tbuckley/cabot-search huggingface dataset:
Differential effects of bay- and fjord-region diol epoxides of polycyclic aromatic hydrocarbons on Mdm2 and p53 phosphorylation
Authors: Ase Mattsson, Maria Malmlof, Albrecht Seidel, Ulla Stenius, Bengt Jernstrom
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4262 

The polycyclic aromatic hydrocarbons (PAHs) dibenzo[ a,l ]pyrene (DBP) and benzo[ a ]pyrene (BP) are widespread environmental contaminants and potent carcinogens. The fjord-region DBP is several orders of magnitude more mutagenic/carcinogenic than BP, a fact that can be ascribed to differences in DNA binding specificity/efficiency of their ultimate carcinogenic diol epoxide (DE) intermediates, differences in structural features of the DNA adducts and differences in DNA adduct recognition, repair and subsequent downstream signaling. Moreover, the acute toxicity of DBP far exceeds that of BP and similar PAHs. We have previously characterized the effect of the ultimate carcinogenic diol epoxides, (+)- anti -BPDE and (-)- anti -DBPDE following short exposure times, on Mdm2 and p53 pathways in A549 human lung epithelial carcinoma cells (G. Paajarvi et al., submitted for publication). We found that (+)- anti -BPDE induced stabilization and chromatin binding of Mdm2 phosphorylated at an antibody 2A10-specific epitope. These effects were transient and correlated with transient p53 Ser15 phosphorylation. In contrast DNA adducts of (-)- anti -DBPDE, which are more refractory to removal (Dreij et al., Chem. Res. Toxicol., 18, 655-664, 2005), were associated with lack of Mdm2 stabilization and chromatin binding, and sustained p53 Ser15. Furthermore, adducts of (-)- anti -DBPDE were associated with increased phosphorylation of p53 at Ser46, a phosphorylation site associated with apoptosis. We also concluded that depending on diol epoxide p53 Ser15 phosphorylation and antibody 2A10-site specific phosphorylation of Mdm2 are induced by non-identical signaling pathways. In this study we have exposed A549 cells to several DEs belonging to either the bay or fjord region category in order to see if the differential signaling pathways observed with (+)- anti -BPDE and (-)- anti -DBPDE can be extended to bay and fjord region DEs in general. The results available so far indicate significant response differences. The bay region DEs used here (derived from chrysene and dibenzo[ a,h ]anthracene) seem to induce transient Mdm2 stabilization and p53 Ser15 phosphorylation whereas the fjord region DEs (derived from benzo[ c ]- and benzo[ g ]chrysene, and benzo[ c ]phenanthrene) induce sustained p53 Ser15 phosphorylation and no apparent effect on Mdm2 stabilization. We interpret the results as reflecting differences in adduct regognition/repair efficiency and that this depends on well established differences in structural features of bay and fjord region DEs. As previously observed with (-)- anti -DBPDE, the fjord region DEs induce p53 Ser46 phosphorylation.
Breast sentinel lymphadenectomy—Is immediate intra-operative assessment warranted?
Authors: L. J. Tafe, G. J. Tsongalis, P. A. Kaufman, C. P. Moore, W. A. Wells
Journal: Journal of Clinical Oncology (2006)

