tbuckley/cabot-search huggingface dataset:
Cellular Hierarchy as a Determinant of Tumor Sensitivity to Chemotherapy
Authors: Ignacio A. Rodriguez-Brenes, Antonina V. Kurtova, Christopher Lin, Yu-Cheng Lee, Jing Xiao, Martha Mims, Keith Syson Chan, Dominik Wodarz
Journal: Cancer Research (2017)

Chemotherapy has been shown to enrich cancer stem cells in tumors. Recently, we demonstrated that administration of chemotherapy to human bladder cancer xenografts could trigger a wound-healing response that mobilizes quiescent tumor stem cells into active proliferation. This phenomenon leads to a loss of sensitivity to chemotherapy partly due to an increase in the number of tumor stem cells, which typically respond to chemotherapy-induced cell death less than more differentiated cells. Different bladder cancer xenografts, however, demonstrate differential sensitivities to chemotherapy, the basis of which is not understood. Using mathematical models, we show that characteristics of the tumor cell hierarchy can be crucial for determining the sensitivity of tumors to drug therapy, under the assumption that stem cell enrichment is the primary basis for drug resistance. Intriguingly, our model predicts a weaker response to therapy if there is negative feedback from differentiated tumor cells that inhibits the rate of tumor stem cell division. If this negative feedback is less pronounced, the treatment response is predicted to be enhanced. The reason is that negative feedback on the rate of tumor cell division promotes a permanent rise of the tumor stem cell population over time, both in the absence of treatment and even more so during drug therapy. Model application to data from chemotherapy-treated patient-derived xenografts indicates support for model predictions. These findings call for further research into feedback mechanisms that might remain active in cancers and potentially highlight the presence of feedback as an indication to combine chemotherapy with approaches that limit the process of tumor stem cell enrichment. Cancer Res; 77(9); 2231-41. ©2017 AACR.
Vaginal bleeding in women with leukemia.
Authors: S. Ghazal, S. Barton, R. Boyajian, J. H. Antin, R. M. Stone, E. S. Ginsburg
Journal: Journal of Clinical Oncology (2011)

6577 Background: Vaginal bleeding (VB) in premenopausal women with leukemia may require transfusions which cause additional morbidity. This study investigates the frequency of VB in women with leukemia admitted to Brigham & Women’s Hospital and reports strategies used in managing VB. Methods: Retrospective chart review of first leukemia admissions for chemotherapy between 1/1/03 and 1/1/08. 114 women ages 18-44 were identified. Exclusion criteria included bleeding diatheses, pregnancy, and hysterectomy. Patients were compared based on presence or absence of VB as documented in the medical record. Results: 69 of 114 patients (60.5%) developed VB (Table). There was no significant difference in the rate of VB among acute (n=95) and chronic (n=19) leukemia patients. Patients with VB had significantly more packed red blood cell and platelet transfusions and a longer length of stay which did not reach statistical significance. Of 69 patients with VB, 53 (76.8%) received therapy for VB. 24 patients received OCPs alone, 10 leuprolide acetate, 12 leuprolide and OCPs, and 7 other combination therapy. Of patients with VB 21/53 (39.6%) received prophylactic therapy, 23/ 53 (43.4%) received therapy for treatment, and the timing of therapy was unclear in the remaining 9/53 (17%). VB stopped in only 28 of 53 (52.8%) patients receiving therapy. It was unclear which therapy was most effective in preventing or managing VB. Only 39 of 69 (56.6%) patients with VB had a recorded last menstrual period so the proportion of VB due to expected menstruation was unknown. 8 of 45 (17.8%) patients without VB received hormonal treatment for prevention of VB. Conclusions: VB occurred in the majority of women during their first leukemia admission and was associated with significantly more blood and platelet transfusions. Further research in effective management of VB in these patients is indicated. Comparison of leukemia patients admitted for chemotherapy with and without VB (mean ± SD). Bleeding (n=69) No bleeding (n=45) P value Age 33.3 ± 7.8 34.3 ± 8.1 0.435 Admission hematocrit 28.8 ± 4.9 29.7 ± 5.2 0.222 Admission platelets 135.6 ± 105.7 160.5 ± 202.0 0.947 Length of stay (days) 32.0 ± 11.8 28.0 ± 15.3 0.107 No. of PRBC transfused 11.3 ± 7.5 6.8 ± 5.7 <0.0005 No. of bags platelets transfused 8.4 ± 8.2 7.6 ± 11.7 0.007
Phase II randomized study of the safety, efficacy, metabolism, and molecular targets of erlotinib in African Americans (AA) with NSCLC.
Authors: M. A. Villalona-Calero, T. Stinchcombe, M. A. Phelps, S. L. Starrett, A. C. Papp, A. M. Ghany, W. J. Hicks, G. A. Otterson, M. A. Socinski, W. Zhao
Journal: Journal of Clinical Oncology (2010)

