tbuckley/cabot-search huggingface dataset:
Long-term safety and efficacy of pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients enrolled in the MM-002 phase II trial.
Authors: David Samuel DiCapua Siegel, Paul Gerard Guy Richardson, Ravi Vij, Craig C. Hofmeister, Rachid C. Baz, Sundar Jagannath, Christine Chen, Sagar Lonial, Andrzej J. Jakubowiak, Nizar J. Bahlis, Kevin W. Song, Andrew Belch, Noopur S. Raje, Chaim Shustik, Suzanne Lentzsch, Min Chen, Mohamed H. Zaki, Kenneth Carl Anderson
Journal: Journal of Clinical Oncology (2013)

8588 Background: MM-002 is a randomized, open-label, multicenter phase II trial evaluating the safety and efficacy of POM with or without LoDEX in advanced RRMM pts. Methods: Pts who had received ≥ 2 prior therapies, including lenalidomide (LEN) and bortezomib (BORT), and were refractory to their last treatment were randomized to POM+LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (according to EBMT criteria and investigator assessment), response duration, overall survival (OS), and safety. The efficacy outcomes are based on the intent-to-treat population (POM+LoDEX, n = 113; POM, n = 108). Results: The median number of prior therapies in each group was 5 (range 1–13). In the POM+LoDEX arm, 30 (27%) pts had high-risk cytogenetics, including del(17p13) and/or t(4p16/14q32). The overall response rate (≥ partial response) was 34% and 15% with POM+LoDEX and POM, respectively, with a median duration of 8.3 (95% CI: 5.8–10.1) and 8.8 (95% CI: 5.5–11.4) mos, respectively. At least minimal response was observed in 45% and 31% of pts, respectively. Median PFS was 4.6 (95% CI: 3.6–5.5) and 2.6 (95% CI: 1.9–2.8) mos with POM+LoDEX and POM, respectively, with a median follow-up of 16.0 and 12.2 mos. Median OS was 16.5 (95% CI: 12.4–18.5) and 13.6 (95% CI: 9.6–18.1) mos, respectively. The most common treatment emergent Gr 3/4 adverse events (AEs) reported in the safety population (n = 219) were neutropenia (44%), anemia (23%), thrombocytopenia (21%), and pneumonia (18%); there were no reports of Gr 3/4 peripheral neuropathy. The incidence of deep-vein thrombosis was low (2%). AEs were managed through dose reductions or interruptions, and supportive care with G-CSF (52%), RBC transfusions (47%), and platelet transfusions (17%). Discontinuations due to AEs were 10%. Conclusions: POM with or without LoDEX is clinically effective and generally well tolerated in RRMM pts who have received multiple prior treatments, including LEN and BORT. AEs were predictable and manageable. Updated data will be presented at the meeting. Clinical trial information: NCT00833833.
Comparative effectiveness of initiating colorectal cancer (CRC) screening (Scr) at age 45.
Authors: Afsaneh Barzi, Rebecca Siegel, Stacey A. Fedewa, Heinz-Josef Lenz, David I. Quinn, Ahmedin Jemal, Sarmad Sadeghi
Journal: Journal of Clinical Oncology (2017)