10533 Background: Sentinel lymphadenectomy is the standard of care in breast cancer evaluation. Since conventional axillary dissection is only considered for patients (pts) with sentinel lymph node positive (SLN+) disease, there is increasing interest in immediate intra-operative assessment of SLN by frozen section or RT- PCR. Methods: Institutional SLN cases (2003–2004) were retrospectively reviewed. Each SLN (submitted in toto for processing with 21 tissue levels/block, H&amp;E staining, and cytokeratin (CK) immunostudies) was evaluated for tumor deposit size, distribution and extranodal extension. Results: 80% (n = 222) of pts had SLN biopsy: 50% at primary excision, 21% at mastectomy, 9% at re-excision and 20% as a separate procedure. 1–4 SLN were sampled in 41%, 25%, 19%, and 14% respectively with no node identified in 1 case. Of all, 31% (n = 68) had &gt;/=1 (+) node and 72% of those (n = 50) had a completion axillary dissection. 50% of pts required separate surgical procedure. Only 21% (n = 14) of pts with SLN+ had subsequent (+) axillary nodes on completion dissection. Nodal deposits ranged in size from &lt;/= 0.02 cm (13%) to &gt;2.0 cm (1%). The majority (26%) were in the micrometastasis range of &gt;0.02&lt;0.2 cm, where CK-immunostaining was useful to confirm detection. 19% were &gt;/=0.2&lt; 0.5 cm, 25% &gt;/= 0.5&lt;1.0 cm, and 15% &gt;/= 1.0&lt;2.0 cm. 3% SLN showed CK(+)-only cells without H&amp;E confirmation. Tumor sites were parenchymal (1%), subcapsular (31%), or both (68%). Only 7% of nodes with subcapsular metastases were associated with subsequent positive axillary nodes. In 91% (n = 62) of SLN+ cases, metastases were identified in the first 3 tissue levels. Extranodal extension was seen in 22%. Conclusions: Overall, 31% were SLN+; 21% of those were node + in subsequent axillary sampling. These findings do not support the labor and expense of immediate intraoperative SLN assessment. 3-level tissue processing with simultaneous RT-PCR could be performed on all SLN. Subsequent tissue leveling and immunostaining could potentially only be performed on PCR+ cases to provide metastasis size and extranodal extension. PCR probes can also facilitate detection of novel prognostic markers. Additionally, identification of only subcapsular deposits may warrant foregoing subsequent axillary sampling in some clinical scenarios. No significant financial relationships to disclose.
Economic consequences of molecular profiling for metastatic solid tumors.
Authors: Andrew Peter Dean, Mira Marinova, Ingrid Hayden, Ashling Byrne
Journal: Journal of Clinical Oncology (2014)

e17548 Background: Molecular profiling (MP) is swiftly gaining momentum as a useful technique for guiding therapy of solid tumors. Technological advances provide increasing numbers of biomarker/drug associations with a 2013 report (von Hoff) showing an average of 27 profiled targets per tumor in an incredible series of 35,000 solid tumors, although clinicians fear that potential therapies identified this way may be prohibitively expensive. This is the first study to directly assess the economic implications of MP guided therapy. Methods: 50 consecutive patients with solid tumors were profiled with Caris Molecular Intelligence at our institution. Response to and costs of MP guided therapy were gathered prospectively. Results: 10 patients with rare tumors had 169 targets for 128 drugs identified - 64 predicted clinical benefit and 105 lack of benefit. 8 patients (80%) responded to MP guided therapy. High cost biological therapy was suggested in only 1 case - sunitinib for leiomyosarcoma which was down staged for successful curative surgery. Of 40 heavily pretreated patients, 636 targets were identified, 253 favorable (for 350 drugs) - 20 patients (50%) derived clinical benefit from MP guided treatment. Only 2 of these showed favorable profiles for high cost biological therapy. One patient with metastatic squamous cell carcinoma of cervix demonstrated a complete response to sunitinib and another benefited from trastuzumab plus erlotinib for adenocarcinoma of pancreas. The vast majority of treatments suggested were common off patent chemotherapy drugs available in low cost generic versions. Conclusions: In economically challenging times, MP appears to offer a favorable cost benefit ratio identifying 6 beneficial drugs per patient for both rare tumors and heavily pretreated cases. Very high response rates with low cost drugs were seen in rare tumors and a surprisingly good response rate was recorded in heavily pretreated cases. This study suggests that reservations that MP guided therapy is expensive are unfounded.
Genetic variations in cytarabine pathway genes as determinants of outcome in acute myeloid leukemia.
Authors: Jatinder Kaur Lamba, Stanley Pounds, Xueyuan Cao, Kristine Radomski Crews, Susana Raimondi, Dario Campana, Sharyn D. Baker, Raul Correa Ribeiro, Jeffrey E. Rubnitz
Journal: Journal of Clinical Oncology (2013)

