tbuckley/cabot-search huggingface dataset:
Development of automated brightfield <i>HER2</i> and chromosome 17 centromere (CEN17) double <i>in situ</i> hybridization application for breast carcinomas and its performance comparison to manual <i>HER2</i> fluorescence <i>in situ</i> hybridization (FISH)
Authors: H. Nitta, B. Hauss-Wegrzyniak, M. Lehrkamp, F. Gaire, M. Kurosumi, M. Dietel, M. Loftus, J. Pettay, R. R. Tubbs, T. M. Grogan
Journal: Journal of Clinical Oncology (2008)

11080 Background: HER2 dual color FISH is a ‘gold standard’ quantitative assay for selecting breast cancer patients for trastuzumab therapy. Current HER2 FISH procedures are labor intensive, manual methods that require skilled technologists. Also, a specialized fluorescence microscope with oil immersion objectives in a dark room is necessary for the analysis and FISH slides are difficult to archive. Our objectives were: 1) to develop an automated BDISH application for HER2 and CEN17 that produces permanent slides and 2) to compare the assay performance with HER2 FISH tested breast carcinomas cases. Methods: BDISH assay was developed with a nick translated HER2 DNA probe and a CEN17 oligoprobe on an automated slide stainer. Detection of HER2 and CEN17 signals was accomplished with the silver, hydroquinone, and H2O2 reaction and the fast red and naphthol phosphate reaction, respectively. BDISH specificity was optimized with xenograft tumors [MCF7 (non-amplified HER2) and BT-474 (amplified HER2)]. BDISH performance was evaluated with 237 routinely processed breast carcinoma cases. Interpretation was conducted with a conventional brightfield microscope without oil immersion objectives. Data were analyzed for the concordance between BDISH and FISH scores for HER2 gene status assessment. Results: Specific signals for single HER2 copies were visualized as discrete black dots while single CEN17 copies were detected as slightly larger red dots in the same cells of xenograft tumor sections. Overall concordance was 93% between BDISH and FISH of breast carcinoma cases. Interobserver concordance was 97%. Investigation for the discordant cases with BDISH slides revealed that the heterogeneity of tumor cell populations within the same tissue section was a significant reason for the discordance. Conclusions: We successfully developed an automated BDISH assay that is specific for HER2 and CEN17 targets. Our study demonstrated a high concordance between observers interpreting BDISH results of clinical breast carcinoma cases. The majority of BDISH discordance with FISH was due to the tumor cell heterogeneity in the tumor sample. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ventana Medical Systems, Inc. Ventana Medical Systems, Inc. Ventana Medical Systems, Inc. Ventana Medical Systems, Inc. Ventana Medical Systems, Inc. Ventana Medical Systems, Inc.
Multimodality evaluation of excision repair cross-complementation 1 (ERCC1) expression as a predictive biomarker for platinum resistance in epithelial ovarian cancer (EOC).
