tbuckley/cabot-search huggingface dataset:
Factors predicting endoxifen levels in breast cancer patients taking standard-dose tamoxifen and following dose escalation.
Authors: Peter Fox, Bo Gao, Bavanthi Balakrishnar, Alexander M Menzies, Shang Heng Yeap, Sayed Sahanawaz Ali, Val Gebski, Pamela Provan, Sally Coulter, Christopher Liddle, Rina Hui, Richard Kefford, Jodi Lynch, Nicholas Wilcken, Rosemary L Balleine, Howard Gurney
Journal: Journal of Clinical Oncology (2013)

543 Background: Tamoxifen (TAM) is transformed via CYP2D6 to its major active metabolite endoxifen (Endox). Recent data suggest that 15nM Endox may be a therapeutic threshold for breast cancer . This study identified predictors of achieving specified Endox target levels (15nM and 30nM) on standard dose TAM, and following dose escalation. Methods: Baseline Endox was measured in 122 breast cancer pts on TAM 20mg pd. Pts with baseline Endox &lt;30nM underwent incremental dose escalation to a maximum of 60mg pd until Endox reached 30nM or dose limiting toxicity. Clinical data were collected and CYP2D6 genotype was used to specify extensive, intermediate or poor metabolizer categories (EM, IM, PM). Multiple regression analyses examined associations between Endox and potential predictive factors. Results: Baseline Endox ranged from 3.1-72.2nM (mean 27.6nM). In 19% (n=23), baseline Endox was below 15nM and 62% (n=76) were below 30nM. Low baseline Endox was associated with CYP2D6 genotype (IM or PM, p&lt;0.001) and younger age (p=0.02). Following dose escalation, 96% (n=117) attained an Endox level of 15nM and 76% (n=93) reached 30nM. Baseline Endox level was the only variable independently associated with achieving both targets (p=0.02, p&lt;0.001 respectively). CYP2D6 genotype did not independently predict attainment of Endox targets following dose escalation (p&gt;0.4). The ratio of Endox to its precursor N-desmethylTAM, an indicator of CYP2D6 activity, was stable with dose escalation, suggesting that CYP2D6 was not saturated. Conclusions: Although IM/PM predict for low Endox on 20mg TAM, only low baseline Endox predicted failure to achieve both 15nM and 30nM targets following dose escalation. These results suggest a role for Endox level monitoring to determine optimal TAM dose. Clinical trial information: NCT01075802. [Table: see text]
Prevalence of low-penetrance KRAS (codons 12/13 and 61) and BRAF mutations in metastatic colorectal carcinoma.
Authors: Federico Rojo, Trinidad Caldes, Sandra Zazo, Miguel de la Hoya, Cristina Carames, Atocha Romero, Gloria Serrano, Inmaculada Bando, Ana Leon, Javier Sastre, Jose Ignacio Martin-Valades, Lourdes Cillero, Angel Campos, Belen Gavina, Alberto Lendinez, Cristina Bausela, Dolores Ferrandez, Teresa Ramos, Jesus Garcia-Foncillas, Eduardo Diaz-Rubio
Journal: Journal of Clinical Oncology (2012)