531 Background: The incidence of CRC in age group 45-50 is rising based on SEER data. We investigated the outcomes of lowering Scr age to 45 from a societal perspective. Methods: A Markov model was built to represent the natural history and incidence of CRC in US general population (GP). Individual level simulation was used to compare 14 Scr strategies (ST). Effectiveness in life years (LY) &amp; number of prevented (Prev) CRCs, and costs in US$ ($) inclusive of CRC Scr and treatment were measured. LY and $ were discounted at 3%. Incremental cost effectiveness ratios (ICERs) were calculated. Individuals in a cohort of GP aged 45-75 were followed for up to 35 years with Scr starting at age 50 (@50) or 45 (@45). Results: Colonoscopy (CS) @50 ranked 1 with the highest LY and lowest $ &amp; ICER followed by CS @45 (ranked 2) with an ICER of $23074. All other STs had lower LY &amp; higher $ and were dominated by CS. By starting Scr @45, the number of Prev CRC increased favoring Scr @45. LY changes were minimal but favored Scr @45. When CS was removed from Scr options, Fecal Occult Blood Test (FOBT) @45, CT Colonography (CT) every 10 years @50 and CT every 5 years @45 dominated remaining STs with ICERs of $0, $5585, and $31058, respectively. When CT and FOBT were removed from Scr options, FOBT+FS @45 and DNA @45 dominated remaining STs with ICERs of $0 and $650790, respectively. Results remained stable in sensitivity analyses. Conclusions: LY, Prev CRC improved as a result of Scr @45. When dominating STs were sequentially removed, STs beginning @ 45 remained cost effective with ICERs of &lt;$50,000. The advantages of @45 are the result of earlier start and longer duration of Scr. Of note, DNA was not cost effective with ICER of &gt;$650K after CS and CT were removed from calculations. [Table: see text]
Hypermethylation of the KEAP1 gene in colorectal cancer and association with disease progression.
Authors: Evaristo Maiello, Paola Parrella, Tiziana Pia Latiano, Raffaela Barbano, Lucia Anna Muscarella, Barbara Pasculli, Annamaria la Torre, Michelina Coco, Gabriele Di Maggio, Vito Michele Fazio
Journal: Journal of Clinical Oncology (2013)

e14655 Background: Aberrant methylation of the KEAP1 (Kelch-like ECH-associated protein 1) gene promoter is emerging as a main mechanism of dysregulation of the NrF2 (nuclear factor-erythroid 2-related factor 2 ) which plays a pivotal role in the cellular response to oxidative stress. Under basal conditions, Nrf2 is retained in the cytoplasm by the binding with Keap1 and it is maintained at a reduced level by the Keap1-dependent ubiquitination and proteasomal degradation systems. Reduced Keap1 expression by promoter aberrant methylation allows Nrf2 to translocate in the nucleus and to activate the detoxification pathway leading ultimately to drug resistance. Methods: We determined KEAP1 promoter methylation status in 50 metastatic colorectal cancer (CRC) and 9 normal colonic mucosa samples by using quantitative methylation specific PCR in real time (QMSP). The median age of the patients cohort was 65 (IQR 57-74) years. At diagnosis 12 patients were staged Duke D and 38 were staged as Duke C. As first line treatment the FOLFOX or FOLFIRI therapeutical schemes were used. Results: Methylation was detected in 20 out of 50 CRC (40%) and methylation levels were significantly higher in tumour samples (Median 0.65, IQR 0-8.28) as compared with normal colonic mucosa (Median 0, IQR 0-0.08) (P=0.03). Tumours from patients who experieced disease progression had significantly higher methylation levels (Median 0.53; IQR 0-7.61) as compared with patients showing partial response (Median 0, IQR 0-2.21) or disease stability (Median 0, IQR 0-0) (P=0.03 Kruskall Wallis Test). Conclusions: Our results suggest that Keap1 aberrant methylation is a frequent event in colorectal cancer and is associated with response to chemotherapeutical treatments.
KRAS: To be or not to be targeted? Biologic and computational analyses in pancreatic adenocarcinoma.
Authors: Kalliopi Andrikou, Francesco Piva, Matteo Santoni, Alessandro Conti, Alessandra Mandolesi, Alessandro Bittoni, Chiara Pellei, Andrea Lanese, Cristian Loretelli, Marina Scarpelli, Giovanni Principato, Stefano Cascinu
Journal: Journal of Clinical Oncology (2014)

