tbuckley/cabot-search huggingface dataset:
A novel combinatorial therapy using cytolytic NK cells and anti-EGFR moAb to improve the treatment of EGFR expressing solid tumors.
Authors: Jan Spanholtz, John Veluchamy, Henk M.W. Verheul, Tanja D. de Gruijl, Hans J. Van Der Vliet
Journal: Journal of Clinical Oncology (2015)

e14017 Background: The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. However, NK cell therapy directed against solid tumors is under early development. Epidermal growth factor receptor (EGFR) targeted therapies using monoclonal antibodies (moAbs) such as Cetuximab and Panitumumab are widely used for the treatment of colorectal cancer and head and neck squamous cell carcinoma. The clinical efficacy of this approach has been hampered by several factors, including mutations in RAS, allowing tumors to escape from anti-EGFR moAb therapy. It is well established that NK cells can kill tumor cells by natural cytotoxicity and additionally be activated upon binding of moAbs through Fc receptors (FcγRIIIa) mediating antibody dependent cellular cytotoxicity (ADCC). Methods: In the current setting we combined isolated and activated Peripheral Blood NK cells (PBNK) with anti-EGFR moAbs to increase killing of EGFR+cancer cell lines, including those with RAS mutations. Results: In vitro 4h cytotoxicity experiments using cell lines SW480 (EGFR+, RASmut, BRAFwt) and COLO320 (EGFR-, RASwt, BRAFwt), at a low E:T ratio of 1:1, demonstrated that PBNK cells can kill RAS wild type (COLO320, 30 ± 14 % n = 7), and RAS mutant (SW480, 16 ± 9 % n = 5) tumor cells irrespective of their EGFR expression levels. Furthermore, killing of SW480 was significantly higher (p < 0.0001) upon co-culture with NK cells in the presence of Cetuximab (28 ± 6 %, n = 5), whereas the killing of COLO320 was not increased, as expected, upon addition of anti-EGFR moAbs. Conclusions: Cetuximab mediated higher CD16 dependent anti-tumor ADCC activity of NK cells on EGFR expressing RAS mutant tumor cells as compared to Panitumumab. Overall our studies provide a clear rationale to further develop NK cell immunotherapy in combination with Cetuximab for patients with EGFR+ solid tumors.
Prognostic value of mid-treatment total lesion glycolysis in p16+ oropharyngeal cancer.
Authors: Erqi L. Pollom, Jie Song, Ben Y Durkee, Sonya Aggarwal, Timothy Bui, Ruijiang Li, Quynh-Thu Le, Billy W. Loo, Wendy Hara
Journal: Journal of Clinical Oncology (2015)

6047 Background: To determine whether total lesion glycolysis (TLG) measured during radiation for locally advanced oropharyngeal cancer (OPC) correlates with outcomes. Methods: Patients with Stage ...
Investigation of a possible escape mechanism in colorectal cancer patients
Authors: M. Bueter, M. Gasser, D. Meyer, N. Schramm, A. Mueller, A. M. Gassel, A. Trumpfheller, S. Mueller, A. Thiede, A. M. Waaga-Gasser
Journal: Journal of Clinical Oncology (2004)