e14147 Background: In patients with metastatic colorectal cancer (mCRC), activating mutations within KRAS, which result in EGFR-independent intracellular signal transduction activation, are found in approximately 35-40% of patients with mCRC have been significantly associated with lack of response to cetuximab or panitumumab therapy. Although current guidelines recommend testing for frequent KRAS codons 12/13 mutations, emerging data indicate that additional KRAS and BRAF mutations are also predictive of non-responsiveness to anti-EGFR antibodies in mCRC. This study is aimed to analyze the prevalence of low-penetrance KRAS and BRAF V600 mutations in caucasian mCRC population. Methods: A two-institution retrospective cohort of 1,238 consecutive KRAS wild type mCRC patients previously studied for 7 mutations in codons 12/13 (G12D, G12A, G12V, G12S, G12R, G12C and G13D) by the CE-IVD marked ARMS-scorpion real-time polymerase chain reaction PCR (Therascreen, Qiagen) was assayed by the diagnostic TaqMelt PCR assay cobas KRAS mutation and cobas BRAF V600 mutation tests (Roche), which are designed to detect 19 mutations in KRAS codons 12, 13 and 61 (including G12F, G13C, G13R, G13S, G13A, G13V, G13I, Q61H, Q61K, Q61R, Q61L, Q61E and Q61P) and BRAF V600 (V600E, V600K and V600D) mutations. An additional cohort of 146 KRAS mutated patients by ARMS-scorpion PCR was studied. DNA was obtained by cobas DNA preparation kit from one single 5µm formalin-fixed paraffin-embedded tissue section. Results: In all samples, sufficient DNA was obtained for KRAS and BRAF mutational studies. Among 1238 KRAS codons 12/13 wild-type patients by ARMS-scorpion PCR,166 (13.4%) showed KRAS mutations, 117 (9.5%) in codons 12/13, and 49 (4%) in codon 61. BRAF V600 mutations were detected in 9% cases. In ARMS-scorpion PCR KRAS mutated patients, mutations were confirmed by cobas in all cases. Conclusions: The cobas mutation tests are robust and reproducible assays that, 1) detects a higher incidence (13.4%) of mutations in codons 12, 13, and 61 of the KRAS gene in wild-type mCRC population, 2) a relevant rate of BRAF mutations is present in the same population, and 3) requires a very small amount of tissue.
The effects of short‐term omission of daily medication on the pathophysiology of heart failure
Authors: Silviu Dovancescu, Pierpaolo Pellicori, Thato Mabote, Azam Torabi, Andrew L. Clark, John G.F. Cleland
Journal: European Journal of Heart Failure (2017)

Abstract Aims Pharmacological therapies for heart failure ( HF ) aim to improve congestion, symptoms, and prognosis. Failing to take medication is a potential cause of worsening HF . Characterizing the effects of short‐term medication omission could inform the development of better technologies and strategies to detect and interpret the reasons for worsening HF . We examined the effect of planned HF medication omission for 48 h on weight, echocardiograms, transthoracic bio‐impedance, and plasma concentrations of NT‐proBNP . Methods and results Outpatients with stable HF and an LVEF &lt;45% were assigned to take or omit their HF medication for 48 h in a randomized, crossover trial. Twenty patients (16 men, LVEF 32 ± 9%, median NT‐proBNP 962 ng/L) were included. Compared with regular medication, omission led to an increase in NT‐proBNP by 99% (from 962 to 1883 ng/L, P &lt; 0.001), systolic blood pressure by 16% (from 131 to 152 mmHg , P &lt; 0.001), and left atrial volume by 21% (from 69 to 80 mL , P = 0.001), and reductions in transthoracic bio‐impedance by 10% (from 33 to 30 Σ, P = 0.001) and serum creatinine by 8% (from 135 to 118 µmol/L, P = 0.012). No significant changes in body weight, heart rate, or LVEF were observed. Conclusions The characteristic pattern of response to short‐term medication omission is of increasing congestion but, in contrast to the pattern reported for disease progression, with a rise in blood pressure and improved renal function. In stable HF , weight is not a sensitive marker of short‐term diuretic omission.
Two-stage hepatectomy for colorectal liver metastases: A multi-institutional retrospective review.
Authors: Nicholas G Berger, Bradford Kim, Sepideh Gholami, Georgios A Margonis, Cecilia Ethun, Jack P Silva, Susan Tsai, Kathleen K. Christians, Harveshp Mogal, Callisia Clarke, Shishir Kumar Maithel, Timothy Pawlik, Michael Ian D'Angelica, Thomas A. Aloia, T. Clark Gamblin
Journal: Journal of Clinical Oncology (2017)