Authors: C. O. Michie, L. Song, D. Faratian, J. Orr, T. Rye, J. Clark, J. M. Bartlett, D. J. Harrison, D. Melton, A. Williams, C. Gourley
Journal: Journal of Clinical Oncology (2011)

5055 Background: Pre-chemotherapy identification of platinum-resistant EOC would facilitate use of alternative treatment strategies. Small studies have proposed ERCC1 as a platinum resistance marker. Here we evaluate the utility of quantitative ERCC1 mRNA and protein expression as biomarkers in a large cohort. Methods: Tissue microarrays (TMAs) were constructed in triplicate from 470 advanced EOC patients treated with first-line platinum-based chemotherapy and with prospectively collected clinical and survival data. Following ERCC1 antibody validation (FL297 & SC17809 clones), immunohistochemistry (IHC) was performed. The intensity and frequency of positive staining were evaluated by both automated scoring and a human observer blinded to the case details. Quantitative analysis of protein and gene expression were also assessed using automated quantitative analysis (AQUA) of the TMAs and qRT-PCR from mRNA extracted from the same tissue specimens. Expression by each assay was correlated with survival using a minimum p-value method with subgroup analyses taking into account histology, grade, stage and chemotherapy. Results: 457 samples were suitable for IHC/AQUA and 354 for mRNA. There was correlation between IHC results and AQUA (Spearman R value=0.33; p<0.0001), between IHC and mRNA (R=0.16; p=0.002) and between AQUA and mRNA (R=0.12, p=0.03). The median ERCC1 histoscore for patients with platinum-resistant disease (n=171) was 172 (maximum = 300; IQR 154-190), for platinum-sensitive EOC (n=286) was 177 (ns; IQR 160-194) and platinum-refractory disease subset (n=97) 169. No statistically significant difference was identified, either for PFS or OS, for any subgroup analyzed. No trend towards shorter survival in those with higher ERCC1 expression was seen using any assay. Conclusions: Several small studies have suggested that ERCC1 expression, quantified by either IHC or qRT-PCR, can predict platinum resistance. In this, by far the largest cohort, and using quantitative methodologies, we were unable to demonstrate any association with clinical outcome. Using these assays, ERCC1 as a single gene biomarker is not useful in EOC.
A phase I study of XL647, an EGFR, HER2, VEGFR2 inhibitor, administered orally daily to patients (pts) with advanced solid malignancies (ASM)
Authors: H. A. Wakelee, J. M. Fehling, J. R. Molina, J. L. Lensing, R. P. Funke, D. Miles, B. I. Sikic
Journal: Journal of Clinical Oncology (2008)

3528 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis and angiogenesis, including EGFR/ErbB1, HER2/ErbB2 and VEGFR2/KDR. The purpose of the present study is to determine the MTD of daily XL647 dosing, and to evaluate pharmacokinetics and pharmacodynamics in pts with ASM. Methods: Cohorts of ASM pts received escalating dose levels of XL647 daily for repeated 28 day cycles. PK sampling was conducted at each dose level. Plasma markers reflecting effects of XL647 on angiogenesis are being analyzed. Eyebrow hair bulbs from a subset of pts are being evaluated as a potential surrogate for the effects of XL647. DCE-MRI studies are being conducted in pts enrolled in the MTD cohort. Response was assessed by RECIST. Results: Enrollment has been completed with 31 pts enrolled (range 26–79 yrs; 20M/11F). Dose levels of 75 mg (n=3), 150 mg (n=3), 200 mg (n=3), 300 mg (n=18) and 350 mg (n=4) were studied. A DLT of Grade (G) 3 pneumonitis occurred in 1/6 pts at 300 mg. At 350 mg 2/4 pts developed a DLT of clinically asymptomatic G3 QTc prolongation (by machine, G2 by manual re-read): 300 mg was declared the MTD. Twelve pts have been enrolled in the expanded MTD cohort. Nine pts remain on study with the majority discontinued due to PD. Two pts withdrew consent and 2 discontinued due to AEs (G3 pneumonitis and G3/4 transaminitis). To date, twelve pts had SD for > 3mo. The most common AEs include G1/2 rash, diarrhea, fatigue, dysgeusia, and clinically asymptomatic QTc prolongation. Preliminary PK analysis indicates rapid absorption (median tmax = 4 hours) with steady state concentrations reached by Day 15. Average steady state concentrations were about 3.4-fold higher compared to Day 1. XL647 caused a significant reduction in phosphorylation of the downstream signaling kinases AKT and ERK in eyebrow hair bulbs at a dose of 150 mg; analysis continues. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no PK/pharmacodynamic relationships have been identified to date. Conclusions: The MTD of XL647 is 300 mg when administered daily. XL647 is generally well-tolerated at doses up to 300 mg. Phase 2 studies are ongoing in NSCLC pts at this dose level. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Exelixis, Inc. Exelixis, Inc. Exelixis, Inc. Exelixis, Inc. Exelixis, Inc.
