tbuckley/cabot-search huggingface dataset:
Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors.
Authors: Y. Kang, C. Yoo, B. Ryoo, H. Chang, J. Lee, M. Beck, T. Kim, M. Ryu
Journal: Journal of Clinical Oncology (2011)

306 Background: Pharmacokinetic study in patients with gastrointestinal stromal tumors (GISTs) suggested that plasma concentrations of imatinib decrease following long-term exposure. We therefore measured changes in imatinib plasma trough levels (C min ) after long-term exposure. Methods: Between November 2009 and May 2010, follow-up (FU) imatinib C min was measured in 65 patients who received the same dose of imatinib for at least 9 months after a previous baseline (BL) measurement. Total 244 blood samples were obtained (127 at BL and 117 at FU) and plasma level was measured by liquid chromatography-tandem mass spectrometry. Results: Median patient age was 54 years (range, 28–76 years) and 42 (64.6%) patients were male. Sixty-one (93.8%) patients were treated with 400 mg/day imatinib and 4 (6.2%) with 300 mg/day. The median interval from initiation of imatinib to BL test was 6.4 months (range, 0.5–66.6 months), and the median interval between BL and FU test was 13.1 months (range, 9.6–18.4 months). The mean ± standard deviation imatinib C min was significantly higher at FU than at BL (1442 ± 693 ng/mL vs 1221 ± 624 ng/mL, p&lt;0.001). The mean inter- and intra-subject variabilities were 49.2% and 25.5%, respectively, at BL, and 44.2% and 20.4%, respectively, at FU. Multivariate analysis showed a significant correlation between the ratio of FU to BL imatinib C min and that of albumin (r=-0.397, p=0.001). In per-sample analysis, imatinib C min was significantly correlated with age, hemoglobin, albumin, creatinine clearance, previous major gastrectomy and time between initiation of imatinib and plasma level tests. Conclusions: Steady-state imatinib C min did not decrease but remained stable in most GIST patients during long-term treatment. Changes in imatinib C min were associated with changes in albumin concentration. Monitoring of imatinib C min only for concerns about time-dependent decreases in imatinib exposure is not necessary. [Table: see text]
Individualized indication for neoadjuvant treatment based on metabolic response Assessed by 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in adenocarcinoma of the esophago-gastric junction (AEG)
Authors: F. Lordick, K. Ott, W. A. Weber, H. J. Stein, K. Becker, H. Wieder, N. Roethling, M. Hennig, C. Peschel, M. Schwaiger, J. R. Siewert
Journal: Journal of Clinical Oncology (2005)

4041 Background: FGD-PET was found to be a valuable tool for the prediction of response during neoadjuvant chemotherapy (CTx) in locally advanced AEG. Histological responses were seen in 53% of metabolic responders whereas in unselected patients the rate was found to be only 24% (JCO 2001; 19: 3058–65). In the MUNICON protocol the indication for two courses of neoadjuvant chemotherapy depends on early metabolic response assessed by FDG-PET. Methods: Patients (pts) with cT3 AEG receive neoadjuvant platin/5FU-based CTx. By definition, pts with a decline of FDG tumor uptake >35% 2 weeks after the onset of CTx compared to baseline PET are metabolic responders. They continue with CTx for a duration of 3 months. Metabolic non-responders discontinue CTx and proceed to surgery. Histological response is defined as <10% residual tumor cells in the resected tumor. The primary endpoint of this study is to compare survival in responding and non-responding pts. Results: 96 pts (median age 61 yrs, range 35–77; 90 males) have been enrolled so far, 50 pts are metabolic responders (52%), 45 pts are non-reponders (47%), 1 pt (1%) died before response assessment. 87/96 pts (91%) underwent resection. R0 resection was achieved in 72/96 pts (75%), thereof 44/50 metabolic responders (88%) and 28/45 non-responders (62%). Histological remission was seen in 26/96 pts (27%). All of them had been classified as metabolic responders, indicating a histological response rate of 52% in this group. None of the metabolic non-responders had achieved a major grade of histological regression. Data on survival are not part of this analysis. Recruitment will be finished until 5/2005. Conclusions: The interim analysis of the MUNICON trial confirms previous findings. An individualized treatment approach in locally advanced AEG proves to be feasible. Early metabolic response assessment by FDG-PET aids to select patients for neoadjuvant chemotherapy who have a good chance for histolopathological response. No significant financial relationships to disclose.
Incidental prostate cancer in patients with radical cystectomy for bladder cancer.
Authors: Hooman Djaladat, Max H. Bruins, Eila C. Skinner, Gus Miranda, Jie Cai, Hamed Ahmadi, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2013)