351 Background: A significant number of patients with colorectal liver metastases (CRLM) present with unresectable bilobar disease. Two-stage hepatectomy with portal vein embolization (PVE) have been described as a treatment for CRLM allowing for volume regeneration of a functional liver remnant. No large-scale multi-institutional studies exist. The aim of this project was to describe outcomes following two-stage hepatectomy, including overall survival (OS), recurrence-free survival (RFS), and complications. Methods: Patients completing two-stage hepatectomy for CRLM at five US institutions were identified and retrospectively analyzed (2000-2015). Overall survival and recurrence-free survival following second-stage surgery, short-term mortality, Clavien-Dindo complications, and readmission rates were examined. Results: A total of 209 patients were identified. Mean age was 52 (SD +/-11.4), 59.8% were male, and 87.0% had synchronous disease. A total of 65.1% of patients underwent PVE, and 27.3% underwent hepatic artery infusion pump placement. 88.3% of cases underwent neoadjuvant chemotherapy. Following the first stage, 30-day morbidity was 24.4%, with 4.8% major (Clavien-Dindo grade ≥3) complications, and 30-day readmission was 6.7%. Mean time between first and second stage was 4.1 months (S.D. +/-3.1), and 57.5% received systemic chemotherapy between the two resections. Following the second stage, overall complications were 47.4% with 23.9% major complications, and 30-day readmission was 9.7%. Mortality following second stage was 3.8% at 30 days, and 5.3% at 90-days. Following the second stage, RFS at 1-, 3-, and 5-years was 80%, 46%, and 29% respectively. OS at 1-, 3-, and 5-years was 87%, 64%, and 45% respectively. Conclusions: Two-stage hepatectomy for CRLM provides acceptable recurrence-free and overall survival in the context of advanced bilobar disease. Major complications and readmission following the first stage are rare. Following the second stage, short-term major morbidity, mortality, and readmissions are also acceptable. For well-selected patients, two-stage hepatectomy remains a safe and effective treatment for CRLM, with potential for more widespread adoption.
Phase I/II study of the TLR3 agonist poly-ICLC as an adjuvant for NY-ESO-1 protein vaccination with or without Montanide ISA-51 vg in patients with melanoma.
Authors: Rachel Lubong Sabado, Anna C. Pavlick, Sacha Gnjatic, Patrick Alexander Ott, Farah Hasan, Meredith Spadaccia, Isabelita Vengco, Rose Marie Holman, Caroline Muren, Crystal Escano, Ethel Yepes, Claire Stein, Achim A Jungbluth, Linda S. Pan, Ralph Rudolph Venhaus, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2014)

TPS9119 Background: Poly-ICLC is a synthetic dsRNA complex which directly activates DCs and also triggers NK cells to kill tumor cells. Compared to LPS and R848, Poly-ICLC is the most potent TLR adjuvant due to its induction of cytokines such as IL-12 in the absence of IL-10, and maintenance of high levels of CD80 and CD86 in DCs. This study assessed the therapeutic potential of TLR3 activation by adding Poly-ICLC to a NY-ESO-1 protein vaccine with and without Montanide in surgically resected stage IIB-IV melanoma patients. Methods: In Phase I of the study, patients received subcutaneous injection of 100μg NY-ESO-1 protein and 1.1mL Montanide emulsified in escalating doses of Poly-ICLC: 0.35mg (cohort 1; N=3), 0.70mg (cohort 2; N=3), or 1.4mg (cohort 3; N=3). The cycles of vaccination were repeated every 3 weeks for a total of 4 cycles. In Phase II of the study, patients were randomized to subcutaneous vaccination of 100μg NY-ESO-1 protein with 1.4 mg Poly-ICLC, the dose established in the Phase I of the study, (Arm A; N=12) or with 100μg NY-ESO-1 protein, 1.4mg Poly-ICLC and 1.1ml Montanide (Arm B; N=12). The cycles of vaccination were repeated every 3 weeks for a total of 4 cycles. Blood samples were collected at baseline, one week after each cycle of vaccination, and at follow-up visit for the assessment of NY-ESO-1-specific humoral and cellular immune responses. Clinical trial information: NCT01079741.
Is PET-CT guided management for patients with locally advanced head and neck squamous cell cancer (HNSCC) cost-effective? Results from a UK non-inferiority phase III randomized trial.
Authors: Alison Florence Smith, Peter Hall, Claire Hulme, Janet Dunn, Joy K Rahman, Christopher C McConkey, Hisham Mehanna
Journal: Journal of Clinical Oncology (2015)