e15207 Background: KRAS mutations have been shown to play a key role in pancreatic cancer progression, but little is known about the relationship between KRAS and other signaling pathways. A better definition of these pathways may help to improve targeted therapies according to the KRAS-mutation status Methods: Mutational status of KRAS gene and the correlation with the expression level of a panel of 29 genes in 91 patients with PDAC have been detected and analyzed. Survival analysis was conducted to assess the association between different KRAS mutations and/or gene expression levels. Bioinformatics analysis was carried out to predict the effect of KRAS nucleotide variations on pre-mRNA splicing, mRNA export and protein alteration Results: KRAS mutations were identified in 49 tumors (54%), whereas 42 tumors (46%) had WT KRAS genotype. Our analysis showed that Smad4 (p=0.003), Muc6 (p=0.009), VEGFR-2 (p =0.020) and VEGFB (p=0.026) were significantly more expressed in WT KRAS while SHH (p=0.012) and IHH (p=0.031) were more expressed into MT KRAS samples. Bioinformatics analysis was performed to investigate the severity of aminoacidic substitutions, showing that G-R and G-S KRAS mutations were less severe than the others. However, no significant difference in terms of overall survival was found between WT vs MT patients and comparing the different types of KRAS mutations. Conclusions: Our results suggest that the frequency of patients with PDAC who had WT KRAS tumors was higher than previously described. Patients with WT KRAS tumors may have a disease that is biologically different than those with mutated KRAS. These results suggest that patients with WT KRAS tumors may benefit from treatment with anti-angiogenic agents, whereas the use of Hedgehog inhibitors could be more effective in patients with MT KRAS tumours.
Patent Foramen Ovale and Cryptogenic Stroke
Authors: Chandra Kunavarapu, Jeffrey A Switzer, Fenwick Nichols
Journal: New England Journal of Medicine (2008)

and the corresponding editorial by Messé and Kent 3 (March 21 issue) illustrate a major problem in clinical trials.When it is not obvious which of two therapies is better, sufficient numbers of events are essential to reach a conclusion.Performing a prospective, randomized trial is not enough.In the PC Trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism), 1 primary-end-point events occurred in only 18 patients in the two groups, even though 414 patients and 29 international sites participated.Any difference may have been due to chance.The investigators in the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) 2 trial enrolled 980 patients at 69 sites, yet there were only 25 primaryend-point events.The proper conclusion of these studies, even though they were well designed and carefully performed, is that too few events were observed to draw any conclusion.When the Early Breast Cancer Trialists' Collaborative Group 4 performed the first metaanalysis of the value of adjuvant tamoxifen -one of the most effective medications in our pharmacopoeia -for breast cancer, only 6 of 42 randomized trials had shown significant benefit.Only trials with many patients and many events are likely to overcome the play of chance.
Examining the dilemmas of prognostic information disclosure and understanding in those with terminal cancer: In-depth interviews with advanced cancer patients in phase I trials
Authors: F. J. Hlubocky, C. K. Daugherty
Journal: Journal of Clinical Oncology (2006)

8516 Background: Timely and accurate prognostic information is essential if patients are to make ethically appropriate medical decisions. Yet, prior research indicates advanced cancer patients (acp) with limited prognoses either misunderstand or fail to receive physician (md)-disclosed information regarding prognoses. Methods: Using semi-structured quantitative and qualitative interviews, acp were queried about prior discussions of prognosis (dop) with md and perceptions about treatment benefit. Results: To date, 87 (93%) acp receiving experimental (phase I) chemotherapy have been interviewed: median age 61 (33–82); 52% male; 80% Ca; 90% married; 58% &gt;high school education. Quantitative interview data include: Likert scores (1–10) of likelihood of chemotherapy in: “stabilizing” cancer (mean 7.6); “halting” cancer (mean 7.1); producing “remission” (mean 6.9); and “curing” (mean 2.9). In response to a specific query, only 52% reported having dop with their md regarding life expectancy and 42% actually stated they initiated this dop. Although 45% denied any dop with md, a significant number of this group provided subsequent qualitative descriptions of dop within our interviews. As well, 61% described receiving specific quantitative estimates indicating a priori dop. When asked about their own thoughts on prognosis, only 4% described quantitative estimates or timeframes. Overwhelmingly so, patients were hopeful for a positive outcome or prolonged survival due to phase I trial participation. Several were currently deferring further dop. Conclusions: Despite prior data indicating that acp have a poor understanding of their prognoses, our findings indicate that at least 75% of interviewed acp recalled having had at least one specific dop and two-thirds describe having received a quantitative estimate of their prognosis. The majority of acp in phase I trials continue to have significant beliefs in the benefits of further therapy. No significant financial relationships to disclose.
Genetically engineered natural killer (NK) cell immunotherapy for children poor risk b-cell (CD20+) leukemia and lymphoma (L/L).
Authors: Yaya Chu, Janet Ayello, Jessica Hochberg, Carmella Van de ven, James Murphy, Mitchell S. Cairo
Journal: Journal of Clinical Oncology (2012)