225 Background: Radical cystectomy is the gold standard surgical treatment for invasive bladder cancer. Prostate adenocarcinoma is often found incidentally in the cystoprostatectomy specimen. The clinical significance of this type of cancer has not been well characterized. We reviewed the cohort of male patients with bladder cancer who underwent radical cystectomy and found to have incidental prostate adenocarcinoma. Methods: 1,964 patients with primary transitional cell carcinoma of bladder underwent radical cystectomy between 1971 and 2008 with a median follow-up of 12.1 yrs (0.1-36) at USC. 1553 of them were male (79%) and 559 (36%) had incidental pathologic prostate adenocarcinoma (PC-group). Prostate and bladder cancer characteristics, recurrence and overall survival (OS) in the cohort of PC-group are reviewed. Results: Median age in the PC-group was 69 yo (35-92). The incidental PC was organ confined (OC) in 527 patients (94%). 32 (6%) had non-OC prostate cancer, treated by adjuvant radiation (5), hormone ablation (3) with a median follow-up of 3.9 yrs (0.1-16). Median pre-op PSA was 1.66 (0.01-83) in PC-group and 1.31 (0.01-33.2) in non-PC group. Gleason score was ≤ 6 in 458 (82%), 7 in 78 (14%) and ≥ 8 in 12 (2%) cases. Reviewing bladder cancer in the PC vs. non-PC group, 84 and 83% had high-grade cancer, 63 and 58% had associated CIS, 41 and 36% had multifocal disease and 29 and 27% had LVI respectively (P &gt; 0.05). Incidental PC did not have significant effect on recurrence (P=0.3) and OS (P=0.4) after cystectomy for bladder urothelial cancer. No patient died of PC. 5-year OS rate was 60 ± 2% in both PC and non-PC groups. 10-year OS rate was also comparable at 42 ± 2% in PC and 44 ± 2% in non-PC-group. Conclusions: Incidental prostate adenocarcinoma is reported in more than one third of patients who undergo radical cystectomy for bladder cancer. It is organ confined in most of the cases and has no correlation with bladder cancer stage. Outcome of patients with incidental prostate adenocarcinoma at the time of radical cystectomy relies exclusively on the bladder cancer.
Ibrutinib + durvalumab (MEDI4736) in patients (pts) with relapsed or refractory (R/R) pancreatic adenocarcinoma (PAC): A phase Ib/II multicenter study.
Authors: Erkut Hasan Borazanci, David S. Hong, Martin Gutierrez, Drew W. Rasco, Tony R. Reid, Michael H. Veeder, Ahmed Tawashi, Jennifer Lin, Isaiah W. Dimery
Journal: Journal of Clinical Oncology (2016)

TPS484 Background: PAC is an aggressive disease characterized by poor prognosis and is inadequately treated with available therapies. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase (BTK) that was shown to inhibit mast cell degranulation in the PAC tumor microenvironment with subsequent inhibition of tumor cell proliferation, angiogenesis, and collagen deposition (Chang, 2011; Masso-Valles, 2015). Durvalumab, a human IgG1 monoclonal antibody (mAb), binds PD-L1 with high affinity and prevents interaction with PD-1 and CD80 (IC 50 values of 0.1 nM and 0.04 nM, respectively), facilitating antitumor T-cell responses (Stewart, 2015). Ibrutinib + anti-PD-L1 mAbs inhibited tumor cell growth and led to enhanced anti-tumor immune responses in mouse models (Sagiv-Barfi, 2015). This trial (PCYC-1135; NCT02403271) evaluates the safety and efficacy of ibrutinib + durvalumab in pts with PAC, breast cancer, and non-small cell lung cancer. Study details presented here focus on the cohort of pts with PAC. Methods: Key inclusion criteria include pathologically confirmed PAC, R/R disease (failed ≥ 1 prior systemic therapy), stage III-IV disease, ≥ 1 measurable lesion by RECIST 1.1 criteria, and adequate hematologic, renal, hepatic function. Key exclusion criteria include any history of central nervous system involvement; prior treatment with ibrutinib/BTK inhibitor or treatment with antibodies targeting PD-1, PD-L1, PD-L2, CD137, or CTLA-4; history of allogeneic organ transplant; or treatment with a strong cytochrome P450 3A inhibitor. Primary objectives are safety, tolerability, and efficacy of the combination; secondary objectives include pharmacokinetics and pharmacodynamic assessments of the combination. The phase 1b portion will assess the dose-limiting toxicities (DLTs) and determine the recommended phase 2 dose (RP2D). Ibrutinib will be administered at the standard dose with the potential for dose level reductions if DLTs occur in combination with durvalumab. After RP2D determination, enrollment in phase 2 will occur until a total of 130-160 pts (across all 3 disease cohorts) are treated. Enrollment for phase 1b began in March 2015. Clinical trial information: NCT02403271.
Using a combination of urine and plasma biomarkers for the development of a scoring sytem that can diagnose and predict prognosis of prostate cancer.
Authors: Maher Albitar, Wanlong Ma, Kevin Diep, Ferras S. Albitar, Herbert A. Fritsche, Neal D. Shore
Journal: Journal of Clinical Oncology (2014)

