tbuckley/cabot-search huggingface dataset:
Development of novel metastatic prostate cancer cell lines by “organoid” in vitro culture technology.
Authors: Ian Vela, Dong Gao, Anuradha Gopalan, Andrea Sboner, Eva Undvall, Jackline Wanjala, Phillip Iaquinta, John Wongvipat, Wouter Karthaus, Hans Clevers, Stephen Barnett Solomon, Himisha Beltran, Myriam Kossai, Juan Miguel Mosquera, Mark A. Rubin, Brett Stewart Carver, Howard I. Scher, Charles L. Sawyers, Yu Chen
Journal: Journal of Clinical Oncology (2014)

33 Background: The inability to propagate patient-derived prostate cancer cells in vitro is a major impediment in the mechanistic understanding of tumorigenesis and therapeutic response. In order to generate accurate in vitro models that represent the diversity of in situ prostate cancer, we have developed a three-dimensional “organoid” system to culture metastasis samples and integrated it into our precision medicine workflow of attaining and characterizing pre-treatment biopsies. Methods: Biopsy samples of prostate cancer metastases, both soft tissue and bone, acquired at the time of therapeutic or diagnostic interventions following informed consent and institutional review board approval were obtained from two institutions. Samples were digested in Type II Collagenase (Gibco) and re-suspended in growth factor reduced Matrigel (BD), plated on plastic, and overlaid with prostate culture media (PCM). PCM consists of serum free Advanced DMEM/F12 (Gibco) with multiple growth factors optimized to propagate benign primary prostate cells. Cultures were maintained at 37°C in 5% CO2. Results: In the initial 51 samples, 15 continuous organoid cultures (29%) were established from distinct sites (9 of 32 bone, 6 of 19 soft). Tumor content of the biopsy represents a major determinant of organoid growth. Once established, organoids propagate indefinitely with different kinetics (approximately 48 hours to 1 week doubling time), and can be cryopreserved. Histological analysis shows that the organoids recapitulate the structure of the in situ cancer and genomic analysis using array CGH and whole-exome sequencing (WES) shows the presence of typical copy number alterations including TMPRSS2-ERG interstitial deletion, PTEN loss, CHD1 loss, and AR amplification. WES of two organoid/metastasis pairs shows that the growth conditions do not generate additional mutations. Conclusions: This novel tissue culture technique enables the development of new cell lines derived from metastatic deposits. This advance will facilitate research by availing new and varied cell lines, which will hopefully be more closely aligned to the spectrum of behavior of the clinical disease in comparison to the limited and problematic cell line models currently available.
Minimal Residual Disease Monitoring in Childhood Precursor B Lymphoblastic Leukemia with t(12;21)(p13;q22); ETV6-RUNX1: A Comparison Between Quantitative RT-PCR and Flow Cytometry
Authors: Sofie J Alm, Charlotte Engvall, Julia Asp, Lars Palmqvist, Jonas Abrahamsson, Linda Fogelstrand
Journal: Blood (2014)
Usefulness of circulating tumor cell detection in pancreatic adenocarcinoma diagnosis.
Authors: Paul Basile, Isabelle iwanicki-Caron, Emmanuel Toure, Michel Antonietti, Stephane Lecleire, Aude Di Fiore, Alice oden-Gangloff, France Blanchard, Francoise Lemoine, Frédéric Di Fiore, Jean-Christophe Sabourin, Pierre Michel
Journal: Journal of Clinical Oncology (2013)