e13022 Background: A majority of children with CD20+ L/L at relapse have a chemotherapy resistant phenotype (Cairo et al Blood, 2007; JCO, 2012). Novel, non-chemotherapy-based therapies are desperately needed for this poor risk population. NK cells play an important role in tumor surveillance post allogeneic stem cell transplantation (Beziat V et al, Leukemia, 2009) but cell number and tumor recognition limit adoptive NK cell therapy (Shereck/Cairo, PBC 2007). PBNK cells expanded with genetically engineered K562-mbIL15-41BBL cells (geK562) have been previously reported (Imai C et al, Blood. 2005). Objective: We investigated the functional activities and cytolytic effect of anti-CD20 chimeric antigen receptor (CAR + ) engineered PBNK cells expanded with mK562 against CD20+ L/L both in vitro and in vivo. Methods: Peripheral blood mononuclear cells (PBMC) were expanded with mitomycin C treated geK562 cells in culture medium with 10 IU/ml IL-2 for 7 or 14 days. CD56 and CD3 expression were evaluated by flow cytometry. Retrovirus preps that express CAR+ or CAR- were generated independently. The CAR+ was constructed in a MSCV-anti-CD20BB-CD3-zeta-GFP plasmid (generously supplied by Dario Campana, MD, PhD). Expanded PBMC were transduced with retroviruses as described (Imai C et al, Blood. 2005). NK cytotoxicity was assessed by europium release assay at 2:1 E:T ratio against CD20+ Ramos. Results: CD56+CD3- PBNK cells were significantly increased compared to media alone at day7 (60.94+ 3.63% vs 8.05+0.49%, n=6, p&lt;0.001). CD56-CD3+ PBT cells were significantly reduced compared to media alone at day 7 (22.08+2.22% vs 75.73+0.75%, n=6, p&lt;0.001). CAR+ and CAR- retrovirus supernants infected expanded PBMC at 1%-10% range. The anti-CD20 CAR expression was further confirmed by flow cytometry and western blot. We also observe that cytotoxicity was enhanced with CAR+ PBNK compared to CAR- PBNK (41+ 1.1% vs 24.5+ 3.7%) against Ramos at E:T ratio 2:1. Conclusions: PBNK can be expanded with geK562. Anti-CD20 CAR enhances PBNK anti-tumor activity against CD20+ Ramos. Future directions include characterizing the cytotoxicity activity of engineered PBNK against L/L in vitro and survival in xenogafted mice.
Evaluation of possible linkage between everolimus benefit in estrogen receptor (ER)-positive breast cancer and genomic alterations of the PI3K/AKT/mTOR pathway.
Authors: Esther P. Black, Edward H. Romond, Juliann Chmielecki, James Sun, Vera Kadamyan, Mara D. Chambers, Rachel Lauren Stewart, Emily Van Meter Dressler, Murtaza Mehdi, Craig Horbinski, Suleiman Alfred Massarweh
Journal: Journal of Clinical Oncology (2015)