10005 Background: Cytarabine (ara-C), a key component of AML therapy, is a prodrug that requires activation to ara-CTP, which inhibits DNA/RNA synthesis and triggers leukemic cell death. Thus, cellular pathways involved in ara-CTP metabolism and/or cell death are likely to influence treatment response. Methods: In the present study, we used a pathway-directed approach to identify the genetic predictors of ara-C response in 187 pediatric patients enrolled in the St. Jude AML02 trial. Patients were randomized to receive the first course of remission induction therapy containing either high- or low-dose ara-C, combined with daunorubicin and etoposide. SNPs in 14 key ara-C pathway genes were genotyped and screened for association with multiple endpoints, such as in vitro ara-C LC50 in diagnostic leukemic cells, minimal residual disease levels (MRD), event-free survival (EFS), overall survival (OS), and rate of relapse. Because AML is a very heterogeneous disease with multiple clinical, cytogenetic, and molecular features that are associated with response, we also evaluated SNPs in ara-C PK genes in the context of prognostic factors of proven clinical utility. Results: Ara-C pathway SNPs were significantly associated with clinical outcome. Known variables such as treatment, core-binding factor leukemia, MRD after one course of therapy, age at diagnosis, 11q23 rearrangements, megakaryoblastic leukemia without t(1;22), and FLT3-ITD accounted for 18.7% of variability in EFS. Additional variation in EFS could be explained by individual SNPs or a combination of SNPs within ara-C pathway genes. For instance, our analysis showed that incorporation of a DCTD SNP into existing model could enhance the percent total variation in EFS explained from 18.7% to 22.9%. Inclusion of all DCTD SNPs in the model increased the percent total variation in EFS explained from 18.7% to 29.7% Conclusions: Overall our results indicate that genetic variation in the ara-C pathway genes had a prognostic relevance that was similar to that of well-known factors. Understanding this variation can provide additional insights into the factors influencing treatment response and could lead to the identification of new prognostic markers.
Randomized phase III trial of busulfan plus melphalan versus melphalan alone for multiple myeloma.
Authors: Muzaffar H. Qazilbash, Peter F. Thall, Patricia S Fox, Partow Kebriaei, Qaiser Bashir, Nina Shah, Borje Andersson, Yago Nieto, Ben Valdez, Simrit Parmar, Yvonne Dinh, Chitra Hosing, Uday R. Popat, Jatin J. Shah, Robert Z. Orlowski, Richard E. Champlin
Journal: Journal of Clinical Oncology (2014)

8538 Background: High-dose melphalan at 200 mg/m2 (Mel) is the standard for autologous hematopoietic stem cell transplantation (auto-HCT) for multiple myeloma. Two recent retrospective analyses suggested that a combination of busulfan and melphalan (Bu-Mel) may be associated with a longer progression-free survival (PFS). In this randomized phase III trial we compared the safety and efficacy of Bu-Mel vs. Mel. Methods: Patients were randomized to either Bu-Mel or Mel. In the Bu-Mel arm, Bu 130 mg/m2 was infused daily for 4 days, either as a fixed dose, or to target an average daily area under the curve of 5000 μmol-min, followed by 2 daily doses of Mel at 70 mg/m2. The primary endpoint was day +90 CR (IMWG criteria) rate. Secondary endpoints were 100-day treatment-related mortality (TRM) and grade 3-4 non-hematologic toxicity. Log-rank test was used to compare PFS and OS by treatment arm. Results: Ninety-two patients (Bu-Mel: 49, Mel: 43) were enrolled between October 2011 and August 2013. Median ages at auto-HCT were 58.4 and 58.5 years in Bu-Mel and Mel arms, respectively (p=0.75). Ten (20%) and 11 (26%) patients had high-risk chromosomal abnormalities in Bu-Mel vs. Mel, respectively (p=0.62). Forty-four (90%) and 40 (93%) patients received bortezomib-based induction therapy in the Bu-Mel and Mel, respectively (p=0.71). At the time of auto-HCT, 8/0 (18%) and 7/3 (23%) patients were in CR/near (n)CR in Bu-Mel and Mel arms, respectively (p=0.44), Grade 3-4 non-hematologic toxicity was seen in 41 (84%) and 20 (47%) patients in Bu-Mel and Mel, respectively (p=0.0003). There was no 100-day TRM in either arm. At day 90, 8 (18%) and 15 (35%) patients had achieved a CR (p=0.05), and 13 (27%) and 20 (47%) patients had achieved a CR + nCR (p=0.05) in Bu-Mel and Mel, respectively. All 49 patients in Bu-Mel and 43 in Mel had started maintenance therapy after day 90. Median follow up was 11.7 months (range 0.7-24.6), One-year PFS was 93% and 82% (p=0.26), and 1-year OS was 100% and 100% in Bu-Mel and Mel arms, respectively. Conclusions: Bu-Mel was associated with a significantly lower day 90 CR rate and a significantly higher rate of grade 3-4 non-hematologic toxicity, compared to Mel. A longer follow up is needed to evaluate the impact of Bu-Mel on PFS. Clinical trial information: NCT01413178.
Patients with metastatic renal cell carcinoma who have benefit from axitinib dose titration: Analysis from a randomized, double-blind, axitinib dose titration phase II study.
Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, A H. Bair, Brian I. Rini
Journal: Journal of Clinical Oncology (2017)