163 Background: Relying solely on serum prostate-specific antigen (sPSA) to screen for prostate cancer (PCa) can lead to unnecessary biopsies. Biomarkers from urine and plasma were isolated to develop a detection scoring system for the presence of prostate cancer as well as to better predict aggressiveness. Methods: Urine and plasma specimens were analyzed from 141 patients (61 newly diagnosed PCa patients, 60 benign prostate hyperplasia (BPH) patients, and 20 post-prostatectomy patients) using polymerase chain reaction (PCR) for the levels of UAP1, PDLIM5, IMPDH2, HSPD1, PCA3, PSA, TMPRSS2, ERG, GAPDH, and B2M genes. Patient age, sPSA level, and PCR data were entered through multiple algorithms to determine models most useful for detection of cancer and predicting aggressiveness. Results: We developed an algorithm for distinguishing PCa from BPH (area under the receiver operating characteristic curve [AUROC] of 0.78). Another algorithm distinguishes patients with Gleason Score (GS) ≥ 7 from GS &lt; 7 cancer or BPH (AUROC of 0.88). By incorporating the two algorithms into a scoring system, 75% of the analyzed samples showed concordance between the two models (99% specificity and 68% sensitivity for predicting GS ≥ 7), and 25% showed discordance. Conclusions: A scoring system incorporating two algorithms using urine and plasma biomarkers highly predicts the presence of GS ≥ 7 PCa in 75% of patients. In 25% of patients, the system can be used only to distinguish between the presence of cancer and benign pathology. Our algorithms may assist with both biopsy indication as well as patient prognosis. [Table: see text]
Validation of the Decipher prostate cancer classifier for predicting 10-year postoperative metastasis from analysis of diagnostic needle biopsy specimens.
Authors: Cristina Magi-Galluzzi, Kasra Yousefi, Zaid Haddad, Beatrix Palmer-Aronsten, Lucia L.C. Lam, Christine Buerki, Jianbo Li, Michael W. Kattan, Andrew J. Stephenson, Elai Davicioni, Eric A. Klein
Journal: Journal of Clinical Oncology (2016)

59 Background: Accurate riskstratification after diagnosis of prostate cancer (PCa) is key to optimal treatment decision-making. Decipher is an extensively validated genomic classifier of metastasis after radical prostatectomy (RP). Here, we evaluate its ability to predict metastasis from analysis of prostate needle biopsy diagnostic tumor tissue specimens in a cohort of intermediate risk PCa patients treated with RP. Methods: Fifty-seven patients with available diagnostic biopsy specimens were identified from a previously reported post-RP validation study of Decipher in a cohort of 169 patients treated at Cleveland Clinic. The core with at least 1mm tumor of the highest Gleason grade was sampled and subjected to whole transcriptome analysis. Decipher was calculated based on a locked random forest model. Cox multivariable (MVA) proportional hazards model and survival c-index were used to evaluate the performance of Decipher. Results: 61% of patients had biopsy Gleason score 6 and 67% of patients had NCCN intermediate risk disease. With a median 8 years follow up, 8 patients metastasized and 3 of these patients died of PCa. Decipher had a c-index of 0.80 (95% confidence interval [CI], 0.58-0.95) compared to 0.58 (95% CI, 0.18-0.91) for biopsy Gleason score and 0.57 (0.57; 95% CI, 0.23-0.89) for preoperative PSA at 10 years post-RP for prediction of metastasis. A combined model consisting of Decipher, preoperative PSA, and Gleason score had a c-index of 0.84 (95% CI, 0.68-0.96). On MVA, Decipher was the only significant predictor of metastasis when adjusting for age, preoperative PSA and biopsy Gleason score (Decipher hazard ratio per 10% increase: 1.72; 95% CI, 1.04–2.83; P = 0.02). Conclusions: Decipher was able to predict metastatic outcome from diagnostic biopsy specimens in a cohort of primarily intermediate risk men treated with RP. This additional genomic information may help identify patients who may not be optimal candidates for active surveillance and better identify appropriate first line therapy for men with intermediate risk disease.
Expression of EGFRvIII in brain tumor stem cells
Authors: A. Wong, S. Mitra, C. A. Del Vecchio, S. Skirboll
Journal: Journal of Clinical Oncology (2008)

