tbuckley/cabot-search huggingface dataset:
Quantification of MET expression using mass spectrometry (MS): Assay precision and stability in FFPE tumor tissue.
Authors: Todd A. Hembrough, Wei-Li Liao, Sheeno Thyparambil, Les Henderson, Brittany Rambo, Fabiola Cecchi, Donald P. Bottaro, Marlene Darfler, Peng Xu, Shu-Yuan Xiao, Lei Zhao, Timothy D. Veenstra, Jon Burrows, Daniel Virgil Thomas Catenacci
Journal: Journal of Clinical Oncology (2014)

16 Background: Overexpression of MET in gastroesophageal cancer (GEC) is associated with poor prognosis and potentially predictive of anti-MET therapeutic benefit. IHC has been the method chosen to quantify MET expression to date. However, IHC is semi-quantitative, suffers from cross-reactivity, and is low throughput. Moreover, MET IHC is hampered by antigenic instability in FFPE sections, limiting its utility to recently cut FFPE sections. Increasing recognition of the importance of other biomarkers in GEC suggests that ‘economic’ testing of scarce samples will be required. We sought to develop a MET quantitative assay within our ‘GEC-plex’ Liquid-Tissue-selected reaction monitoring (LT-SRM) MS test. Methods: We used trypsin digestion mapping of rMET to identify unique peptides for MS assay development. The assay was pre-clinically validated in 5 cell lines, where electrochemiluminescence (ECL) immunoassay measurement of MET was also performed. To assess the MET MS assay stability from archival FFPE sections, freshly cut FFPE tissue sections were immediately microdissected, processed and analyzed, while adjacent sections were processed and analyzed one year after cutting, to compare temporal quantification from the same FFPE samples (n=33). MET expression was assessed in GEC cases (n=121), and compared to IHC and FISH in select cases. Results: Tryptic digestion mapping of rMET showed that peptide TEFTTALQR was optimal for MET quantification. The LLOD for this peptide was 150 amol with CV&lt;20%. Validation of the MET MS assay on 5 cell lines revealed concordance when compared to ECL (R 2 =0.99). The MET MS assay demonstrated temporal stability of serial sections cut from 33 samples analyzed one year apart: CVs&lt;20%, R 2 =0.75. Analysis of 121 GEC FFPE tissues showed a broad range of MET expression levels (&lt;150-4600 amol/ug), with 36/121 (29.7%) having detectable levels, similar to that observed using IHC. MS expression thresholds were determined that reliably identified MET gene amplification; sensitivity and specificity of these thresholds will be presented. Conclusions: ‘GEC-plex’ has a quantitative, sensitive, and specific MET MS assay that can be multiplexed along with other GEC biomarkers.
Combination Therapy of Humanized Chimeric-Anti-Human VLA4 Monoclonal Antibodies and Anti-Cancer Drugs for AML.
Authors: Takuya Matsunaga, Kazunori Kato, Maki Tanaka, Yukari Masuta, Kageaki Kuribayashi, Naofumi Takemoto, Ikuta Tanaka, Akihito Fujimi, Takehide Akiyama, Hirofumi Hamada, Yoshiro Niitsu
Journal: Blood (2004)
The role of skin toxicities in prolonged pemetrexed treatment: A case-control study.