6010 Title: Despite ongoing controversy, planned node dissection (ND) remains a common treatment strategy after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with HNSCC. Accurate detection of persistent disease using combined Positron Emission and Computerised Tomography (PET-CT) could reduce unnecessary and expensive node dissections (ND) in low-risk patients and potentially improve overall outcomes. Methods: 564 patients with N2/N3 oropharyngeal, laryngeal, oral, hypopharyngeal or occult HNSCC were randomized (1:1) to receive either planned ND (before or after CRT), or PET-CT surveillance (CRT followed by PET-CT, with ND administered if incomplete response in the neck nodes). To accurately inform reimbursement decisions, individual patient data from the trial was used to assess within-trial (2-year) cost-effectiveness of PET-CT surveillance versus planned ND from an NHS secondary care perspective. Health benefit was measured using quality-adjusted life-years (QALYs) and costs are reported in 2015 GBP. Probabilistic analysis was conducted using bootstrap methods. Results: PET-CT surveillance was cost-effective over the trial period, producing an average per-person cost saving of £1,415 (95% CI: -607 to -2,218) and a health gain of 0.07 QALYs (95% CI: -0.04 to 0.19) compared to planned ND. The average cost was £12,127 (95% CI: 11,601 to 12,686) for PET-CT surveillance vs. £13,542 (95% CI: 12,968 to 14,131) for planned ND; the average QALYs were 1.26 (95% CI: 1.18 to 1.34) vs. 1.19 (95% CI: 1.10 to 1.27). At a £20,000 per QALY threshold, the probability that PET-CT was the cheapest, most effective and most cost-effective strategy was 99%, 91%, and 98%, respectively. Expanding the analysis to include additional NHS, personal social services and societal costs increased the expected costs for each arm but did not alter the overall cost-effectiveness of PET-CT surveillance. Conclusions: Results of the economic evaluation indicate that PET-CT surveillance is cost-effective over a short time horizon. Clinical trial information: NCT00720070.
Defining the immunologic phenotype of thymic epithelial tumors.
Authors: Jarushka Naidoo, Keith Steele, Camelia S. Sima, Jianda Yuan, Paul B. Robbins, Andre L. Moreira, Maria Catherine Pietanza, Jedd D. Wolchok, Gregory J. Riely, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2015)

7516 Background: Thymic epithelial tumors (TETs) are associated with immune dysfunction and are poorly responsive to conventional therapies. We aimed to characterize the immune microenvironment in TETs, to identify potential targets for immunotherapy. Methods: Tumor tissue from 24 TETS was identified. Tumor-infiltrating lymphocytes (TILs: CD3+ and CD8+ T-cells), PD-L1 expression on tumor cells (antibody: E1L3N), and a panel of co-stimulatory (CD137, GITR, OX40, ICOS) and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) on immune cells, was investigated by immunohistochemistry. PD-L1 positivity was defined as ≥ 25% of tumor cells with positive membranous staining. TILs and immune cell checkpoint molecule staining were semi-quantitatively scored as: low = 0-1, high = 2-3. Associations between clinicopathologic factors, immune checkpoint molecule expression and TILs, was evaluated. Overall survival (OS) was measured from the time of cancer diagnosis, assuming that immune markers do not change throughout the course of disease. Data was analyzed using Fisher’s exact, Wilcoxon rank sum and log-rank tests, and Cox proportional hazards model. Results: Tumor tissue from B2/B3 thymomas (n = 12) and thymic carcinomas (n = 12) was evaluated. CD8+ TILs was seen in all tumors. Sixty-three percent of TETs (n = 15/24) were PD-L1+. PD-L1 positivity was more common in thymomas than thymic carcinomas (11/12 vs. 4/12, p < 0.01). When analyzed as a continuous variable, PD-L1 expression had an inverse correlation with risk of death (p = 0.02). Eighteen pts with TETs (n = 18/24, 75%) had high TIM-3 expression. Two immunologic parameters correlated with improved OS: PD-L1+ tumor cells (p < 0.01) and high TIM-3 expression (p = 0.01). There was a positive correlation between PD-L1+ tumor cells and CD8+ T-cells (p = 0.02), PD-L1+ tumor cells and high TIM-3 expression (p = 0.03), CD8+ T-cells and high TIM-3 expression (p = 0.03). Conclusions: TETs possess a robust TIL infiltrate. The majority of tumors have high expression of the co-inhibitory checkpoint molecule TIM-3, and are PD-L1+. These parameters may correlate with OS. These data support the immunotherapeutic targeting of the PD-1/PD-L1 and TIM-3 pathways in patients with TETs.
Phase II study of lapatinib in combination with vinorelbine, as first- or second-line therapy in women with HER2-overexpressing metastatic breast cancer.
Authors: Helen K. Chew, Lee Steven Schwartzberg, Suprith Badarinath, Peter Rubin, Grace Shumaker, James P. Daugherty, Michelle DeSilvio, Janine M. Mahoney
Journal: Journal of Clinical Oncology (2013)