2002 Background: The presence of cancer stem cells (CSCs) has been demonstrated for glioblastomas (GBMs) and medulloblastomas. To target brain tumor CSCs and not normal stem cells, it would be desirable to identify specific markers. CD133+ has been used to isolate CSCs, but is also present on neural and hematopoietic stem cells. A tumor specific alteration of the EGF receptor, EGFRvIII, is present in many solid tumors, making it ideal for targeted therapies. We asked if EGFRvIII is expressed in brain tumor CSCs. Methods: Freshly resected brain tumors were dissociated using a modified protocol to preserve cell surface makers. Cells were then directly propagated in defined serum free stem cell growth media or first sorted for CD133 and EGFRvIII using FACS and then grown in defined media. Western blots and/or RT-PCR was used to analyze cells for expression of EGFRvIII and stem cell markers. Results: Tumor spheres were isolated from all brain tumors attempted: 11 GBMs, 1 ependymoma, 2 medulloblastomas and 1 atypical teratoid/rhabdoid tumor. All primary tumor spheres could form secondary tumor spheres, indicating an ability to self-renew. 8 of 11 GBM tumor spheres were positive for EGFRvIII, as well as 1/1 ependymoma, 1/2 medulloblastomas and 1/1 AT/RT. While EGFRvIII is rapidly lost when brain tumors are maintained in culture, EGFRvIII expression was present for up to 3 months in the tumor spheres. To verify this was an enriched stem-cell population, we showed co-expression of EGFRvIII with the stem cell markers CD133, Sox2, and nestin. EGFRvIII expression was lost when the tumor spheres were exposed to differentiation conditions (serum, NT3, BMP, BDNF and GDNF), suggesting EGFRvIII expression is limited to CSCs. In FACS sorted GBM cells, EGFRvIII was co-expressed with a high fraction (70±8%, n=8) of the CD133+ population, confirming EGFRvIII is present on CSCs. In an in-vitro limiting dilution assay, EGFRvIII+/CD133+ cells from GBM tumors (n=3) have an approximately 2–3 fold higher propensity to form spheres compared to the presence of EGFRvIII or CD133 alone, while EGFRvIII-/CD133- cells showed little viability. Conclusions: These data suggest that EGFRvIII is frequently expressed in GBM tumor stem cells and may be present in other types of brain tumor CSCs. The EGFRvIII+ population is more viable and so it may be a useful marker to define CSCs. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Celldex Therapeutics Celldex Therapeutics
Stress and empathy among internal medicine trainees on an inpatient hematology-oncology ward.
Authors: Daniel Curtis McFarland, Katherine Kirkwood, Robert G. Maki
Journal: Journal of Clinical Oncology (2014)

231 Background: Effectively managing patient distress in oncology is challenging. Just as patients and their families experience distress over cancer, trainees in oncology also experience distress. This study evaluates whether increased physician-in-training distress acutely reduces empathy. Terror Management Theory provides the theoretical framework for the hypothesis. Methods: 35 internal medicine interns and residents completed a pre and post rotation Impact of Events (IES) and Interpersonal Reactivity Index (IRI) for comparison after 2-4 weeks. IES and IRI measure distress and empathy respectively. Results: Overall IRI empathy decreased (paired t-test, p=0.02) but only significantly in the Fantasy subscale (p=0.008). Empathy scores were below historical controls and did not differ between males and females (p=0.06). Pre and post rotation IES scores averaged 19.7 and 20.7. Distress was significant (&gt;8) in 82% and 88% and severe (&gt;33-PTSD range) in 20% and 22% of Pre/Post IES, respectively. Time on the ward averaged 2.6 weeks and residents attended to 4.6 actively dying patients, of which 38% stated it was "the most stressful experience"; however, 56% found "meaning" in the work. 48% mentioned patient death as the traumatic event (responding to IES). Conclusions: Residents demonstrated pathological levels of distress which affected aspects of empathy in a short period of time and related predominately to death experiences. Ultimately, physician self-management of vicarious distress during oncology training and enhanced maintenance of empathy could improve patient distress management, but this idea will require further study. [Table: see text]
Resource utilization among neuroendocrine tumor patients in the United States.
Authors: Roman Casciano, Maruit Chulikavit, Rohan Parikh, Lee Stern, Zhimei Liu, Xufang Wang, Kris Grzegorzewski, Jonathan R. Strosberg
Journal: Journal of Clinical Oncology (2012)