Authors: A. Ruppert, B. Eguia, J. Fillon, A. Lavole, M. Wislez, V. Gounant, C. Epaud, B. Milleron, C. Frances, J. Cadranel
Journal: Journal of Clinical Oncology (2011)

e18025 Background: Pemetrexed is approved to treat non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), and has an overall favorable toxicity profile. A case of pemetrexed-induced cutaneous adverse events (CAE), i.e., periorbital edema with conjunctivitis and edema of the limbs, leading to severe fluid retention, was diagnosed in our unit. The aim of this study was to evaluate the incidence and risk factors for CAEs. Methods: Patients treated with pemetrexed for NSCLC and MPM were identified from a prospective cohort. In order to detect pemetrexed-associated CAEs, questionnaires were answered by patients and the referring oncologist. Results: Included, were 107 patients treated with > 4 cycles of pemetrexed. Forty-nine patients were alive at the study’s endpoint. Pemetrexed-induced CAEs were observed in 37/107 (35%) of total patients (TP) and 25/47 (53%) of the alive population (AP). Conjunctivitis was the most frequent CAE: 27/107 (25%) in TPs, 21/47 (44%) in APs. Periorbital edema occurred in 16/107 (15%) TPs and 14/47 (30%) APs. Limb edema was present in 14/107 (13%) of TPs and 12/47 (25%) APs. Eleven patients had ≥1 grade 2/3 CAEs. Only two cases of CAE influenced pemetrexed treatment. No significant differences in age, body-surface area, smoking status, and performance status were detected. Patients with CAE had more cycles of pemetrexed (7 vs. 5.5; p=0.028). In univariate and multivariate analysis, gender ratio was statistically different (p=0.031): 48% (12/25) of women in the CAE group vs. only 18% (4/18) in the control group. Conclusions: Pemetrexed induces frequent conjunctivitis, peripheral edema, and edema of the limbs. Female gender appears to be an independent risk for CAE. CAEs are frequently disabling and symptomatic treatment should be proposed, but usually do not need pemetrexed to be stopped. Optimal management of CAEs may help to continue pemetrexed treatment if indicated.
What is the impact of reduction mammoplasty for women undergoing breast-conserving surgery for breast cancer?
Authors: Jolinta Yin-Chu Lin, Rachel Bluebond-Langner, Enid Choi, Sally B. Cheston, Elizabeth M. Nichols, Randi Jill Cohen, Soren Bentzen, Cynthia Drogula, Susan Kesmodel, Emily Catherine Bellavance, Paula Rosenblatt, Katherine Hanna Tkaczuk, Sheri Slezak, Steven J. Feigenberg
Journal: Journal of Clinical Oncology (2015)

49 Background: Reduction mammoplasty (RM) at time of breast conserving surgery (BCS) is an increasingly popular procedure that reduces redundant breast folds and skin toxicity from whole breast irradiation (WBI). However, the tissue manipulation may obscure the lumpectomy cavity (LC) and hinder the ability to deliver a radiation boost to the LC, potentially impacting local control. We studied the impact of RM on acute radiation side effects and the use of LC boost. Methods: From Jan 2012 to Dec 2014, 652 consecutive women with DCIS or Stage I-III invasive cancer were treated with curative intent BCS and WBI at an urban university and 2 community practices. We reviewed the charts on an IRB-approved study with the primary endpoint of ≥ grade 3 radiation dermatitis scored via the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoint was the use of LC boost. Tested variables included age, race, body mass index, menopausal status, multi-focal disease, stage, tumor grade, receptor status, chemotherapy administered, specimen volume, 3D or intensity modulated radiation, fractionation, nodal irradiation, and planning treatment volume (PTV). Student's t-tests and Pearson's chi-square tests were utilized. Results: Forty-three (7%) of 652 patients underwent RM. Larger volumes of tissue were removed from the RM patients (median 366.5 g v 35.3 g, P= 0.0001). No grade 4 toxicities and few (2-3%) grade 3 toxicities were seen, P= 1.00. Narcotic use was similar (4-5%), P= 0.70. A LC boost was used in 476 (73%) patients; RM significantly decreased the use of a boost [16/43 (37%) v 460/609 (76%)], P= 0.0001. RM patients were more likely to have neoadjuvant chemotherapy, stage III or multi-focal disease, higher BMI, nodal irradiation, and conventional fractionation (P&lt; 0.05). Subgroup analysis of the patients with available PTVs (67%) revealed similar volumes (P= 0.16). Conclusions: RM was associated with a decrease in the use of LC boost without significant differences in acute toxicities; however, the result is not surprising given that PTVs were similar. Further investigation is needed to better delineate LCs in patients undergoing RM to increase the use of LC boosts.
