaluate the changes in MGMT that occur due to MRI findings. Methods: 100 pts <60 y.o. with core biopsy-proven DCIS (± microinvasion) were prospectively enrolled. After evaluation with mammography ± ultrasound (US), the operative plan was recorded. 86 were BCT candidates. Additional (addl) suspicious MRI findings and subsequent MGMT changes were then prospectively recorded. Significance was tested by chi squared. Results: See Table. Of 41 pts with addl MRI findings, 12 had BCT with 1 excision, 16 had attempted BCT but required subsequent TM or reexcision, 5 had TM as 1st operation a result of MRI, 17/41 (41%) had 1 operation. Of 45 pts with no additional MRI findings, 28 had BCT with 1 excision, 17 had attempted BCT but required TM or reexcision. 28 (62%) had 1 operation. Overall, MRI altered MGMT in 32/86 (37%) pts. Of these, 9 (10%) were spared an operation. To benefit these 9 pts, 28 procedures in 19 (22%) pts were generated. Among pts with no addl MRI findings, BCT was more likely to be successful (84% vs. 56%, p= 0.004) and to require 1 operation (62% vs. 29%, p= 0.002). Among pts with addl MRI findings, TM was more likely to be elected by pts (20% vs. 0%, p=0.002) or required (24% vs. 16%, p=0.3). Conclusions: MRI detects additional findings in 1/2 pts with core bx-proven DCIS, resulting in changes in MGMT for over 1/3 pts, reducing the number of operations in 10%. Additional MRI findings are associated with lower rate of successful BCT and higher required TM rate. For each pt for whom an operation is prevented, 2 pts have additional tests. Pts with additional MRI findings are more likely to elect TM. Pts with MGMT altered Additional procedures in 19 pts Pts saved an operation Pts electing mastectomy (TM) post-MRI Pts requiring TM Pts with successful BCT Pts with additional MRI findings (N = 41/86) 32/41 (78%) 28 9/41 (22%) 8/41 (20%) 10/41 (24%) 23/41 (56%) Separate lesions (N = 11) 11 16 0 2 1 8 Index lesion larger (N = 23) 15 5 7 3 8 12 Separate lesion and index lesion larger (N = 4) 3 3 1 2 1 1 MRI mass (N = 2) 2 2 1 0 0 2 Adenopathy (N = 1) 1 2 0 1 0 0 Pts without additional MRI findings (N = 45/86) 0 0 0 0 7/45 (16%) 38/45 (84%) Total (N = 86) 32/86 (37%) 28 9/86 (10%) 8/86 (9%) 17/86 (20%) 61/86 (71%) No significant financial relationships to disclose.
Retrospective study regarding the efficacy of second- or higher-line chemotherapy (CT) of patients in advanced or recurrent gastric cancer (ARGC) after the failure of S-1 or S-1 combination chemotherapy (S+α).