Alkylator-Based Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) in Lymphoma: A Registry Study Comparing Thiotepa-, Busulfan-, Melphalan- and Treosulfan-Containing Regimens On Behalf of the EBMT Lymphoma Working Party
Authors: Peter Dreger, Herve Finel, Renato Fanin, Paolo Corradini, Michele Falda, Jürgen Finke, William Arcese, Piero Galieni, Luca Castagna, Domenico Russo, Mats L Brune, Rosanna Scimè, Enrico Maria Pogliani, Fabio Benedetti, Norbert Schmitz, Ariane Boumendil
Journal: Blood (2012)
Assessing information and service needs of adolescents and young adults (AYA) at a large adult tertiary care cancer center.
Authors: A. A. Gupta, K. Edelstein, M. Petrovic, S. M. Smit, N. D'Agostino
Journal: Journal of Clinical Oncology (2011)

e19515 Background: AYA with cancer are a constituency with unique psychosocial and medical needs. Currently, adult oncology programmes are not adequately meeting these needs; focused attention through innovative approaches and programmes are necessary. The objective of this study was to identify important information and service needs of AYA cancer patients. Methods: A modified, validated version of Zebrack’s (2008) supportive care needs survey was administered to ambulatory patients (< age 35 years) who were on therapy or within 5 years of completing therapy. Participants were asked to rate the importance of 18 different sources of information or resources in an AYA programme, on a scale from 1-10. A score of ≥8 was set as the cut off indicating significant importance. Results: Median age of the respondents was 28 years (range 17-35); 61% were male. The most common diagnoses were: lymphoma (28%), leukemia (19%), testis (16%), CNS (9.5%) and sarcoma (8.6%). 40% were currently receiving cancer treatment; the majority were single/never married (67%) and lived at home with their parents (47%) or with a partner (33%). Only 38% of respondents felt it was important or very important to receive their care in a dedicated unit with other young people. More than 80% rated the following items as significantly important: information on their specific malignancy (treatment, risk of recurrence), effects of treatment on fertility, information on maintaining a healthy diet, and exercise/physical fitness during cancer treatment. 50-80% of respondents rated certain items as significantly important including: information on alternative therapy; treatment of infertility; automatic referral to a social worker; counselling to help family members cope; vocational training/education; and counselling for depression, anxiety and emotional stress. Substance abuse counselling and spiritual care resources were rated as significant by < 20% of the sample. Conclusions: AYAs have clear supportive care preferences and needs. Developing programmes that incorporate the services identified as important should improve quality of life, psychosocial adjustment and other outcomes during and after cancer therapy.
Assessment of hyaluronic acid in tumor microenvironment (TME) of intrahepatic cholangiocarcinoma (CCA).
Authors: Leslie Jane Padrnos, Mathieu Marella, Heidi Kosiorek, Komal Thind, Brandon Barrett, Sheryl Garrovillo, Ping Jiang, Taofic Mounajjed, Ramesh K. Ramanathan, Mitesh J. Borad
Journal: Journal of Clinical Oncology (2016)

248 Background: Improved understanding of TME in CCA may allow for development of novel therapeutics targeting stromal components. Hyaluronic acid (HA) is a polysaccharide that has been found in the TME of a number of solid tumors characterized by desmoplastic stroma, such as pancreatic cancer. Elevated HA levels were prognostic in these malignancies. HA prevalence and association with clinic-pathological features in CCA is unknown. Methods: A retrospective study was conducted using clinically annotated formalin-fixed paraffin embedded tissue from resected intrahepatic CCA samples. Specimens were analyzed for HA, scored using a positive pixel count algorithm (Aperio Imagescope) and positivity was calculated as % of total pixel count. Clinical variables were examined by chi-square or ANOVA F-test. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier method and compared via log-rank test. Multivariate analysis was conducted using Cox proportional hazards regression models. Results: 142 patient samples were stained for HA. HA was identified in all samples (100%), with a range of HA positivity of 32.8 – 91.8%. Median HA value was 67.1% and 95% of patients had HA positivity ≥ 45%. Factors associated with higher than median HA ( &gt; 67%) included perineural invasion (PNI) (40% vs. 21%, p = 0.011), necrosis (67% vs. 41%, p = 0.003), lymph node positivity (32% vs. 14%, p = 0.027), and small tumor size ( &lt; 6.8 cm vs. &gt; 8.4cm, p = 0.014). Stratification of HA staining by median positivity value was not an independent predictor of survival based on multivariate analysis. OS for patients with HA &gt; 67% was 40.1 months (mo) vs 48.5 mo with HA ≤ 67%, p = 0.537. PFS for patients with HA &gt; 67% was 14.4 mo vs. 25.7 mo with HA ≤ 67%, p = 0.177. Conclusions: Prevalence of HA staining in resected CCA is higher than seen in many solid tumors and is ubiquitous in our study. Absence of statistically significant association with OS and PFS might be attributable to ubiquitous prevalence, narrow signal range, and association with known negative prognostic factors. Further pre-clinical and clinical evaluation would be warranted.