7569 Background: We sought to characterize clinical outcomes, EGFR/RAS mutations, EGFR amplification, pharmacokinetics (PK) and pharmacogenetics (PG) in AA patients receiving erlotinib for previously treated NSCLC. Methods: Pts received erlotinib in a phase II 2-stage minimax randomized study, at the standard 150 mg daily (Arm A), or escalated after 1 cycle to achieve skin rash (Arm B). Primary endpoint was disease control rate (DCR, RECIST CR+PR+SD) at 3 months. PBMCs and tumor tissue were collected from all pts to identify SNPs in metabolizing enzymes, and tumor mutations/amplification. PKs from parent drug and active metabolite (OSI-420) were evaluated at days 1 and 28. Results: Of 42 pts randomized, 39 (37 current/former smokers) started erlotinib, 21 on Arm A, 18 on Arm B. DCR at 3 months in 37 pts to date is 32% (30 and 35%, Arms A and B, respectively). Grade ≥3 adverse events included rash (2 pts), and muscle weakness, dyspnea, dehydration, thrombosis, anemia, 1 pt each. No skin rash on the first two months was associated with early PD (10/11). PK analysis in 26 pts showed higher parent drug and metabolite Cmax and AUCs in pts with grades 0-1 vs. grades 2-3 rashes (cycle 2 OSI-420 mean Cmax of 107 ± 83 ng/mL vs. 243 ± 165 ng/mL, respectively; ANOVA p-value = 0.01). SNP presence in CYP3A4 and CYP3A5 also trends with PK, but not statistically significant due to high variability in PK parameter estimates. One EGFR exon 19 short in frame deletion mutation and a novel exon 20 missense R776L (c.2373 G>T) mutation were identified among 28 samples already analyzed. EGFR was amplified in 9/20 samples. 5 pts had Kras mutations: 3 G12C (c.32 G>T), 1 G12D (c.33 G>A), and 1 G12V (c.33 G>T). Silent mutations indicating SNPs in EGFR exon 20 Q787Q (c.2470 G>A) and Kras (-9, C>T), 9 base pairs upstream of the transcription site, were noted. Conclusions: Erlotinib has similar efficacy and toxicity in AA as reported for caucasians. Absence of rash predicted for worst outcome, but the dose-to-rash strategy did not show meaningful differences. PKs, although highly variable, correlate with rash occurrence and may relate to CYP genotype. A larger sample size will be required to evaluate the role of the PBMC/tumor SNPs identified. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech
Comparison of orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) activity as prognostic factors in resectable colorectal cancers (CRC)
Authors: T. Ochiai, K. Nishimura, M. Kitajima, H. Noguchi, Y. Tsuruoka, Y. Takahashi, T. Kamano
Journal: Journal of Clinical Oncology (2005)

3643 Background: Phosphoribosylation of 5-FU is an essential step leads to tumor growth inhibition and OPRT is the main enzyme that involves in this conversion of 5-FU to FUMP. We have reported the prognostic value of OPRT in resectable CRC patients in ASCO 2004 (#3574). In this study, the prognostic relevance of OPRT, TS and DPD activity in resectable CRC patients treated by oral 5-fluoropyrimidines were compared to further clarify the prognostic value of OPRT among 5-FU metabolic enzymes. Methods: Surgical specimen was obtained from resectable CRC patients who were subsequently treated by oral 5-FU-based adjuvant chemotherapy. TS, DPD and OPRT activity in the extract of tumor tissue was determined enzymatically. The cut-off value of TS, DPD and OPRT were determined by maximal χ2 Method: Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier estimate. Results: During 1999 to 2003, tumor tissue was collected from 90 CRC patients and then the patients were followed for 5.2 years (Median). The cut-off value of OPRT, TS and DPD were determined to be 0.147 nmol/min/mg, 0.044 pmol/mg and 72.10 pmol/min/mg, respectively. OPRT was only factor significantly influenced to DFS and OS among these enzymes. 5-year DFS of all patients were 76.6% and 50.0% (p=0.015, log-rank test) and OS were 83.8% and 48.8% (p=0.008) for OPRT high (n=70) and low group (n=20), respectively. The Cox regression analysis revealed that node status (p=0.032) and OPRT (p=0.021) were significant factors for DFS, and OPRT (p=0.014) and thymidylate synthase (p=0.032), lymph invasion (p=0.005) and vascular invasion (p=0.003) were significant factors for OS. Conclusions: OPRT activity in tumor tissue was a strong predictor of prognosis in resectable CRC patients treated by oral 5-FU-based adjuvant chemotherapy, and was useful to pick up high risk patients independent from known prognosis factors. No significant financial relationships to disclose.
Clinical Implications of Novel Genomic Discoveries in Chronic Lymphocytic Leukemia
Authors: Gregory Lazarian, Romain Guièze, Catherine J. Wu
Journal: Journal of Clinical Oncology (2017)

Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy with a remarkably heterogeneous course, ranging from indolent disease with no need for immediate therapy to rapidly progressive disease associated with therapeutic resistance. The recent US Food and Drug Administration approvals of novel targeted therapies such as inhibitors of B-cell receptor signaling and B-cell lymphoma 2 have opened up new opportunities in the clinical management of patients with CLL and heralded a new era in the clinical treatment of this disease. In parallel, the implementation of novel sequencing technologies has provided new insights into CLL complexity, identifying a growing list of putative drivers that underlie inter- and intratumor heterogeneities in CLL affecting disease progression and resistance. The identification of these novel genomic features that can indicate future drug resistance or guide therapeutic management is now becoming a major goal in CLL so that patients can best benefit from the increasingly diverse available therapies, as discussed herein.
How do parents with advanced cancer communicate with their children? A qualitative study.
Authors: Claire Emery Hailey, Justin M Yopp, Deborah Mayer, Eliza M Park
Journal: Journal of Clinical Oncology (2016)

241 Background: Parents with advanced or incurable cancer may struggle when communicating with their children about their illness. Most literature on family communication about cancer reflects the opinions of parents with early-stage cancer or the experiences of children. The life-limiting nature of incurable illness distinguishes the experiences of parents with advanced cancer. Therefore, the aim of this study was to describe how parents with advanced cancer communicated about their illness with their dependent children. Methods: We conducted semi-structured interviews with 46 patients with stage IV solid tumor malignancies who had at least one child under 18 years of age. Interviews addressed illness-related communication with children as well as other topics related to the experience of parenting with advanced cancer. Data were analyzed using thematic content analysis. Results: Parents usually sought to protect their children by limiting details about their illness or framing discussions in an optimistic manner. Age and developmental stage of children greatly influenced how parents communicated and what information was divulged. Disclosure about the life-limiting nature of their illness varied significantly. Parents identified several barriers to communication including children’s avoidance of discussion, personal difficulty accepting the terminal nature of their illness, uncertainty about prognosis, and concerns about how to communicate with their children. Despite these barriers, many parents had not received professional guidance to facilitate their communication. Conclusions: Parents with advanced cancer reported a wide diversity in motivations and techniques in discussing their illness with their children. Despite the availability of child-focused communication resources, parents identified several barriers to illness-related communication with their children. Results from this study can provide guidance for clinicians to help patients overcome these challenges and to assist parents with the difficult task of communicating with children about their illness. Future research interventions to address communication barriers may lead to improved outcomes for patients and their families.
L-asparaginase (L-ASP)-related toxicities with Erwinia L-ASP in a large compassionate-use protocol.
Authors: P. V. Plourde, S. Jeha, L. B. Silverman, J. B. Nachman, S. R. Rheingold, G. V. H. Dahl, E. A. Raetz, T. Mercedes, T. Corn
Journal: Journal of Clinical Oncology (2011)