Authors: Kazuma Kobayashi, Yuji Negoro, Yasuhiro Hata, Sojiro Morita, Keisuke Aiba, Akihito Tsuji
Journal: Journal of Clinical Oncology (2013)

129 Background: At the 2007 ASCO meeting, two RCTs from Japan showed that S-1 (S) and S-1/CDDP (S+P) therapy now are an accepted standard 1st-line chemotherapeutic regimens for ARGC. Today in Japan, S+α are the mainstay CTs for ARGC. However, it is important to acquire a longer survival for ARGC and therefore development of a 2nd or higher line CT after S+α failure is thus required. At the 2012 ASCO meeting, WJOG4007G trial showed that weekly PTX was regarded as a temporary standard 2nd-line CT for ARGC after the failure of S+P. However, some clinical questions to appropriate 2nd-line CT have been unsolved. The present study set out to identify the factors, which make it appropriate to perform the CT after S+α failure, and to examine the validity of this treatment. Methods: Sixty-one pts with ARGC who failed to sufficiently respond to S+α therapy between Dec. 2004 and May 2010 were retrospectively reviewed. Results: The patient characteristics were: mean age, 63.8 y.o.; sex, M/F=42/19; patient status: unresectable: 35, non-curative operation: 17 and postoperative recurrence: 9. The initial CT regimens consisted of S: 32, S+α: 29. The 2nd-line CT regimens included Taxanes (TA): 40, CPT-11 (IRI): 20, S+α: 1. The median number of 2nd or higher treatment courses was 2 (1-6). The RR of 2nd-line CT was 24.6%. The mTTF and MST since the 2nd-line CT was administered were 112 days and 311 days, respectively. The transition rate to 3rd-line was 65.6%. The OS since the S+α administration significantly correlated with the TTF of S+α (p&lt;0.001), while the OS since the 2nd-line CT administration (2nd OS) was independent of the TTF of S+α. The 2nd OS did not correlate with either the specific type of 2nd-line CT. However, the 2nd OS of pts receiving both TA and IRI was significantly longer than ones only either TA or IRI (p=0.0012). Conclusions: The findings of this study suggest that the addition of a 2nd or higher line CT is expected to result in a longer survival for pts with ARGC, even when the anti-tumor effect was deemed to be insufficient following the S+α therapy, and that the strategy of using all available agents in the treatment course of ARGC might be needed.
Implementation and evaluation of a tobacco cessation program in an outpatient oncology center.
Authors: Thomas A. Hensing, Bruce Brockstein, George W. Carro, Shannon Maureen Gavin
Journal: Journal of Clinical Oncology (2012)

117 Background: Tobacco use is the leading preventable cause of premature death in the United States and has a causal link to various cancer types. Continued tobacco use after a cancer diagnosis may decrease survival, reduce treatment efficacy, prolong/increase treatment toxicity, and increase the risk for recurrence. The combination of support from trained professionals and appropriate medications increases the chances of quitting successfully. In the literature, the advice of a physician improves quit rates to about 10% and the combination of tobacco cessation medication and behavioral support can increase the rate to 20-35%. There is a lack of data on the impact of a tobacco cessation program integrated into a cancer center. The objective of this project is to implement and prospectively evaluate a tobacco cessation program in a hospital-based outpatient cancer center across three treatment sites. Methods: A multidisciplinary group at the cancer center was established to oversee the development and implementation of the program including: pharmacist training to become a certified Tobacco Treatment Specialist, electronic medical record documentation tool establishment, and development of patient education tools. The pharmacist provided one-on-one counseling for each referred patient. Assessment of the 3, 6, and 12 month quit rates was performed. Results: The tobacco cessation program at the cancer center has been available for approximately one year to all patients and their family members. Of the 67 patients referred to the tobacco cessation program, 27 (40%) patients followed through with the referral and met with the tobacco treatment specialist. The 3, 6, and 12 month quit rates are 68%, 50%, and 50%, respectively. Conclusions: The tobacco cessation program at the cancer center is evolving into a successful program. The quit rates of the program have exceeded those reported in the literature. The accessibility of the tobacco cessation program has enhanced the comprehensive care provided to the patients at the cancer center.
Gemcitabine for advanced endometrial carcinoma (EMC): A review of the MSKCC experience.