2588 Background: Anti-tumor specific immune responses are modulated during tumor development via different escape mechanisms abrogating immunological tumor destruction. We analyzed p53 specific immune responses in colorectal cancer patients depending on UICC stage and characterized their regulatory T cell functions independent of the p53 mutational status. Methods: Peripheral blood lymphocytes (PBMCs) from patients (UICC-stage I-IV, n=24) were stimulated with 10 pools of synthetic overlapping p53 peptides encompassing the full length wild-type (wt) p53 sequence and Il-10 and IFN-γ expression was assessed (ELISA, ELISPOT). PBMCs, tumor specific cells, and tumor specimens were further characterized (cytospins, FACS, immunohistology).Results: Lymphocyte stimulation with the peptide pools resulted in distinct residues inducing a Th2 (IL-10, n=24) or Th1 (IFN-γ, n=10) type response. T cells from UICC III (n=7) and IV (n=7) patients expressed more IL-10 in response to p53 peptide (residues 291–330) than those in UICC I and II (n=6) (26 and 62 spots/105 cells vs 14 spots/105 cells, respectively), indicating that the UICC stage may be crucial in IL-10 production in response to p53 peptides. In contrast, residues 331–370 led to IFN-γ production but no correlation was observed between UICC stage and Th1 response. Markedly elevated amounts of CD4+, CD25+, and CD56+ cells in the PBMCs, as well as intensified staining for p53 (clone DO-7) were observed in patients expressing higher levels of IL-10 (cytospins, immunohistology). Conclusions: Within the whole p53 protein sequence comparably more determinants inducing a Th2 type immune response were observed suggesting that the type of the tumor specific immune response to p53 depends on presentation and recognition of specific wt p53 residues. IL-10 production seems to overweigh IFN-γ indicating that specific p53 epitopes may directly influence the outcome of immunological surveillance in colorectal cancer patients. This study offers new insights in a possible mechanism facilitating the tumor to escape immune surveillance by inducing rather a Th2 (tolerance) than Th1 type response (destruction) through p53 overexpression. No significant financial relationships to disclose.
Analysis of prognostic factors after 16 years of follow-up in a randomized phase II trial of neoadjuvant FAC compared with CMF in stage III breast cancer.
Authors: Julieta Leone, Jose Pablo Leone, Carlos Teodoro Vallejo, Juan Eduardo Perez, Alberto Omar Romero, Mario Raul Machiavelli, Luis Romero Acuna, Maria Ester Dominguez, Mario Langui, Hebe Margot Fasce, Bernardo Amadeo Leone, Eduardo Ortiz, Julian Iturbe, Ariel Osvaldo Zwenger
Journal: Journal of Clinical Oncology (2013)

11118 Background: Neoadjuvant chemotherapy is a standard treatment in stage III breast cancer. Prognostic factors can help to identify patients (pts) with high risk of recurrence. The aim of this study was to assess several prognostic factors after a long follow-up, in stage III breast cancer pts, treated with neoadjuvant chemotherapy. Methods: We evaluated 126 pts with stage III breast cancer that participated in a phase-II randomized trial of neoadjuvant 5-fluorouracil, doxorubicin and cyclophosphamide (FAC every 21 days) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF days 1 and 8 every 28). Chemotherapy was administered for three cycles prior to definitive surgery and radiotherapy, and then for six cycles as adjuvant. Response was assessed by WHO criteria. Results: The median age was 52 years (range 24-75). Median follow-up was 4.5 years (range 0.2-16.4), disease free survival (DFS) 4.8 years and overall survival (OS) 6.4 years. Results of the phase-II study showed no difference in efficacy between groups. Univariate analysis showed that the number of pathologically involved lymph nodes (pLN), pathologic response and estrogen and progesterone receptor status correlated with DFS and OS. Number of pLN was the only prognostic factor with statistical significance in Cox regression test for both, DFS and OS (P=0.0004 and P=0.0006, respectively). In a subgroup analysis of pts with pLN, we found no difference in survival when we compared FAC with CMF. Conclusions: The prolonged follow-up of this study provides a unique opportunity to evaluate factors that predict long-term outcomes. After 16 years of follow-up, the number of pLN remains the most powerful predictor of survival. The subset of pts with pLN had similar survival regardless of the regimen used. Clinical trial information: NCT00002696.
Biomarker analysis of glioblastoma and potential implications for therapy.
Authors: Joanne Xiu, Rebecca Anne Feldman-Moreno, David Arguello, Zoran Gatalica, Anatole Ghazalpour, Ryan P. Bender, Michael Castro, Sandeep K. Reddy, Gargi Dan Basu, Les Paul
Journal: Journal of Clinical Oncology (2013)