157 Background: For pancreatic tumor, guidelines recommend pancreatic cytology examination by EUS-FNA as the first diagnostic procedure in unresectable patients. Detecting CTCs in blood could play the role of a “liquid biopsy”. The usefulness of CTC detection in the clinical management of these patients has not been established yet. Here, we aimed to prospectively evaluate the accuracy of a diagnostic method based on CTC detection. Methods: All patients referred from January 2011 to March 2012 for EUS-FNA procedure in a context of pancreatic solid tumor diagnosis were prospectively enrolled after their consent. Prior EUS-FNA procedure a sample of peripheral blood was collected. CTCs were analyzed using the ScreenCell method. Cells were considered as tumoral if they met these morphological criteria: nuclear diameter &gt;14 µ, anisocytosis, anisocaryosis, nuclear membrane irregularities, large nucleolus, clots of tumoral cells with platelets and fibrin. All analysis was performed by a pathologist blinded to the EUS-FNA results. The diagnosis of pancreatic adenocarcinoma was defined either by pathological evidence based on FNA or surgical specimen, or by clinical outcome with metastatic evolution and CA19.9 serum level rather than 10 fold normal value. Results: A total of 40 patients were included. A pancreatic adenocarcinoma was confirmed in 27/40 patients (68.3%). In 21 of the 27 patients, pathological proof of adenocarcinoma was obtained by EUS-FNA. For the diagnosis of adenocarcinoma, sensitivity and specificity of EUS-FNA were 77.8% and 100% respectively. The diagnostic accuracy of FNA was 85%. CTC detection was positive in 15 patients. Sensitivity and specificity were 55.5% (CI95% [40.1%; 70.9%]) and 100% (CI95% [75%; 100%]) respectively. The diagnostic accuracy of CTC was 70%. Metastatic statuses, lymph node involvement, vascular invasion, size of tumor and CA19.9 serum level were not statistically associated with CTC detection. Conclusions: We suggest that CTC detection be applied as first-line procedure before EUS-FNA in the strategy of pancreatic tumor diagnosis. With the implementation of this blood test on a routine basis, approximately one half of these patients could avoid invasive EUS-FNA procedure.
Utilization of a virtual collaboration portal to improve communication, education, and quality of care across a network of practices.
Authors: Jennifer Trageser, Max Rush, Hk Kahng, Rowena Schwartz, Roy A. Beveridge, Debra A. Patt
Journal: Journal of Clinical Oncology (2012)

320 Background: Technological advancements allow community oncologists to improve quality of patient care. By offering online access to treatment protocols, colleague collaboration, and clinical resources in a centralized environment, practices may realize efficiencies that can translate to better patient care. Methods: We characterized development and ongoing enhancements of The Oncology Portal from Dec 2010 to April 2012, provided to &gt;1,000 physicians. Characterization is qualitative and quantitative. Qualitative characteristics of functionality enhancements accommodated clinical communication and educational content. Quantitative analysis evaluated discussion notifications, content consumption clicks and discussion posts and comments. Results: The Portal leveraged evolving technology to implement incremental, strategic enhancements for medical oncologists, radiation oncologists, gynecologic oncologists, pharmacists, researchers, and mid-level providers. These enhancements provided the framework to drive practice efficiency and improve patient care by extending access to all practice clinicians. Initial enhancements included expanding discussion boards to include researchers and mid-level providers. Additional enhancements included mobile access to discussions, wiki, and two expert programs. Educational content was augmented to include evidence-based resources, including journals, drug information, conference coverage, treatment guidelines, disease-specific CME, and clinical trials. A respectable increase in utilization was observed, as shown in the Table. Conclusions: Portal enhancements and expanded content occurred gradually, utilization increased across the network over the study period, and interest in The Portal remains high. Utilization was likely facilitated by content enhancements improving practice quality and efficiency. [Table: see text]
Neoadjuvant chemoradiation (CRT) with or without panitumumab (Pan) in patients with K-ras unmutated, locally advanced rectal cancer (LARC): Final results of a randomized multicenter phase II trial (SAKK 41/07).
Authors: Daniel Helbling, Gyorgy Bodoky, Oliver Gautschi, Stefanie Hayoz, Fred Bosman, Axel Madlung, Beat Gloor, Roger Burkhard, Daniel Rauch, Ralph C. Winterhalder, Piercarlo Saletti, Lukas Widmer, Markus M. Borner, Daniela Baertschi, Pu Yan, Dieter Koeberle
Journal: Journal of Clinical Oncology (2015)

762 Background: We conducted a randomized phase II multicenter trial evaluate the anti-epidermal growth factor receptor (EGFR) panitumumab (P) in combination with CRT with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS LARC. Methods: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT either with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Secondary end-points were pathological response, R0-resection, sphincter preservation, downstaging, time to local relapse, time to distant failure and disease-free survival (DFS). Results: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT either with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). Secondary end-points were pathological response, R0-resection, sphincter preservation, downstaging, time to local relapse, time to distant failure and disease-free survival (DFS). Conclusions: An addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. Up to date no local recurrence occurred and DFS compared favorably to other trials. Clinical trial information: NCT00814619.
Molecular diagnostics in clinical oncology: In situ genotyping of KRAS mutations on colorectal and lung cancer tissue sections.
Authors: P. Micke, I. Grundberg, K. Edlund, M. Sundstrom, J. Imgenberg-Kreuz, J. Botling, M. Nilsson
Journal: Journal of Clinical Oncology (2011)