The accuracy of endoscopic ultrasonography for identifying stomach neoplasm before endoscopic submucosal dissection.
Authors: Pil Hun Song, Hyun Sung, Jeonghun Lee, Won Jae Yoon, You Sun Kim, Jeong Seop Moon, Soo Hyung Ryu, Sang Woo Lee, Hyun chae Jung
Journal: Journal of Clinical Oncology (2016)

22 Background: The treatment of stomach neoplasm was determined by the identification on of invasion extent and perigastric lymph node through endoscopic ultrasonography (EUS). In this study, we investigated diagnostic accuracy of EUS examination before endoscopic submucosal dissection (ESD). Methods: A retrospective study was conducted to both EUS and ESD for stomach neoplasms that were performed at Seoul Paik Hospital between January 2006 and July 2015. We compared the accuracy of EUS according to the location of lesion, tumor size and ulcer presence or absence on lesion. Results: 49 patients were enrolled in this study; their mean age was 64.14 ± 11.33 years. There were 40 male (81.6%) and 9 female (18.4%) patients. The cases of confined to the mucosa on pathology finding were 41 (83.6%) and involved to submucosal layer(sm) 1 were 3 (6.1%) and sm2 were 2 (4%) and sm3 were 1 (2%) and proper muscle layer were 2 (4%). The cases of lymphatic invasion were 2 (4%). The sensitivity and accuracy of antrum were 91.6 % (95% CI: 0.81-1.03) and 83.3 % (95% CI: 0.70-0.97), body of stomach were 92.3 % (CI: 0.78-1.07) and 83.3% (CI: 0.66-1.00), respectively. Whether lesions were no significant differences in any location. The tumor size was divided by smaller than 20 mm group, 20-30 mm group and more than 30 mm group. The smaller than 20 mm group, 20-30 mm group and more than 30 mm group were 36, 9, 2 patients. The remaining 2 patients were not described. The sensitivity and accuracy of smaller than 20 mm group were 96.6 % (95% CI: 0.90-1.03) and 83.3 % (CI: 0.71-0.95) and 2-30 mm group were 66.7 % (CI: 0.29-1.04) and 77.8 % (CI: 0.51-1.04), respectively. All patients were divided by ulcer presence or not. 27 patients were ulcer presence and 22 patients were not. The sensitivity and accuracy of ulcer presence group were 77.3 % (CI : 0.60-0.95) and 74 % (CI : 0.57-0.90), ulcer absence group were 95 % (CI : 0.85-1.04) and 91 % (CI : 0.79-1.02). Conclusions: The EUS for stomach neoplasm was reliable of lesion without ulcerous finding, smaller than 20 mm in diameter and irrespective of stomach neoplasm location.
MGCD265, an oral Met/VEGFR multitargeted receptor tyrosine kinase inhibitor, in combination with erlotinib: Phase I clinical experience.