2041 Background: Glioblastoma multiform (GBM), the most aggressive CNS cancer, has limited effective therapeutic options, with underlying molecular heterogeneity contributing to the differences in treatment response. Our study was designed to interrogate biomarkers from a large cohort of GBM patients to seek therapeutic implications. Methods: Data was analyzed from 570 high grade astrocytoma patients (vast majority GBM) who received tumor profiling at Caris Life Sciences from 2009 to 13. Test methodologies included IHC, FISH, CISH, Sanger SEQ, MGMT promoter methylation and NextGen SEQ (Illumina TruSeq). Results: In our patient cohort, 59% had MGMT methylation and 70% had negative MGMT IHC, predicting potential response to temozolomide. Protein expression for ERCC1, TOPO1, and TS was 53% negative, 49% positive, and 37% negative, indicating potential benefit from cisplatin, irinotecan and fluorouracil, respectively. Drug pumps PGP and MRP1, were positive by IHC in 10% and 67% of patients, suggesting possible resistance to etoposide, vinca alkaloids and methotrexate. For targeted therapies, c-Kit IHC was positive in 7% patients, mutated in 6% and PDGFRA IHC was positive in 27%, indicating potential benefit from imatinib and other TKI’s. RAS/RAF and PIK3CA/mTOR pathway activation was also noted with BRAF, KRAS, PIK3CA mutations and PTEN loss, observed in 8%, 3%, 7% and 10% of cases, respectively. TS negativity was seen in 91% of MGMT methylated patients and in 37% of MGMT unmethylated patients (p = 0.025, student’s t-test), revealing a possible novel combination therapy of fluoropyrimidines with temozolomide for a select cohort. Similarly, biomarker profiles of molecular subgroups defined by EGFR amplification (44% in our cohort) and IDH1, p53 mutations will be analyzed for therapeutic implications. Conclusions: By profiling tumor biomarkers from a large cohort of GBM patients using validated assays in a single facility, we demonstrate the vast molecular heterogeneity of GBM and highlight the importance of individualized therapy based on a patient’s unique tumor profile. Incorporating a comprehensive biomarker analysis into clinical management of this aggressive cancer allows for an informed selection of more effective therapies.
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association
Authors: Brian W. McCrindle, Anne H. Rowley, Jane W. Newburger, Jane C. Burns, Anne F. Bolger, Michael Gewitz, Annette L. Baker, Mary Anne Jackson, Masato Takahashi, Pinak B. Shah, Tohru Kobayashi, Mei-Hwan Wu, Tsutomu T. Saji, Elfriede Pahl
Journal: Circulation (2017)

Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries.To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and long-term outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up.These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances.
Serum lactate dehydrogenase (LDH) as a prognostic selection criterion for ipilimumab treatment in metastatic melanoma.
Authors: Christian U. Blank, Sander Kelderman, Harm van Tinteren, Bianca Heemskerk, Rob van den Brom, Geke A. Hospers, Alfons JM van den Eertwegh, Ellen Kapiteijn, Jan Willem De Groot, Rob L. Jansen, W. Edward Fiets, Marcin Krzystanek, Zoltan Szallasi, Andrew James Scott Furness, Alex Renn, Martin Eric Gore, Paul Lorigan, Ton Schumacher, John B. A. G. Haanen, James M. G. Larkin
Journal: Journal of Clinical Oncology (2013)