e14136 Background: Activating mutations in the KRAS gene are present in different cancer types and are strongly associated with resistance to epidermal growth factor receptor (EGFR) inhibitor therapy. However, in clinical practice mutation analysis is not reliable for a significant number of patients due to small biopsies, tumor heterogeneity, low tumor cell content and poor DNA quality. Methods: To improve the diagnostic accuracy, we developed a genotyping assay that in situ targets KRAS-mutations in codon 12 and 13 on tissue sections by the use of multiple mutation specific padlock probes and rolling-circle amplification. Thus, the distribution of wild type (green fluorescence) and mutated (red fluorescence) KRAS alleles can be determined for single cancer cells in different parts of a heterogonous tumor without the use of microdissection. Results: We demonstrate reliable KRAS genotyping on cytologic tumor imprints as well as on fresh frozen and formalin-fixed paraffin-embedded tissue sections from colorectal and lung cancer. Conclusions: This in situ method offers single cell mutation detection for clinical diagnostics and holds great promise as a tool to investigate the role of oncogenic mutations in complex tumor tissues.
An independent, external validation study of proposed genetic biomarkers of irinotecan toxicity and pharmacokinetics.
Authors: F. Innocenti, G. L. Rosner, W. Qiao, A. M. de Graan, M. J. Ratain, R. H. N. van Schaik, J. Ramirez, R. Mathijssen
Journal: Journal of Clinical Oncology (2011)

e14022 Background: Pharmacogenetic studies have proposed a large number of genetic variants as predictors of outcome of chemotherapy. The vast majority of them failed to replicate, leaving very few validated associations. UGT1A1*28 is a validated marker of severe neutropenia of irinotecan. In addition to UGT1A1*28, we proposed other variants in the irinotecan pathway as associated with neutropenia and pharmacokinetics in 85 refractory cancer patients treated with 300-350 mg/m2 three-weekly single-agent irinotecan (Innocenti et al., JCO 2009). These variants were associated with ANC nadir and the pharmacokinetics of irinotecan and its metabolites SN-38 (active) and SN-38G (inactive). In this study, we aimed to independently validate these variants. Methods: 112 refractory cancer patients (Caucasians, 1 African) from The Netherlands were genotyped for 10 variants in ABCC1, ABCC2, SLCO1B1, TCF1, and UGT1A1. In the replication set, patients received irinotecan as 600 mg (flat dose, n=60), 350 mg/m2 (n=33), and 380-1,060 mg (flat dose calculated according to the algorithm of van der Bol JM et al., CCR 2010, n=19). ANC nadir and pharmacokinetic results were already available. After multivariate analysis by linear regression, a p<0.05 and same direction of the effect were used as the validation criteria. Results: For ANC nadir, both UGT1A1*93 (p=0.04) and SLCO1B1*1b (p=0.04) were replicated. SLCO1B1*1b had a protective effect on neutropenia. For irinotecan pharmacokinetics, replicated variants were ABCC2 -24C>T for irinotecan AUC (p=0.04), UGT1A1*93 for SN-38 AUC (p<0.001), and UGT1A1*28 for the SN-38G/SN-38 AUC ratio (p<0.001). The other 7 gene variants failed to replicate. For some variants, the lower significance is due to a higher interpatient phenotypic variation in the replication set. Differences in irinotecan dosing between the two studies did not impact the ability to reproduce associations. Conclusions: This prospective study 1) validated, besides UGT1A1*93, the new marker SLCO1B1*1b for irinotecan neutropenia, 2) failed to confirm previously reported variants, and 3) provided a study framework to conduct external validation in cancer pharmacogenomics.
Response to neoadjuvant trastuzumab and chemotherapy in ER+ and ER- HER2-positive breast cancers: Gene expression analysis.
Authors: G. Bianchini, A. Prat, M. Pickl, A. Belousov, A. Koehler, V. Semiglazov, W. Eiermann, S. Tjulandin, M. Biakhov, A. Lluch, M. Zambetti, F. J. Vazquez Mazon, J. Baselga, L. Gianni
Journal: Journal of Clinical Oncology (2011)