9534 Background: L-ASP is an important component of the multi-agent chemotherapy in children and young adults for treatment of acute lymphoblastic leukemia (ALL). The pegylated E. coli derived form, Oncaspar (PEG-ASP) is most commonly used because of its longer half-life; however, clinical hypersensitivity reactions can occur in 10-30% of patients requiring its discontinuation. Erwinia L-ASP (E) is an L-ASP derived from a different bacterium and is immunologically distinct from the E. coli L-ASP. We conducted a compassionate use trial of E in patients with ALL and hypersensitivity to PEG-ASP to collect safety information. Methods: Patients were ≥ 1 year of age with ALL who developed a clinical hypersensitivity reaction to PEG-ASP. Patients with a history of pancreatitis, previous allergic reaction to E, or pregnant, were excluded. E was administered at 25,000 IU/m2 IM/IV/SC 3 times per week on a Monday/Wednesday/Friday schedule for 2 weeks to replace each dose of PEG-ASP. The study was IRB approved at each institution and patients/family provided informed consent. Safety information on E-related adverse events (AEs) was captured on Case Report Forms (CRFs) submitted to the Sponsor when the patient completed his/her entire E treatment plan. Results: Between February 2006 and April 2010, 569 patients were treated with E and had CRFs completed. The average age was 9.4 years (range 1-66). The majority of patients (61.2%) were male. 13.9% of patients withdrew due to AEs, 7.6 % due to allergic reactions. Anaphylactic and hypersensitivity reactions were reported in 6.5% and 4.6% respectively. The incidence of pancreatitis was 2.5% thromboembolic disorders 1.3%, hyperglycemia 1.4% and elevation in liver enzymes 1.6%. There were 5 deaths on study (4 relapses, 1 thromboembolic event). Conclusions: This is the largest study of patients treated with E to determine the toxicity profile. E was well tolerated with no unexpected toxicities identified. This compassionate use trial showed E was well tolerated and permitted continued asparaginase treatment in 85% of patients with hypersensitivity reactions to E.coli formulations. Updated data will be presented.
Interstitial lung diseases during treatment with sunitinib or mTOR inhibitors in metastatic renal cell carcinoma.
Authors: Philipp Ivanyi, Thomas Fuehner, Meike Adam, Christian Eichelberg, Edwin Herrmann, Axel S. Merseburger, Viktor Grünwald
Journal: Journal of Clinical Oncology (2013)

420 Background: Targeted therapies are the mainstay for metastatic renal cell carcinoma (mRCC) treatment. Interstitial lung disease (ILD) represents an adverse event (AE) of such therapies while its incidence and management is poorly defined. Here, the experience on ILD with targeted agents in mRCC is reported. Methods: Retrospective analysis of mRCC patients receiving sunitinib, everolimus, or temsirolimus at three German tertiary centers between January 2006 and August 2009 was performed, accessing ILD incidence, management, and outcomes. Results: In total 26 ILD patients were identified out of 306 mRCC patients (8.5%) treated with targeted therapies. Median treatment duration to ILD diagnosis was 3.8 (range 0.98-21.5) months. ILD occurred in 6 of 204 sunitinib treated patients (2.9%), and in 20 of 102 mTOR inhibitor (mTORi) treated patients (19.6%). Cough represents the predominant symptom (69.2%, n=18). Chest CTs revealed 4 patterns: interstitial (n=13), nodular (n=3), ground glass opacities (n=8), or complex patterns (n=2). Pulmonary function tests (PFT) illustrates frequently a restrictive disorder (n=9), often accompanied by a diminished diffusion capacity (n=8). In 53.8% (n=14) a bronchoscopy with broncho-alveolar-lavage (BAL) was performed (lymphocytic cellularity n=6, eosinophilic cellularity n=4). Dose reduction (42.3%, n=11), temporary interruption (46.2%, n=12), or treatment withdrawal (53.8%, n=14) occurred frequently. Nine patients (34.6%) received steroids. Continuation of targeted therapies was maintained in 65.4% (n=17). No patient died from ILD. Conclusions: ILD represents a frequent AE with targeted therapies and also occurs in sunitinib treated patients. For diagnosis of ILD chest CTs are mandatory, whereas PFT and BALs are important subsidiary tools. Clinical relevance of ILD may vary and management of ILD ranges from watch and wait to termination of treatment and steroid pulse therapy. Severe complaints were more frequently associated with eosinophilic BAL, often required an aggressive treatment. However, in most patients, temporary interruption and/or dose reduction with subsequent continuation of targeted therapy remain sufficient to manage ILD.
Understanding the genomic underpinnings of metastatic chromophobe renal cell carcinoma.
Authors: Jozefina Casuscelli, Patricia Wang, Almedina Redzematovic, William Lee, Venkatraman E. Seshan, Ronglai Shen, Nicholas Donin, Yingbei Chen, John C. Cheville, Allan J. Pantuck, Robert Houston Thompson, Jonathan A. Coleman, Paul Russo, Victor E. Reuter, Satish Tickoo, A. Ari Hakimi, James Hsieh
Journal: Journal of Clinical Oncology (2016)