Authors: P. J. O'Dwyer, K. P. Papadopoulos, A. W. Tolcher, U. R. Teitelbaum, K. Harlacker, M. Beeram, D. Sohal, M. Mehran, M. Tawashi, M. A. Drouin, C. R. Maroun, J. Wang, M. Fournel, A. Karam, J. M. Besterman, A. Patnaik
Journal: Journal of Clinical Oncology (2011)

3083 Background: MGCD265 targets wild type Met, as well as clinically relevant Met mutants, VEGFR-1,-2 and -3, Ron and Tie-2. MGCD265 combinability with erlotinib is being evaluated in patients (pts) with advanced malignancies. Combining Met and EGFR inhibitors has recently been shown to be synergistic and can overcome resistance to either Met or EGFR inhibitors. Methods: Eligible pts in the initial cohort received MGCD265 at 96 mg/m2 once daily (QD) and erlotinib at 100 mg QD. Subsequent cohorts received full dose erlotinib (150 mg QD) with incremental doses of MGCD265, initially on a QD schedule and thereafter twice daily (BID) during a 21-day cycle. The primary objective was to determine the safety profile. Secondary objectives include anti-tumor activity, pharmacodynamics (PD) and pharmacokinetics (PK). Results: Pt characteristics (n=33): gender: 23 M/10 F; median age: 57 (range 39-76) years; ECOG 0/1: 18/15. Dose limiting toxicities include: diarrhea (1/8 pts at MGCD265 96 mg/m2 QD + erlotinib 100 mg); rash (1/9 pts at MGCD265 144 mg/m2 QD + erlotinib 150 mg) and fatigue (1/9 pts at MGCD265 144 mg/m2 QD + erlotinib 150 mg). The BID regimen of MGCD265 has been introduced at 72 mg/m2. One pt with NSCLC experienced a partial response (after 2 cycles of treatment and continuing) and one pt with gastric cancer had resolution of ascites and a decrease in gastric wall thickness (cycle 15 and continuing). Molecular profiling of the archived tumor biopsy from this latter pt showed high levels of Met and phospho-Met protein expression in the absence of MET and EGFR gene amplification or detectable mutations. Prolonged disease stabilization was observed in another pt with gastric cancer (8 cycles and continuing). Ten other pts completed 4-10 cycles. To date, a decrease in HGF plasma levels was observed in Cycle 1 Day 8. Preliminary PK data with MGCD265 in QD dosing indicated no drug-drug interaction and MGCD265 steady state plasma concentrations were multiples above the IC50 for Met and VEGFR2. Conclusions: Clinical data to date indicate that MGCD265 can be combined with full dose erlotinib with early signs of clinical activity. This combination merits additional testing in NSCLC and gastric cancer.
Frequency of mitochondrial point mutations and deletions in late-stage colorectal cancer patients.
Authors: P. Martin, S. Noonan, M. Biniecka, E. Fox, A. Maguire, J. Hyland, D. O'Donoghue, K. Sheahan, H. Mulcahy, D. Fennelly, J. O'Sullivan
Journal: Journal of Clinical Oncology (2011)

e14144 Background: Defects in mitochondrial function have been proposed to contribute to progression of cancer. This dysfunction may result from impairment in cellular respiration, forcing the cell to revert to glycolysis for energy. This switch causes cells to become cancerous. This study examined the frequency of random mitochondrial mutations and deletions in late stage colorectal cancer tumours and their corresponding normal tissue. This analysis was performed using a novel random mutation capture assay which has the sensitivity to detect one mutation in one hundred million base pairs. Methods: Mitochondrial DNA was extracted from 20 patients with late stage colon cancer and adjacent normal tissue. This DNA was and digested with TAQ 1α for 10 hours.QPCR was performed across the TAQ1α restriction sites. The primer sequences used for identifying random mitochondrial mutations is: 5’ACAGTTTATGTAGCTTACCTCC 3’ and 5’ TTGCTGCGTGCTTGATGCTTGT 3’. The primer sequences used to determine mitochondrial DNA copy number are 5’ACAGTTTATGTAGCTTACCTCC 3’ and 5’-TTGCTGCGTGCTTGATGCTTGT 3. PCR was performed to assess single nucleotide polymorphisms. We will assess mutation frequency of TAQ1 restriction site (TCGA) located in the gene encoding the 12S rRNA subunit (bp 634-637). By flanking multiple TAQ1 restriction sites with a primer pair, the detection prevalence of the RMC assay can be skewed towards DNA deletions. As a result, the expected frequency of a PCR product due to mtDNA point mutations drops exponentially to 1x10-15. In contrast, mtDNA deletions occur at a higher rate, and hence, every mutation detected with these primer pairs will be a deletion. Results: A statistically significant increase in the frequency of deletions was detected in normal versus tumour tissue (p=0.021), however levels of point mutations did not differ between tumour and normal. Conclusions: The lower rate of deletions seen in tumour tissue versus adjacent normal may be explained by the Warburg theory where anaerobic metabolism is predominant in cancer. In contrast, normal cells generate energy by oxidative phosporylation, and cancer cells generate energy through glycolysis which could result in lower levels of mitochondrial deletions in tumours.