529 Background: HER2-positive/ER+ and HER2-positive/ER– breast cancers have different patterns of gene expression and intracellular pathway activation. We assessed the role of selected biomarkers in predicting the likelihood of achieving a pathological complete response (pCR) in the NeOAdjuvant Herceptin (NOAH) trial, which recruited 334 patients. Methods: Formalin-fixed paraffin-embedded core biopsies were collected from 114 women randomized to receive trastuzumab (H) with doxorubicin/paclitaxel followed by CMF (Arm CTH) or chemotherapy alone (Arm CT). Expression of the following genes and metagenes was profiled on Affymetrix 2.0 Plus: MYC, PIK3CA, PIK3R1, PTEN, amphiregulin (AREG), epiregulin, 8q24 and 8q22 amplicons, plasma cell (PC) and IGF metagenes. ER status was based on ESR1 gene expression. pCR was defined as the absence of residual invasive tumor in the breast and axillary lymph nodes. Biomarkers were assessed as continuous variables by univariate logistic regression analysis. Results: 80 samples (70%) were ER– and 34 (30%) were ER+. In the CT arm AREG (p=0.03) and 8q22 (p=0.06) were associated with lower pCR rates among ER– samples, while PTEN (p=0.01) was associated with higher pCR rates. Among ER– samples in the CTH arm, AREG (p=0.04) and IGF (p=0.007) were associated with resistance, while PC showed a trend for higher pCR rate (p=0.079). There were significant interactions between the treatment arms and 8q22 (p=0.03) and PC (p=0.04). In the high tertile of 8q22 the pCR rates were 0% (0/12 Arm CT) and 67% (10/15 Arm CTH) while for PC the pCR rates were 13% (2/15 Arm CT) and 83% (10/12 Arm CTH). There were no statistically significant associations for ER+ tumors, but a significant interaction for the likelihood of pCR and ER status was observed for PTEN (p=0.006) and PC (p=0.05) in the CT Arm and for AREG (p=0.03) in the CTH Arm. Conclusions: High expression of the PC metagene and the 8q22 amplicon, and low expression of the IGF metagene, were associated with the increased pCR rate reported with the addition of H to CT in HER2-positive/ER– tumors. The concept that HER2-positive/ER+ and HER2-positive/ER– tumors are driven by different biologic pathways warrants further investigation.
A Phase I, Multi-Dose, Dose Escalation Study of SGN-40 (anti-huCD40 mAb) in Patients with Refractory or Recurrent Multiple Myeloma.
Authors: Mohamad A. Hussein, Ruben Niesvizky, Nikhil Munshi, James C. Berenson, Kenneth C. Anderson, Kate Ryan, Karen Baumgartner, Dennis M. Miller, Michael McDonald
Journal: Blood (2004)
Development and validation of an ADT resistance signature to predict adjuvant hormone treatment failure.
Authors: Jeffrey Karnes, Hussam Al-Deen Ashab, Bruce J. Trock, Ashley Ross, Harrison Tsai, Jeffrey J. Tosoian, Nicholas Erho, Voleak Choeurng, Kasra Yousefi, Zaid Haddad, Firas Abdollah, Eric A. Klein, Paul L. Nguyen, Felix Yi-Chung Feng, Adam Dicker, Robert Benjamin Den, Elai Davicioni, Robert B. Jenkins, Tamara L. Lotan, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2016)

106 Background: Androgen deprivation therapy (ADT) is one of the main treatment options for locally advanced and metastatic prostate cancer. Neuroendocrine prostate cancer (NEPC) is inherently less sensitive or even resistant to ADT. NEPC can be observed de novo (e.g., small cell prostate cancer) but more commonly arises after exposure to ADT. We hypothesized that a gene expression signature of NEPC when measured in primary tumor specimens (RP) of prostatic adenocarcinoma may be useful for predicting patients with innate resistance to ADT. Methods: Expression profiles of 1023 PCa patients treated with RP were obtained from the Decipher GRID database. These were split into training (n=529) and validation (n=494) sets and stratified by the receipt of adjuvant ADT (n=243) or no adjuvant ADT (n=780). A literature review of ADT resistance and neuroendocrine genes identified 1,557 genes as candidates. This set was further filtered, using logistic regression to select a 52-gene ADT resistance signature (ARS). ARS was trained using a generalized linear model with lasso regularization. Survival c-index and Kaplan Meier was used to compare survival differences between treated and untreated patients with high and low ARS scores (defined by median split). Results: In validation cohorts, the ARS was predictive of metastasis in cohorts receiving adjuvant ADT (10-year metastasis free survival c-index of 0.69 (95% CI 0.59-0.78) as compared to 0.45 (95% CI 0.29-0.61) in patients not treated with ADT). Similarly in a separate cohort of untreated patients that received no ADT until after metastatic onset, ARS was not prognostic (c-index 0.53). Among ADT treated patients, those with low ARS scores had a 10 year MFS of 87%, versus 70% in those with high ARS scores (p&lt;0.001). In the subset of men who received ADT after metastatic onset and who developed castrate-resistant prostate cancer (CRPC, n = 41), median time to treatment failure was 1 year in patients with high ARS compared to 2 years for those with low ARS scores (p=0.07). Conclusions: A 52-gene ADT resistance signature was developed which showed significant differences in metastasis-free survival among adjuvant hormone treated but not untreated patients.
Incidence and costs of thromboembolic events in cancer patients: A study on four major cancer localization.
Authors: Isabelle Borget, Alexandre Vainchtock, Nicolas Martelli, Florian Scotte
Journal: Journal of Clinical Oncology (2015)