A Phase I Study of IDH305 in Patients with Advanced Malignancies Including Relapsed/Refractory AML and MDS That Harbor IDH1R132 Mutations
Authors: Courtney D DiNardo, Aaron D. Schimmer, Karen W.L. Yee, Andreas Hochhaus, Alwin Kraemer, Richard D. Carvajal, Filip Janku, Philippe Bedard, Cecilia Carpio, Antje Wick, Gary K. Schwartz, Patrick Schöffski, Patrick Wen, Martin J. van den Bent, Mark Rosenthal, Jessica O'Keeffe, Xueying Chen, Raymond Pagliarini, Virna Schuck, Andrea Myers, Andrew Wei
Journal: Blood (2016)
Effect of prostate-specific membrane antigen (PSMA) radioimmunotherapy on circulating tumor cell (CTC) count.
Authors: Beerinder S Karir, Jaspreet S Batra, Pravin R. Date, Gillian Hodes, Paul J. Christos, Himisha Beltran, David M. Nanus, Neil Harrison Bander, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2015)

199 Background: CTC counts with CellSearch methodology are prognostic; changes following therapy may be associated with improved outcomes. Since FDA clearance, baseline and follow up CTC counts were included in studies of radiolabeled J591. The effect of J591 alone (without an effector molecule) is unknown. Methods: Our phase II single-dose 177 Lu-J591 (Cohort 3), phase I fractionated dose 177 Lu-J591 (expansion cohorts), and phase I fractionated 177 Lu-J591 + docetaxel (all pts) trials were analyzed. Any pt with baseline and at least 1 follow-up CTC count (CellSearch) was included in the analysis. A retrospective subset of patients undergoing J591-based imaging without an effector molecule attached was also analyzed. Results: 48 pts received 177 Lu-J591 with prospectively measured CTC counts with median age of 73.7 years. 26 of 48 (54.2%) had unfavorable (≥5 CTCs/7.5 mL blood) baseline CTCs (median 29, range 5-449 CTCs/7.5 mL). Of the 23 with ≥5 baseline CTCs and available 4-6 wk post-treatment counts, 22 (95.6%) had declines of 15-100%, with 12 (52.2%) converting to favorable counts. Of the 18 with ≥5 baseline CTCs and available 12-14 wk post-treatment counts, 10 (55.5%) had declines of 8-100%, with 7 (38.9%) converting to favorable counts. Of the 22 of 48 (45.8%) with baseline CTC counts &lt;5, 1 became unfavorable at 4-6 wks, later re-converting to favorable (early control rate of 95.5%) and 1 became unfavorable at 12-14 wks (sustained control rate of 95.5%). 7 men with unfavorable counts underwent imaging with 20 mg of J591 without an attached effector molecule; 4 (57%) demonstrated decline in CTCs following the imaging dose, with 1 stable and 2 continued to increase prior to subsequent therapy. Conclusions: In addition to the favorable PSA declines previously reported, radiolabeled J591 results in frequent favorable changes in CTC counts, with &gt;90% of men with baseline unfavorable counts receiving 177 Lu-J591 demonstrating CTC count decline or control in pts with baseline favorable counts. A small retrospective subset suggests that CTC counts may also be controlled with naked (unlabeled) anti-PSMA monoclonal antibody and a prospective study investigating this phenomenon will begin enrollment. Clinical trial information: NCT00195039 , NCT00538668 , NCT00916123 .