3036 Background: Ipilimumab, a CTLA4 blocking antibody, has been shown to improve survival in metastatic melanoma patients in phase III trials. However, only a subset of patients experiences long-term survival benefit. Therefore, we analysed two independent retrospective sets of patients treated in ‘real world’ settings to identify prognostic factors that correlate with better outcome after ipilimumab therapy. Methods: Advanced melanoma patients, eligible for ipilimumab therapy, were treated in the Dutch and UK Expanded Access Programs (EAP) and after European licensing on the 3mg/kg schedule. Baseline characteristics and peripheral blood parameters were assessed and patients were monitored for the occurrence of adverse events and responses. Results: A total of 166 patients were enrolled in the Dutch EAP. Best overall response rate and disease control rate were (DCR) 17% and 35%. Median follow-up was 17.9 months, with a median progression free survival of 2.9 months. Median overall survival (OS) was 7.5 months, and OS at 1 year 37.8% and at 2 years 22.9%. Univariate analysis revealed that gender, age, Breslow thickness, baseline and week 6 lymphocyte count (ALC), and prior treatment had no influence on OS, while mWHO, M stage, baseline LDH, S100, erythrocyte sedimentation rate (ESR), and the slope of ALC did. In a multivariate model only baseline LDH and ESR remained as significant independent prognostic factors. The relevance of LDH was validated in an independent cohort of 68 patients from the UK. Stratifying the patients in the NL cohort according to LDH levels (≤upper limit normal (ULN), 54.4% of patients versus &gt;2xULN, 16.9% of patients) separated into groups of patients observing DCR of 48% versus 14%, and median OS of 13.7 versus 3.1 months, while toxicity was similar in both groups (48% and 41%). None of the patients was alive at 15 months after treatment if baseline LDH was &gt;2xULN in both the NL and UK cohorts. Conclusions: Overall survival upon ipilimumab treatment is lower in an expanded access population as compared to phase III trials. LDH &gt;2xULN at baseline is a potential prognosticator in patients receiving ipilimumab and should be considered in guiding ipilimumab treatment initiation.
Improving outcomes in mantle cell lymphoma patients treated with R-CHOP using autologous transplant.
Authors: Jennifer McQuade, Tahamtan Ahmadi, David L. Porter, Noelle V. Frey, Steven C. Goldstein, Alison W. Loren, Jakub Svoboda, Edward Allen Stadtmauer, Stephen J. Schuster, Sunita Nasta
Journal: Journal of Clinical Oncology (2012)

e18540 Background: Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. There is no standard upfront therapy, although Phase II trials have shown a survival benefit to dose-intensified regimens in selected patients. However, many patients are not candidates for these regimens secondary to age or comorbidites. These patients are often treated with R-CHOP with consideration for consolidation with ASCT. Methods: We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-CHOP (N=32) with or without autologous stem cell transplant (ASCT). The primary study endpoint was PFS as assessed by chart review and confirmed by SSDI database. Results: Median follow up for all pts was 2.5 years. The median age was 62.5, and 80% (n=30) were stage IV at diagnosis. 16 patients underwent consolidative ASCT. Comparing patients treated with R-CHOP vs R-CHOP +ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. The response rate for all patients was 96.9% and 87.5% of patients achieved CR. Median PFS for all patients was 2.8 years: R-CHOP alone 1.9 years vs. R-CHOP+ ASCT 3.9 years (P=0.02, HR 3.44, 95%CI: 1.2-9.5). Conclusions: Outcomes are poor for MCL patients treated with R-CHOP with continuous recurrence despite excellent initial response. Our data suggest an improved PFS in patients with advanced MCL when R-CHOP is consolidated with ASCT in first remission as compared to R-CHOP alone. Prospective RCTs are needed to determine the optimum treatment for patients who are not candidates for dose-intensive therapy.
Predictive value of coexisting KRAS and TP53 mutations on response to chemotherapy in non-small cell lung cancer (NSCLC).
Authors: Pascale Tomasini, Kevin Jao, Suzanne Kamel-Reid, Tracy Stockley, Ming Sound Tsao, Geoffrey Liu, Natasha B. Leighl, Ronald Feld, Penelope Ann Bradbury, Melania Pintilie, Celine Mascaux, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2015)