e14627 Background: Neuroendocrine Tumors (NET) constitute over 100,000 prevalent cases in the United States (US), with predicted increase of incidence in the future. Advanced NET is associated with significant morbidity and mortality. Resource use was assessed for managing advanced NET. Methods: As part of a global study, an online survey was administered to US physicians to quantify resource use among advanced pancreatic (pNET) and lung/gastrointestinal (GI) NET patients. The study collected resource use data (treatments, visits with survey and other physicians, surgery and hospitalizations) for baseline (diagnosis to 1 st progression of disease [PD]), 1 st and 2 nd PD periods. PD was defined as measurable/radiographic evidence of tumor progression. As patients with 2 nd PD were likely to be less, resources were estimated in a hypothetical scenario. Results: 55 US physicians provided data on 110 NET patients (36.4% pNET, 63.6% Lung/GI NET). Average follow up in baseline was 14.0 and 13.3 months for pNET and Lung/GI NET, respectively; in 1 st PD period, it was 5.7 and 7.9 months, respectively. For 2 nd PD, it was assumed to be 12 months. Table 1 shows resource use for baseline and 1 st PD. Increased use of chemotherapy, somatostatin analogs, hospitalization and other physician visits was observed during 1 st PD, especially for pNET patients. Targeted therapy use was minimal at baseline and 1 st PD; however it may increase in 2 nd PD. Conclusions: Among advanced NET patients, resource use is generally high and there appears to be an increase in resource use upon PD, especially in patients with pNET. [Table: see text]
Radiation-induced lung and heart toxicity in patients with early-stage breast cancer treated with hypofractionated radiotherapy following breast-conservative surgery.
Authors: Ioanna Fragkandrea-Nixon
Journal: Journal of Clinical Oncology (2013)

73 Background: Hypofractionated RT for breast cancer (BC), although reducing cost and time, could have negative impact on normal underlying lung and heart. We studied and compared lung function and the post –RT radiological changes using High–Resolution CT (HRCT) in early BC patients, treated with 3-D conformal whole breast radiotherapy (WBRT) using either conventional or hypofractionated regime. Additionaly, in patients with right-sided breast cancer, we monitored changes in LVEF performing MUGA scans. Methods: Between 2008 and 2009, 61 early BC patients (TI-2N0M0) were randomised into Group A (n=31) and Group B (n=30) receiving standard radiotherapy with 50Gy/25f/5w plus boost 10Gy/5f/1w to tumour bed or 43.2Gy/16f/22d plus same boost dose respectively. All patients were subjected to dynamic lung testing, on D0 (before RT), during and after RT at 3 and 6 months. HRCT scans were performed at baseline, and 3, 6, 12 months after RT. Dosimetric factors (CLD, V20, D25, MLD) were calculated. MUGA was performed in patients with right sided BC prior and 6 and 12 months post RT. Results: At 3 months after RT, pulmonary changes were classified at HRCT as follows: 91.8% were Grade 0, 8.19% Grade 1, and 0% Grade 2. At 6 months, 86.98% were Grade 0, 11.47 % Grade 1, and 1.6% Grade 2. At 12 months, 88.52% were Grade 0, 9.19 % Grade 1 and 3.27% Grade 2. Univariate analysis showed strong association between radiation pneumonitis, age and all dosimetric parameters. There was no association between fractionation type and incidence of RN. FEV1, FVC, FEV 25, FEV 50 and DLCO showed no statistically significant reduction in both treatment groups in 3 and 6 months following RT, compared to baseline. Multivariate analysis showed no relation between HRCT findings and age, smoking, chemotherapy, hormonotherapy, V20. No changes were found in LVEF prior and 6 and 12 months post radiotherapy. Conclusions: Lung toxicity as assessed with HRCT and PFTs was minimal in both treatment arms and our results are in consistency with other published data. In our series, no significant changes were found in LVEF in both treatment arms.