Phase I study of sorafenib and cisplatin/pemetrexed regimen in untreated malignant pleural mesothelioma (MPM) patients: Italian SoMe Study.
Authors: V. Mutri, C. Pinto, S. Giaquinta, P. Di Tullio, V. Torri, B. Melotti, F. Sperandi, F. Di Fabio, F. L. Rojas Llimpe, S. Pini, F. Massari, A. Martoni
Journal: Journal of Clinical Oncology (2011)

7087 Background: This phase I study investigated the safety and efficacy of sorafenib in combination with cisplatin and pemetrexed in untreated MPM patients (pts). Methods: Pts with an histological diagnosis of MPM received cisplatin 75 mg/m2 iv and pemetrexed 500 mg/m2 iv on day 1 of a 3-week cycle for a maximum of 6 cycles, and oral sorafenib was administered continuously from day 1 of cycle, at 200 mg twice daily (Level 1) or 400 mg twice daily (Level 2). Maintenance sorafenib treatment was performed at the same level dose in pts with CR/PR/SD. All pts received folic acid and vitamin B12 from 7 to 14 days before the start of treatment until 21 days after the last pemetrexed dose. Tumor response according to RECIST criteria was evaluated by CT-scan every two cycles of chemotherapy. 18F-FDG-PET was performed before the start of treatment and after three weeks. Results: Twelve patients were enrolled (6 pts in each dose level): 11 males, 1 female; median age 61 years (range 43-71); KPS 100 in 2 pts, 90 in 5, 80 in 3, 70 in 2; IMIG stage III in 8 pts, IV in 4; epithelial subtype in 10 pts, sarcomatous in 2; all pts had symptomatic pleural effusion. DLTs were at dose level 1 neutropenia (2 pts G3), thrombocytopenia (1 pt G3), skin toxicity (1 pt G3), and at dose level 2 neutropenia (3 pts G3 and 1 G4), thrombocytopenia (1 pt G3 and 1 G4), skin toxicity (2 pts G3). At the dose level 2 five pts received a dose reduction to 200 mg bid due to toxicity. At least one dose reduction after the 1st cycle of cisplatin/pemetrexed was performed in 1 pt of level 1 and 3 pts of level 2. PRs were observed in 5 (42%) pts (2 pts in level 1, 3 in level 2) and SD in 3 (25%) pts (all pts in level 1); the median TTP was 6 months (range 1-16) and the median OS was 12 months (range 4-23). One pt with PR was submitted to pleuro-pneumonectomy and post-surgery radiotherapy. A marked SUV reduction (>35%) in early PET evaluation after 3 weeks of treatment was observed in all 5 pts with PR. Conclusions: Continuous oral sorafenib 400 mg bid was not tolerated in combination with cisplatin/pemetrexed chemotherapy. Our results in MPM pts suggest a drug interaction that amplifies toxicity with no evidence of tumor control improvement.