438 Background: Axitinib is a potent, selective inhibitor of VEGF receptors. In a randomized, double-blind, phase II study in patients with metastatic renal cell carcinoma, median overall survival (OS) was 42.7 months who underwent axitinib titration versus (vs.) 30.4 months in placebo titration (hazard ratio [HR]: 0.785; 95% confidence interval: 0.485, 1.272). OS Kaplan-Meier curves for two arms appeared to cross over at approximately 24 months and thus we investigated baseline characteristics associated with OS benefit from axitinib titration. Methods: Patients received axitinib 5 mg twice daily (BID) for 28 days. Patients who met the dose titration criteria were randomized 1:1 to axitinib titration or placebo titration. Patients who did not meet the dose titration criteria continued axitinib 5 mg BID. Baseline characteristics were compared between patients with OS ≥ 24 and &lt; 24 months who were randomized to axitinib titration and subsequently, multivariate analysis for baseline characteristics was conducted to investigate effect of interaction with axitinib titration. Results: Fifty-six patients underwent axitinib titration with 53 evaluable for this analysis. Thirty-three patients had an OS ≥ 24 months and had significantly fewer metastatic sites (≤2, ≥3: 52/48% vs. 10/90%), compared to the 20 patients with OS &lt; 24 months. In addition, a lower percentage of patients with OS ≥ 24 months had lymph node metastasis (45 vs. 75%), liver metastasis (15 vs. 45%), duration from diagnosis to treatment &lt;1 year (36 vs. 85%), and baseline hemoglobin (Hb) &lt; LLN (lower limit of normal) (33 vs. 75%), compared to the patients with OS &lt; 24 months. In multivariate analysis in total of 112 patients who were randomized to axitinib or placebo titration, duration from diagnosis and baseline Hb were significantly associated with favorable OS with axitinib titration (p&lt;0.1). Conclusions: Duration from diagnosis and baseline Hb are associated with favorable OS with axitinib titration. Clinical trial information: NCT00835978.
Does gabapentin prevent delayed chemotherapy-induced nausea and vomiting (N/V)? Results of a randomized placebo controlled trial, NCCTG N08C3 (Alliance).
Authors: Debra L. Barton, Jeff A. Sloan, Paul J Novotny, Jyotsna Fuloria, Lisa A. Kottschade, Alan P. Lyss, Anthony John Jaslowski, Miroslaw Mazurczak, Scott Cameron Blair, Shelby A. Terstriep, Charles L. Loprinzi
Journal: Journal of Clinical Oncology (2013)

9513 Background: The need for more research in N/V control is exemplified by agents that are costly, interfere with cytochrome P450 metabolism, and inadequately address delayed N/V. Based on pilot data, there was justification for evaluating whether gabapentin could improve the prevention of delayed N/V from highly emetogenic chemotherapy (HEC). Methods: Patients (pts) about to receive HEC were randomized to prophylactic treatment with 20 mg of dexamethasone (dex) and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by either gabapentin (gaba) 300 mg BID and dex or placebo (plac) and dex. Gaba/plac was started the evening of the day of chemotherapy and continued through day 5 of the first chemotherapy cycle. Dex was given at 8 mg BID days 2-3, then 4 mg BID for day 4, in both arms. The primary endpoint was complete response (CR), defined as no emesis and no rescue medications day 2-6, using a nausea and vomiting diary. The percent of CR were compared in each group by Fisher’s exact test. Secondary outcomes included the Functional Living Index-Emesis (FLIE), satisfaction, and a side effect questionnaire. Results: 430 pts were enrolled in this study between 5/2009 and 2/2011. 47% of pts in the gaba arm and 41% in the plac arm had a CR (p=.23). At some time during days 2-6, 30% in the gaba and plac arms experienced emesis, and 45% and 53% in the gaba and plac arms, respectively, took rescue medication. Mean diary nausea scores over days 2-6 ranged from 0.9 – 1.2 (gaba arm) and 1.0-1.3 (plac arm)(7 = the worst); mean number of diary emetic episodes ranged from 0.1 -0.3 (gaba arm) and 0.1-0.2 (plac arm). The FLIE was not significantly different between arms. Mean vomiting satisfaction was 9.1 in both arms and for nausea was 8.3 for gaba, 8.1 for plac (10= totally satisfied). There were no significant differences in toxicities by CTCAE provider grading or by self-report. Conclusions: In this study, gaba did not improve delayed N/V. Overall, there was little emesis and nausea severity was low. Patients were satisfied with the control of their N/V, irrespective of arm. The use of standard prophylactic guidelines that include a 5HT3RA and dex provided good control of N/V for most patients. Clinical trial information: NCT00880191.
Phase I trial of pomalidomide (P) in patients (pts) with relapsed and/or refractory (R/R) Waldenström's macroglobulinemia (WM).
Authors: Sheeba K. Thomas, A. Georgina Melendez, Lei Feng, Michael Wang, Sattva Swarup Neelapu, Jatin J. Shah, Robert Z. Orlowski, Donna M. Weber
Journal: Journal of Clinical Oncology (2014)