513 Background: Chromophobe renal cell carcinoma (chRCC) is the third most common histologic subtype of kidney cancer. While most of these tumors have an indolent behavior, 7% of patients with chRCC develop metastases, with no currently available standard of care. The Cancer Genome Atlas characterized chRCC, highlighting pathognomonic single copy chromosomal losses of 1, 2, 6, 10, 13 and 17, as well as a minimal mutation burden distinguishing it from all other cancer types. However, only 15% of the analyzed patients had advanced disease. We analyzed metastatic chRCC to further characterize these tumors and elucidate mechanisms leading to aggressive disease using a variety of next generation and whole genome sequencing. Methods: Our cohort of metastatic chRCC consisted of 40 patients with available clinical and pathologic data. Whole genome sequencing (WGS) was performed on 6 patients (4 primary tumors and 2 metastases), 42 additional samples from 33 patients were analyzed using targeted next-generation sequencing (MSK-IMPACT). Notably, we were able to collect and analyze matched primary and metastatic tumors from 7 patients. As control cohort 27 non-metastatic chRCC tumors were sequenced with MSK-IMPACT. Copy number patterns were computed with OncoSNP seq and FACETS. Results: The most commonly mutated genes in the aggressive chRCC tumors were TP53 and PTEN (WGS: TP53 67 %, PTEN 33%; MSK-IMPACT: TP53 61%, PTEN 27%). No other genes were mutated frequently. Primary tumor samples of chRCC did show the typical pattern of chromosomal losses in 1, 2, 6, 10, 13 and 17. Interestingly, these canonical losses could not be detected in the metastases even when accounting for tumor purity. Conclusions: TP53 and PTEN mutations are highly enriched in both primary and metastatic tumors of aggressive chRCC compared to the non-aggressive tumors and likely play a critical role in disease progression. More intriguingly, the observation of differential copy numbers in matched primary and metastatic tumors suggest whole genome or whole chromosome events in these samples. We are currently employing different bioinformatic and cytogenetic platforms to validate our novel hypothesis of chromosomal events as driver for metastatic development in chRCC.
In-transit/local recurrences (IT/LR) in melanoma patients (pts) after sentinel node biopsy (SLNB) and therapeutic lymph node dissection (TLND) - one-center experience
Authors: W. Ruka, Z. Nowecki, P. Rutkowski, Z. Zurawski, W. Dziewirski, S. Falkowski, A. Nasierowska-Guttmejer
Journal: Journal of Clinical Oncology (2005)

7502 Background: One of the major controversies related to SLNB is the suggestion of a higher incidence of IT/LR after completion lymph node dissection (CLND) performed for a positive node. This phenomenon is explained by lymphostasis. The aim the study was to analyze the incidence of IT/LR after SLNB, CLND and TLND done due to clinically detected node metastases and factors influencing IT/LR. Methods: Between 05/1995 and 05/2004 1187 consecutive pts underwent SLNB (median Breslow thickness - 2.5 mm) and 224 of them - subsequent CLND. During the same time period 306 pts underwent TLND (median Breslow - 3.9 mm). The margin of excision of primaries was >1cm in all cases. At a median follow-up time of 3 years we analyzed the incidence of IT/LR as the first relapse site and clinico-pathological parameters affecting these recurrences. Results: In SLN negative cases IT/LR were a rare site of the first recurrence (43/963; 4.5%); in SLN+/CLND IT/LR were detected in 34/224 cases - 15.2%. IT/LR in the SLNB group correlated (logistic regression) with SLN metastases (p < 0.0001), higher Breslow thickness (p = 0.0001) and lower extremity localization (p = 0.03). In the TLND group IT/LR were observed in 36/306 pts (11.8%), i.e. insignificantly less than in all CLND pts (p=0.25), but less common when analyzing only pts who relapsed (TLND: 36/190 - 19% vs. CLND: 34/104 - 33%; p = 0.008). Estimated 3-yr overall survival (from the date of relapse) in IT/LR only pts was better than in pts with the other types of relapses after lymphadenectomy (29% vs. 8%; log-rank test: p = 0.0001) (after CLND and TLND: 28% vs. 8% and 30% vs. 7%, respectively). Conclusions: IT/LR incidence in the entire group of SLN+/CLND pts is slightly higher than that observed in TLND melanoma pts, however it is a significantly more frequent type of relapse in CLND - considering only the pts with recurrences. It may imply a more favorable pattern of recurrence after SLNB. The most important factors affecting IT/LR incidence are: the presence of nodal metastases, Breslow thickness and localization on the lower extremity. No significant financial relationships to disclose.