185 Background: Venous thromboembolic event (VTE) is a common complication for cancer patients, leading to hospitalizations that increase the burden of cancer management. Our study aimed to estimate the incidence and costs of hospitalizations for VTE, in French patients with breast cancer (BC), colon cancer (CC), lung cancer (LC) or prostate cancer (PC), four of the most frequent cancers in France. Methods: We used the French national hospital database (PMSI) to select new patients with BC, CC, LC or PC in 2010, who had at least one VTE-related hospitalization during the following two years. VTE-related stays and patients were identified using the disease-specific ICD-10 codes. Hospital costs were calculated over stays for which VTE was considered as primary/related diagnosis. Costs were estimated from the healthcare system perspective, using the French official tariffs. Results: Among 194,964 patients newly diagnosed in 2010 with BC, CC, LC or PC in 2010, 8,909 (4.6%) were hospitalized for a VTE or experienced VTE at hospital, representing, 12,880 hospital stays. During the two-year follow-up, 2,053 (23.0%) patients were re-hospitalized for a VTE recurrence, representing 3,969 stays (30.8% of admissions for VTE). For one patient with VTE who did not experience recurrence, the mean hospital cost over two years ranged from €3,302 to €3,674. This amount was dramatically increased for patients with recurrent VTE, as it ranged from €5,441 to €5,692 per patient. Hospitalizations for VTE associated with those 4 types of cancer only were responsible for an overall expenditure reaching €13.30 million over two years, including €1.82 million due to recurrent events. Conclusions: VTE-related cancer hospitalizations remain frequent and induce a notable cost. Prevention and management in respect to guidelines would be an efficient way to reduce the incidence of this complication and moderate its economic cost. [Table: see text]
Increased symptom expression among patients (PTS) with delirium admitted to an acute palliative care unit (APCU).
Authors: Maxine Grace De la Cruz, Sriram Yennu, Diane D Liu, Jimin Wu, Akhila Sunkepally Reddy, Eduardo Bruera
Journal: Journal of Clinical Oncology (2015)

56 Background: Previous case reports found that delirium-induced disinhibition may lead to overexpression of symptoms. Our aim was to determine the effect of delirium on the reporting of symptom severity in pts with advanced cancer. Methods: We reviewed 329 consecutive pts admitted to the APCU without a diagnosis of delirium from Jan 2011-Dec 2011. Demographics, Memorial Delirium Assessment Scale (MDAS), ECOG, Edmonton Symptom Assessment Scale (ESAS) on 2 time points were collected. Pts who developed delirium and those who did not develop delirium during the entire course of admission were compared using Chi-Squared test and Wilcoxon rank-sum test. Paired t-test was used to assess if the change of ESAS from baseline to follow-up was associated with delirium. Results: 96/329 (29%) of pts developed delirium during their admission to the APCU. The median time to delirium was 2 days. There was no difference in the length of stay in the APCU for both groups. Table 1 shows the changes in the ESAS scores of the two groups from baseline to follow-up. Pts who did not have delirium expressed improvement in all their symptoms while those who developed delirium during the hospitalization showed no improvement in physical symptoms and worsening in depression, anxiety, appetite and wellbeing. Conclusions: Pts with delirium reported no improvement or worsening symptoms as compared to pts without delirium. Screening for delirium is important in pts who continue to report worsening symptoms despite appropriate management. [Table: see text]