11060 Background: KRAS and TP53 are among the most common mutations in NSCLC. The LACE-Bio group evaluated coexisting KRAS/TP53 mutations in resected NSCLC and found chemotherapy to be deleterious in patients with double mutations. Methods: In an attempt to validate these results,NSCLC patients from Princess Margaret Cancer Centre who were tested for KRAS & TP53 mutations and received chemotherapy for any stage NSCLC were selected. Mutation status was analyzed using Mi-SEQ or Sequenom platforms. TP53 analysis was added for DNA sequenced by Sequenom. Mutation status was correlated with clinical and demographic data. Relapse- or progression-free survival (RFS, PFS) was the main endpoint. Results: Among 186 patients identified, 24 had coexisting KRAS/TP53 mutations, 67 TP53, 27 KRAS; 68 had no KRAS or TP53 mutation (WT/WT). No difference was seen in age, sex or stage among the 4 populations (p = 0.09, p = 0.23, p = 0.36, respectively). There were significantly more Caucasians (96 v 65%, p = 0.009), smokers (29 v 14%, p = 0.007) and adenocarcinoma (96 v 73%, p = 0.046) in the KRAS/TP53 group. 5-year overall survival (OS) was higher in the WT/WT group (68%) compared to KRAS/TP53 48%, KRAS 42%, TP53 41% (log-rank p = 0.02). However, no significant OS difference was seen for KRAS/TP53 compared to the other groups (HR 1.41, CI 0.81-2.45, p = 0.23). Among 98 patients who received adjuvant chemotherapy, there was no significant difference in RFS for the KRAS/TP53 group v all others (HR 1.47, CI 071-3.08, p = 0.3). For 30 stage III patients who received concurrent chemo-XRT, there was no PFS difference for the KRAS/TP53 group v all others (HR 0.80, CI 0.30-2.15, p = 0.65). For 85 patients who received 1st-line palliative chemotherapy, there was no difference in PFS in the KRAS/TP53 group v the others (HR 1.05, CI 0.59-1.87, p = 0.87). Similarly, in 43 patients who received 2nd-line chemotherapy, there was no difference in PFS comparing the KRAS/TP53 group to the others (HR 1.18, CI 0.45-3.13, p = 0.73). Conclusions: We could identify no significant difference in OS, RFS or PFS for patients with NSCLC harboring coexisting KRAS/TP53 mutations who received chemotherapy for any stage compared to patients with KRAS or TP53 mutation or WT/WT tumors.
Single cell phenogenomic subtyping of circulating tumor cells (CTCs) identify intercellular tumor heterogeneity (het) and multiple resistance mechansisms in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Howard I. Scher, Ryon Graf, Adam Jendrisak, Nicole A. Schreiber, Brigit McLaughlin, Stephanie Greene, Angel Rodriguez, Martin Fleisher, Jerry Lee, James Kelvin, Yipeng Wang, Mark Andrew Landers, Ryan Vance Dittamore
Journal: Journal of Clinical Oncology (2017)

139 Background: Genomic profiling of metastatic tumors can identify mCRPC pts w/ “actionable” targets. However, responses from this approach are infrequent and not durable, broadly attributed to intra-tumor and intrer-cellular het. We sought to understand relationships between single CTC phenotypic and genomic patterns present when starting ARSi or taxane therapy (Tx) to develop more effective biomarker-directed treatment approaches. Methods: 9225 CTCs from 319 blood samples from 179 mCRPC pts were detected and digital phenotypically profiled using the Epic Sciences platform. Unsupervised clustering revealed 15 phenotypic CTC subtypes based on digital pathology features (Type ‘A’-‘O’). Phenotypic diversity was determined by a Shannon index of these subtypes in pt samples. Next, 856 CTCs representing each subtype were individually whole genome sequenced for copy number variation and genomic instability, to define phenogenomic single cell profile and taxonomy. Tx outcomes were associated with CTC profiles. Results: Pre-therapy identification of certain CTC phenotypic subtypes was associated with poor overall survival (OS) following ARSi and/or taxanes. 5/15 subtypes existed primarily in pts w/ high CTC het (84-94%, Bonferroni adjusted p &lt; 0.05, permutation test), and linked to amp of AR and cMYC, and loss of TP53 and PTEN. Clusters of genomic events were linked to phenotypic features (i.e. small cell CTC w/AuroraK &amp; nMYC amp) and provide single cell phenogenomic associations with pathways such as AR/PTEN feedback and DNA repair machinery. Conclusions: Presence ofspecific CTC subtypes was associated w/ poor survival on ARSi and/or taxanes and may inform Tx selection. Identifying CTC subtypes present in high het samples can provide insight into individual pt disease evolution and potential approaches to maximize benefit. Longitudinal monitoring of CTC phenogenomics is being studied in novel Tx trials.[Table: see text]