Clinical outcome of chemoradiotherapy in patients (pts) with limited-disease small-cell lung cancer (LD-SCLC) with ipsilateral pleural effusion
Authors: S. Niho, K. Kubota, K. Yoh, K. Goto, H. Ohmatsu, N. Saijo, Y. Nishiwaki
Journal: Journal of Clinical Oncology (2008)

7524 Background: The current standard care for LD-SCLC is a combination of chemotherapy and thoracic radiotherapy (TRT). However, the indications for definitive TRT in LD-SCLC and ipsilateral pleural effusion have not been thoroughly investigated. We retrospectively investigated the clinical course and outcome of LD-SCLC pts with ipsilateral pleural effusion. Methods: The medical records of SCLC pts who received treatment at the National Cancer Center Hospital East between July 1992 and December 2005 were reviewed. Fifty-six of the 338 LD-SCLC pts (17%, 95% CI: 13–21%) had ipsilateral pleural effusion and were included in this study. Since about 1998, definitive TRT was routinely performed if the patient's pleural effusion disappeared after induction chemotherapy. The 56 pts were divided into three subgroups: group A included pts who received chemotherapy and TRT (n=23), group B included pts who did not receive TRT in spite of the disappearance of pleural effusion after first-line chemotherapy (n=8), and group C included pts who did not receive TRT and whose pleural effusion persisted after first-line chemotherapy (n=25). Results: All the pts received platinum-based chemotherapy. The response rate was 71%. Ipsilateral pleural effusion disappeared after first-line chemotherapy in 31 pts (55%). The median overall survival time was 12.9 months (95% CI: 10.2–16.9), and the three and five-year survival rates were 14% and 10%, respectively. Four pts have survived for over five years. In groups A, B, and C, the median survival times were 19.2, 14.7, and 9.2 months, respectively, and the three-year survival rates were 22%, 13%, and 8%, respectively. Disease progression was confirmed in 18 of the 23 pts in group A. At the time of disease progression, ipsilateral pleural effusion recurred in 8 of the 18 pts. Conclusions: Long-term survival was achieved by LD-SCLC pts with ipsilateral pleural effusion who successfully underwent chemoradiotherapy. No significant financial relationships to disclose.
Factors associated with histologic versus cytologic diagnosis of lung cancer.
Authors: C. S. Lathan, A. Cronin, J. C. Weeks
Journal: Journal of Clinical Oncology (2011)

6048 Background: In the era of molecularly targeted agents, optimal lung cancer treatment decision making requires high quality pathology, including histologic rather than cytologic results. If there are differences in the likelihood of histologic diagnosis by race, ethnicity, or socioeconomic status (SES), it could contribute to disparities in lung cancer treatment and outcomes. Methods: We evaluated the nature of the pathologic diagnosis among 3760 lung cancer patients enrolled in CanCORS (the Cancer Care Outcomes and Research Consortium), a multi-region population- and health system-based prospective cohort study. Patients were diagnosed in 2002-2005. Patients were classified as having a histologic or a cytologic diagnosis, on the basis of procedures performed from 3 months before to 3 months after diagnosis, abstracted from medical records. A multivariable generalized logistic regression model was fitted to evaluate the association of clinical, sociodemographic, and health system factors on type of diagnosis, conditional on patients’ not having primary surgery for lung cancer. Results: Overall, 44% of patients had a procedure yielding histology (30% with primary surgery and 14% without). Race, SES, and gender were not significantly associated with having a histologic diagnosis. Older patients were significantly less likely to have histology (in reference to age < 65: odds ratio [OR] 0.70 (95% CI 0.51-0.96) for age 65-74 and OR 0.65 (95% CI 0.46, 0.91). for age 75+) In a secondary analysis substituting geographic region for data collection site, we found that patients treated in the South and Midwest (compared to the West) and those receiving care in staff model HMOs were more likely to have cytology only. Conclusions: In the first several years after the approval of targeted agents for lung cancer, the majority of patients were not receiving histologic diagnoses. We did not identify disparities in care by race or ethnicity; but other non-clinical factors including region of the country and health system characteristics appeared to play a role. Future studies should consider the quality of the pathologic information in evaluating disparities in lung cancer treatment and outcomes.
Angiogenesis in Myelopoliferative Neoplasms
Authors: Luis Arthur F. Pelloso, Daniella Marcia Maranhao Bahia Kerbauy, Juliana Correa da Costa Ribeiro, Leonardo Caires Santos, Cesar Cilento Ponce, Maria Regina Regis Silva, L. F. Chauffaille de Lourdes Maria
Journal: Blood (2010)