621 Background: Lapatinib (L), an inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) is approved in combination with capecitabine for second-line treatment of HER2+ metastatic breast cancer (MBC). Vinorelbine (V)is a semi-synthetic vinca alkaloid approved for use in patients (pts) with MBC. A previous phase I trial provided a maximum tolerated dose of L plus V. Methods: This was a multicenter, phase II study (LPT111110; NCT00709618) to evaluate the efficacy and safety of L plus V in women with histologically confirmed stage IV HER2+ MBC, ≤1 prior chemotherapeutic regimen (no prior L or V was allowed; prior trastuzumab was permitted) and a Zubrod performance status of 0-2. Pts received L (1500 mg daily) plus V (20 mg/m 2 IV on Days 1, 8, 15) in a 4-week treatment cycle until disease progression or study withdrawal. Primary endpoint: overall response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival, time to response (TTR), duration of response (DOR), time to progression, and safety assessments. Results: The study was terminated after three years due to slow enrollment; 60 pts were planned and 44 enrolled and were treated. The ORR was 41% (95% CI: 26.4%-55.4%; 4 complete responses, 14 partial responses). Investigator-assessed median (95% CI) PFS, TTR, and DOR were 24.1 (16.9-36.7), 7.5 (7.1–8.1), and 32.0 (18.0-42.3) weeks, respectively. Survival data are not available since data collection was terminated after discontinuation of study treatment. All pts experienced at least 1 adverse event (AE). Conclusions: The combination of L plus V resulted in a 41% ORR and was generally well tolerated. However, definitive conclusions could not be drawn as the study was terminated early and not powered for inference testing. Further exploration of L plus V is warranted to clearly define the role of this novel combination in the treatment of HER2+ MBC. Clinical trial information: NCT00709618. [Table: see text]
The mTOR Inhibitor, RAD001, Inhibits the Growth of Cells From Patients with Myeloproliferative Neoplasms.
Authors: Alessandro M. Vannucchi, Costanza Bogani, Niccolò Bartalucci, Paola Guglielmelli, Lorenzo Tozzi, Elisabetta Antonioli, Lisa Pieri, Alberto Bosi
Journal: Blood (2009)
A New Sign of Intracerebral Hematoma Expansion
Authors: Zhi-Wei Xia, Quan Cheng, Jing Li
Journal: JAMA Neurology (2017)

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Breast cancer patients stratification by microarray-based gene expression profiling from FFPET samples
Authors: C. Lih, Y. Li, L. Trinh, S. Chien, X. Wu, W. Liu, P. M. Williams
Journal: Journal of Clinical Oncology (2009)

e22041 Background: Microarrays have been used to monitor global genes expression and have aided the identification of novel biomarkers for patients stratification and drug response prediction . To date there has been limited application of microarray- based gene expression analysis to formalin fixed paraffin embedded tissues (FFPET). FFPE tissues are the most commonly available clinical samples with documented clinical information for retrospective clinical analysis. However, FFPET RNA has proven to be an obstacle for microarray analysis because of low yield and compromised RNA integrity. Methods: Using a novel RNA amplification method, Single Primer Isothermal Amplification (SPIA, NuGEN Inc, San Carlos, CA), we amplified FFPET RNA, hybridized amplified, and labeled cDNA onto Affymetrix HG U133plus2 GeneChips. Results: We found that SPIA amplification successfully overcomes the problems of poor quality of FFPET RNA, and produced informative biological data. Comparing the gene expression data from 5 different types of FFPET archival cancer samples (breast, lung, ovarian, colon, and melanoma), we demonstrated that gene expression signatures clearly distinguish the tissue of origin. Further, from an analysis of 91 FFPET samples comprised of ER+, HER2+, triple negative breast cancer patients, and normal breast tissue, we have identified a 103 gene signature that distinguishes the intrinsic sub-types of breast cancer. Finally, the accuracy of gene expression measured by microarray was verified by real time PCR quantitation of the ERBB2 gene, resulting in a significant correlation (R = 0.88). Conclusions: We have demonstrated the feasibility of global gene expression profiling using RNA extracted from FFPET and have shown that a gene expression signature can stratify patient samples into different subtypes of disease. This study paves the way to identify novel molecular biomarkers for disease stratification and therapy response from archival FFPET samples, leading to the goals of personalized medicine. No significant financial relationships to disclose.