530 Background: Everolimus, which inhibits mTOR, is used to treat metastatic ER-positive breast cancer after aromatase inhibitor failure. Because not all patients benefit and toxicity can be prohibitive, it is critical to identify biomarkers of sensitivity to this treatment strategy. Methods: We studied 36 tumors from patients enrolled on protocol NCT00570921 using fulvestrant and everolimus for metastatic ER-positive breast cancer. There were 15 pretreatment tumors from 11 patients who experienced benefit and 14 from 10 patients who did not. DNA was extracted from FFPE tumor tissue and subjected to next-generation-based comprehensive genomic profiling using the FoundationOne assay and alterations were then compared. Results: 9 out of 11 responders (82%) had at least one genomic alteration in the PI3K/AKT/mTOR pathway vs. 7 out of 10 nonresponders (70%). Mutations detected in the responder group were 7 PIK3CA and 1 AKT1, and 1 PTEN truncation, while in nonresponders there were 5 PIK3CA and 2 AKT1 mutations, and 1 RICTOR amplification (in association with a PIK3CA mutation). Interestingly, none of the responders had more than one alteration in individual components of this pathway, while 2 of the nonresponders had more than one alteration observed (one with a concomitant PIK3CA mutation and AKT3 amplification, and one with a PIK3CA mutation and RICTOR amplification). Other notable alterations include mutations in TP53 and GATA3, and amplification of CCND1, with no specific association with everolimus benefit. Additional analysis and frequency of other alterations will be presented in greater detail. Conclusions: In this small study, we did not identify predictors for lack of benefit from everolimus, although it appears that the presence of multiple aberrations in the PI3K/AKT/mTOR pathway may promote de novo resistance. It is possible that genomic alterations alone may not adequately explain breast cancer response to this strategy without functional signaling analysis. Alternatively, it is possible that everolimus benefit in endocrine resistance may be independent of PI3K/mTOR signaling altogether and its mechanism of action is yet to be fully determined.
Serial monitoring of imatinib pharmacokinetics (PK) in perioperative imatinib treatment in patients (pts) with gastrointestinal stromal tumors (GISTs): Results from the multinational phase II trial.
Authors: Changhoon Yoo, Min-Hee Ryu, Yukinori Kurokawa, Han-Kwang Yang, Toshirou Nishida, Seong-Ho Kong, Toshimasa Tsujinaka, Kyung Hee Lee, Hiroshi Yabusaki, Hong-Suk Song, Hiromitsu Akabane, Seock-Ah Im, Kazuaki Tanabe, Hye Jin Kang, Takashi Nomura, Byung Wook Kang, Tetsu Nakamura, Masaaki Okubo, Hirokazu Taniguchi, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2017)

118 Background: Imatinib plasma levels may be affected by the duration of exposure to imatinib and resection of the stomach. Therefore, we performed PK study to monitor imatinib plasma levels serially in the multinational phase II trial of perioperative imatinib for pts with large ( ≥ 10 cm) gastric GISTs without distant metastasis. Methods: In this trial conducted in Japan and Korea, 53 pts received neoadjuvant imatinib 400 mg daily and 40 pts received adjuvant imatinib after surgery. Blood samples for imatinib trough levels (Cmin) were collected after 1, 3, 6 months of each neoadjuvant and adjuvant imatinib and measured by using liquid chromatography-tandem mass spectrometry. For the comparison of imatinib Cmin between different time points, values were dose-adjusted and log-transformed. Results: During the neoadjuvant treatment, imatinib Cmin (mean ± standard deviation) was 2253.0 ± 1148.0 ng/mL (n = 49), 1623.3 ± 832.4 ng/mL (n = 47), and 1852.0 ± 1572.4 ng/mL (n = 45) after 1, 3, and 6 months of imatinib, respectively. During the postoperative treatment, imatinib Cmin was 1436.1 ± 852.8 ng/mL (n = 31), 1357.8 ± 646.4 ng/mL (n = 33), and 1084.2 ± 360.8 ng/mL (n = 31) after 1, 3, and 6 months of imatinib, respectively. In the neoadjuvant setting, imatinib Cmin was significantly reduced after 3 months (p = 0.0001) and 6 months (p = 0.004) compared to the value at 1 month. In 36 patients that imatinib Cmin was measured at both preoperative and postoperative setting, imatinib Cmin was significantly reduced after surgery (1732.4 ± 997.9 ng/mL vs 1282.8 ± 557.3 ng/mL; p = 0.04). The magnitude of changes in imatinib Cmin after surgery was greatest in patients who underwent total gastrectomy (10.6%, n = 2) followed by proximal gastrectomy (8.4%, n = 3), and wedge resection (3.3%, n = 30). There were no significant relationships between imatinib Cmin and toxicity or objective response. Conclusions: Imatinib exposure was reduced until approximately 3 months after imatinib treatment. It was also significantly reduced after surgery and the magnitude of changes might be affected by the extent of surgical resection of stomach.
Medical Care of Detainees in US Military Facilities
Authors: Julio A. Chalela
Journal: JAMA (2017)

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