Authors: R. N. Grisham, C. H. Adaniel, D. M. Hyman, W. Ma, A. Iasonos, C. Aghajanian, J. A. Konner
Journal: Journal of Clinical Oncology (2011)

5098 Background: There are few chemotherapy options for advanced EMC. Gemcitabine is active in several gynecologic malignancies including ovarian cancer, cervical cancer and uterine leiomyosarcoma; and has commonly been used in an off-label setting for treatment of advanced EMC, despite a lack of published data showing efficacy. We performed a retrospective review to determine the progression free survival (PFS) and response rate (RR) of EMC patients treated with gemcitabine at Memorial Sloan-Kettering Cancer Center (MSKCC). Methods: Eligible patients had histologically confirmed advanced (stage IV or recurrent) EMC that was treated with gemcitabine at MSKCC between 1999 and 2009. Response to therapy was determined by review of CT imaging by RECIST 1.1 criteria. Results: There were 68 patients identified who received gemcitabine for advanced EMC between 1999 and 2009; 22 patients were excluded due to lack of available imaging. The median age of the 46 patients included in the analysis was 66 years (range, 52-87). All patients were previously treated with chemotherapy, the median number of prior lines of chemotherapy was 2 (range, 1-8). The median dose of gemcitabine administered was 800mg/m2 infused on day 1 and 8 of a 21 day cycle. The predominant histology was endometrioid (48%, n=22) followed by papillary serous (35%, n=16), clear cell (15%, n=7) and undifferentiated (2%, n=1). The overall RR was 10.9%; 4 patients (9%) achieved a partial response (PR) and 1 patient (2%) achieved a PR that became a complete response after surgical removal of a site of residual disease. Thirteen patients (28%) displayed stable disease (SD) lasting at least 3 months. Of note, 5 of the 7 (71%) patients with clear cell histology displayed SD or PR (n=5).The median PFS was 3.0 months (95% CI, 2.07 to 3.32). Non-hematologic grade 3 and 4 toxicities were rare. Ten patients (22%) were treated with granulocyte-colony stimulating factor (G-CSF) during treatment. Conclusions: In a mixed population of patients with previously treated advanced EMC, gemcitabine was well tolerated and showed modest activity. Patients with clear cell histology appeared to have greater likelihood of benefit.
Longer-term cardiac safety and outcomes of dose dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H) with and without lapatinib (L) in patients (pts) with early breast cancer (BC).
Authors: Patrick Glyn Morris, Neil M. Iyengar, Sujata Patil, Carol Chen, Alyson Abbruzzi, Robert James Lehman, Richard Steingart, Kevin C. Oeffinger, Nancy Lin, Beverly Moy, Steven E. Come, Eric P. Winer, Larry Norton, Clifford Hudis, Chau T. Dang
Journal: Journal of Clinical Oncology (2013)

630 Background: The addition of H to chemotherapy has improved outcomes in HER2-positive early BC. This approach is associated with (w/) an increased risk (&lt;4%) of congestive heart failure (CHF). At a median f/u of 36 months, the addition of anti-HER2 Rx to dose-dense (every 2 weeks) anthracycline-taxane therapy (Rx) was not associated with excess cardiotoxicity. Here we report the incidence of NYHA Class III/IV CHF in 2 phase II studies with longer follow-up. Methods: We conducted a retrospective review of pts w/ HER2 + early stage BC treated at MSKCC and DF/HCC on two trials: In trial A - pts received dd AC (60/600 mg/m 2 ) x 4 → T (175mg/m 2 ) x 4 (w/ pegfilgrastim) w/ H x 1 year. Trial B differed w/ use of weekly T (80mg/m 2 ) x 12 and the addition of L (1000mg orally daily) x 1 year. In both trials, H was begun after completion of AC and concurrent with T. Left ventricular ejection fraction (LVEF) was prospectively assessed by multi-gated acquisition scan serially throughout Rx. Results: Trial A enrolled 70 pts and Trial B enrolled 95 pts w/ the median age of 46 years (range 27-73 years). Overall, the 5-year distant disease-free survival (DDFS) for trials A and B is 92% (95%Cl; 83-97%) and 89% (95%CI; 81-94%), respectively. The baseline median LVEF was 68% (range 52-81%). In total, 28 of 165 (17%) pts had pre-existing hypertension. Now at a median follow-up of 84 and 57 months respectively, only one (1.4%, 95%CI; 1.36-7.7%) and 4 (4.2%, 95%CI; 4.2-10.4%) pts developed CHF. Since our earlier report, 1 additional CHF event occurred (Trial B) at month 44. Conclusions: Longer follow-up of these 2 studies demonstrate that dd AC → TH with or without L is associated w/ a low risk of CHF. This is consistent w/ the long-term cardiac toxicity reported from the randomized phase III studies of H w/ conventionally scheduled anthracycline-based regimens (with or without taxanes). DDFS outcomes are also encouraging. Clinical trial information: NCT00482391.