Minority patients in clinical trials (CT) for advanced non-small cell lung cancer
Authors: C. K. Obasaju, R. B. Catalano, D. M. Marinucci, J. D. Bloss, L. Taylor, M. J. Monberg, R. L. Comis
Journal: Journal of Clinical Oncology (2005)

7153 Background: The ACS projected 2004 incidence of NSCLC in the US is 150,000 new cases. The most recent NCI Surveillance, Epidemiology and End Results (SEER) data report the incidence of NSCLC in black men is 50% > white men with 17,500 (11.5%) of newly diagnosed cases of NSCLC occurring in black (B)/African-American (AA) pts. US census reports B/AA represent 12.3% of the growing population. Yet minority pts are underrepresented in many reported CTs defining the evidence-based SOC for pts with advanced NSCLC. Efforts to correct this discrepancy are important as we advance the SOC. Through its Alpha Oncology (AO) project, the Coalition of National Cancer Cooperative Groups (CNCCG) has made a concerted effort to engage underserved populations by increasing awareness of and participation in CT. Methods: AO developed a site-profiling tool intended to identify institutions with potential to recruit a minority population that more accurately mimics the SEER characteristics. For NSCLC, urban institutions with multimodality cancer programs offering a comprehensive CT portfolio were solicited. AO also targeted a series of programs toward minority-based community physician practices with the goal of overcoming misconceptions and mistrust associated with CT participation. Results: Between July 2000 and Oct 2004, 917 chemonaive advanced NSCLC pts were enrolled into a randomized three-arm firstline CT. 14.2% minority patients were entered. The median minority accrual from the 12 sites identified through the AO profiling system was 26.1% (range 9.7–54.5) and represented 122/130 (94%) of the total minority pts entered. Conclusions: The lack of minority representation in CT is well reflected in the literature, as well as the difficulties in overcoming the barriers to more even distribution. This program demonstrates that minority involvement can be prospectively targeted and enhanced. However, the means to achieve this more accurate balance by overcoming these barriers usually falls outside the monetary infrastructure set up within the traditional CT system. Clearly, long term meaningful improvement must be multifocal between research sponsors, investigators and the communities and institutions in which they serve. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly
Treatment related morbidities of the central and peripheral nervous system associated with different types of multimodality therapy in breast cancer (BC) survivors
Authors: D. L. Citrin, R. Neelam, T. Lay, M. Bregenzer, E. Staren, D. P. Braun
Journal: Journal of Clinical Oncology (2008)

20706 Background: Multimodality therapy (MMTx) has replaced less complex forms of treatment for most BC pts. Unfortunately, improved tumor control may come at the cost of increased treatment-related morbidities (MBDs) and decreased quality of life. The goal of this exploratory study was to compare the incidence of cognitive and functional disturbances experienced by BC pts treated with different forms and complexities of MMTx. Methods: The study population consisted of 45 BC pts who, following mastectomy or lumpectomy received either double (n=24) or triple (n=21) modality treatment with chemotherapy (CTx), hormonal Therapy (HTx) and/or radiation therapy (RTx). All Pts were seen in an Aftercare Program for monitoring and management of health status during treatment and recovery. They received a standardized questionnaire querying the presence and severity of 14 separate MBDs affecting quality of life. Documentation of the presence and severity of MBDs and initiation of management strategies occurred during regular clinical followup. Results: In BC pts who received CTx + HTx (n=13) moderate to severe memory disturbances (31%), neuropathy (23%) and fatigue (23%) were seen. The corresponding values for BC pts receiving CTx + RTx (n=11) were 45%, 45%, and 41%. In pts treated with CTx+RTx+HTx, the values for memory disturbance, neuropathy and fatigue were 26%, 21%, and 32% respectively. No statistical difference by chi-squared analysis was detected for any MBD in multiple comparisons between either double or triple modality treatment groups. Moreover, there was no relation between time off Tx and the incidence of memory disturbance or neuropathy in any group. Fatigue was the only MBD which improved with increased time off therapy. Conclusion: While this exploratory study was based on the expectation that changes in the incidence of specific treatment related MBDs would be detected when comparing comparable BC pt populations treated with increasingly complex forms of MMTx, the results demonstrated that this was not true. Rather, it appears that pharmacogenomic factors may be the primary determinant of MMTx-related MBDs of central and peripheral nervous system functions and fatigue in BC survivors. No significant financial relationships to disclose.