8536 Background: Thalidomide, and its analog, lenalidomide have shown activity in WM, when combined with rituximab. However, neuropathy and anemia respectively, have limited their use. P is a newer generation IMID® which has demonstrated efficacy and tolerability in R/R multiple myeloma. These results provided the rationale for a phase I study of P in pts with R/R WM. Methods: Eligible pts had WM that was R/R to ≥ 1 prior therapy. All pts received daily oral P (28d cycles), starting at a 1mg dose level. Following a 3+3 statistical design, the dose was increased by 1 mg increments until the MTD was reached. Overall response was assessed as per International WM Working Group Response Criteria. Results: Between 10/2010-01/2014, 9 pts (7 males, 2 females) were treated. Median age at enrollment was 64 yrs (range 51-85), median time from 1st therapy was 6.1 yrs (range 2.0-16.3), and median prior therapies was 2 (range 1-5). With a median f/u of 30 mos. (range: 6-36), 8 pts remain alive, and 1 continues to receive therapy. At 1 mg, no DLTs were seen, and pts received a median of 6 cycles (range: 4-12+). At 2 mg, 2 pts experienced DLTs, including dizziness (Gr 4) and syncope (Gr 3) in 1 pt and grade 4 neutropenia in 1 pt. A 3rdpt withdrew after experiencing mild fever, headaches and blurred vision starting on day 4 of cycle 1. Fever and headache resolved with stopping P; blurred vision resolved after plasma exchange. Other grade 3-4 adverse events (AEs) included neutropenia (3 pts) and infection (knee joint, 1 pt). Gr 1-2 AEs include fatigue (6), rash (5), diarrhea (4), nausea/emesis (4), edema (3), myalgias (3), blurred vision (2), peripheral neuropathy (2), dyspnea (2), constipation (2), headache (2), dizziness (2), mucositis (1), infection [otitis media (1);URI –(3)], rash(1), pruritus (1), and night sweats (1). Among 8 evaluable pts, 2 had minor responses, 3 had stable disease (SD), and 3 had progressive disease as best response. Conclusions: The MTD of single agent P is 1 mg/day in pts with R/R WM. P provided ≥ SD in 63% of pts, suggesting that combinations with other effective agents should be studied. Abbreviated dosing schedules, such as d1-21 q28d may permit recovery of cytopenias between cycles, facilitating such combinations. Clinical trial information: NCT01198067.
Social media use amongst oncologists: Results of a national physician survey.
Authors: Rachel Adilman, Yanchini Rajmohan, Martina Trinkaus, Caroline Chung, Madiha Naseem, Nazik Hammad, Robyn Leonard, Gloria Roldan Urgoiti, Edward Brooks, Zia Poonja, Christine E. Simmons
Journal: Journal of Clinical Oncology (2014)

e17519 Background: Cancer care requires coordinated and efficient communication from many healthcare providers. Web-based social media has the potential to improve cancer care by facilitating physician collaboration, knowledge dissemination, and online support for clinical and professional development purposes. However, the current extent to which physicians use social media and their social networking goals remain unknown. This study aimed to identify patterns of social media use among medical professionals involved in cancer care in Canada. Methods: A 9-item survey investigating social media use was designed using anonymous online survey software and distributed via email to 680 oncologists, residents, and medical students in Canada. Physician demographics and patterns of social media use were assessed. Responses were analyzed using descriptive statistics. Results: Of 680 surveys sent 207 responses (30%) were received. 72% of respondents reported that they use social media. Social media use was varied significantly by age cohort, (see table). Most notably, there was a significant difference in the use of social media between those aged 18-34 and those aged 45-54, (91% vs 39%, p < 0.001). Most respondents indicated using Facebook and Twitter for personal use only, while using ASCO Connection, LinkedIn, OncologyEducation, and WinC/AlinC for professional purposes. For all websites in question, the majority of respondents reported using the sites