M281: A Therapeutic Anti-FcRn Blocking Antibody for Rapid Clearance of IgG and IgG Autoantibodies in Immune Cytopenias and Other Auto/Allo-Immune Disease
Authors: Leona E Ling, Sucharita Roy, Thomas Daly, Edward Cochran, Steven Tyler, Lynn Markowitz, Dorota Bulik, Amit Choudhury, James Meador, Viraj Parge, Divya Mekala, Sandra Sipsey, Srishti Gurnani, Jay Duffner, Stan Lee, Nathaniel Washburn, Robin Meccariello, John Schaeck, Jing Wang, Birgit Schultes, Jan L. Hillson, William Avery, Ganesh V. Kaundinya, Anthony M. Manning
Journal: Blood (2015)
Comparative effectiveness of radical cystectomy versus bladder-sparing treatment for muscle-invasive urothelial carcinoma: A population-based report.
Authors: Maxine Sun, Giorgio Gandaglia, Pierre I. Karakiewicz, Jim C. Hu, Simon P. Kim, Paul Linh Nguyen, Toni K. Choueiri, Firas Abdollah, Quoc-Dien Trinh
Journal: Journal of Clinical Oncology (2014)

334 Background: Radical cystectomy (RC) represents the standard of care for patients with muscle-invasive urothelial carcinoma of the urinary bladder (UCUB). Alternative organ-conserving treatments such as chemotherapy and/or radiotherapy have gained interest. We sought to compare survival outcomes of patients according to treatment modalities, in a stage-for-stage analysis. Methods: We relied on the Surveillance, Epidemiology, and End Results Medicare-linked database to identify 12,950 patients diagnosed with T2–T4a N0/x M0 UCUB between years 1992 and 2009. Treatment types include RC (n=5207), chemotherapy/radiation (n=2,669), and surveillance (n=5,074). Following instrumental variable analysis, Cox- and competing-risks regression analyses were performed for prediction of overall survival (OS) and cancer-specific mortality (CSM), respectively. All analyses were stratified according to disease stage (T2, T3, T4a). Results: After adjusting for potential confounders, OS was more favorable for RC relative to chemotherapy/radiation (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.02–2.40) or surveillance (HR: 1.82, 95% CI: 1.20–2.78) in patients with T2 UCUB. For the same stage, CSM rates were lower in the surgery group compared to chemotherapy/radiation (HR: 2.05, 95% CI: 1.14–3.67) or surveillance (HR: 1.95, 95% CI: 1.09–3.48). When analyses focused on individuals with more advanced disease (T3–T4a), no statistically significant difference was observed between chemotherapy/radiation relative to RC for both OS and CSM. Conclusions: In the current retrospective population-based cohort, RC was associated with improved survival outcomes relative to its alternative treatment counterparts. However, this effect was only observable in patients with T2 disease. Conversely, no difference between chemotherapy/radiation vs. surgery was noted in patients with more advanced disease stage.