tbuckley/cabot-search huggingface dataset:
Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia.
Authors: Giovanni Martinelli, Alexander E. Perl, Hervé Dombret, Sabine Kayser, Bjoern Steffen, Philippe H. Rousselot, Elihu Estey, Alan K. Burnett, Neil P. Shah, Guy Gammon, Denise Trone, Mark J. Levis, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2013)

7021 Background: Advanced age and FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220), an oral FLT3 inhibitor active against ITD mutant and wild type FLT3, has shown promising activity in Ph 1 and 2 studies. Methods: Patients (pts) in a Ph 2 open label study (N = 333) of quizartinib monotherapy included 154 aged ≥60 y with known FLT3-ITD status and AML relapsed in &lt;1 y or refractory to 1st line chemotherapy. Median duration of treatment was 14.2 wks (range 0.1–70.6 wks) for FLT3-ITD(+) pts and 9.5 wks (range 1.1–77.0 wks) for FLT3-ITD(-) pts. The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). Results: Of 110 FLT3-ITD(+) pts, 63 (57%) had a CRc (3 CR, 4 CRp, 56 CRi). Of 44 FLT3-ITD(-) pts, 16 (36%) had a CRc (2 CR, 1 CRp, 13 CRi). Median overall survival (OS) in FLT3-ITD(+) pts was 25.3 wks and 16/110 (15%) survived &gt;52 wks. The median age of these pts surviving &gt;52 wks was 69.5 y (range 66–80 y) and median OS was 76.3 wks (range 56.9–96.0 wks). All of these pts responded to quizartinib (2 CR, 2 CRp, 8 CRi, 4 partial remission [PR]). 2 pts were still alive &gt;1 ½ y (OS 93.0 and 96.0 wks). Median OS in FLT3-ITD(-) pts was 19.1 wks and 6/44 FLT3-ITD(-) pts (14%) survived &gt;52 wks. The median age of these pts was 70.0 y (range 65–77 y) and their median survival was 76.6 wks (range 54.9–98.4 wks). 5 of these pts responded to quizartinib (1 CR, 3 CRi, 1 PR). Conclusions: These data for an FLT3-targeted agent show encouraging survival in a subset of elderly pts with relapsed/refractory FLT3-ITD(+) AML. Clinical trial information: NCT00989261. [Table: see text]
Randomized phase II study of docetaxel plus personalized peptide vaccination versus docetaxel plus placebo for patients previously treated for advanced wild-type <i>EGFR</i> non-small-cell lung cancer.
Authors: Shunichi Sugawara, Koichi Takayama, Atsushi Sato, Makoto Maemondo, Shinzo Takamori, Tetsuro Sasada, Tatsuyuki Kakuma, Junji Kishimoto, Akira Yamada, Masanori Noguchi, Kyogo Itoh, Yoichi Nakanishi
Journal: Journal of Clinical Oncology (2015)

e14029 Background: A personalized peptide vaccination (PPV) strategy has been developed as a new immune-system-based therapy. In this method, vaccine antigens are selected and administered based on pre-existing host immunity prior to vaccination. Previous clinical studies on PPV showed promising results for treating various types of advanced cancers, including lung cancer. However, the clinical efficacy of PPV in combination with standard chemotherapy for advanced non-small-cell lung cancer (NSCLC) remains unclear. We therefore conducted this multicenter, randomized, phase II trial. Methods: Fifty previously treated PS0-1 patients with stage IIIB/IV EGFR wild-type NSCLC were randomly assigned to the docetaxel (60 mg/m2on day 1) plus PPV arm based on pre-existing host immunity (n = 24) or to the docetaxel plus placebo arm (n = 26). Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly during the first 8 weeks and biweekly during the subsequent 16 weeks. The first PPV or placebo injection was performed within 3 days of docetaxel administration. The primary efficacy endpoint was progression free survival. Results: The toxicity profile of docetaxel plus PPV was very similar to that previously reported for docetaxel alone. PPV-related toxicity was grade 1 or 2 skin reaction. The median PFS was 53 days in the placebo arm and 59 days in the PPV arm. There was no significant difference between the arms by the log-rank test (p = 0.42). Interestingly, PFS and overall survival in humoral immunological responders were significantly longer than in non-responders, with hazard ratio 0.28 and 0.27 (both p < 0.01), respectively. Conclusions: The primary endpoint was not met in this clinical trial and PPV did not improve survival when combined with docetaxel for previously treated advanced EGFR wild-type NSCLC. However, PPV may be efficacious for humoral immunological responders. Further clinical investigation is needed to identify which patients will benefit from cancer vaccination. Clinical trial information: 000003521.
Individual Patient-Level Meta-Analysis of the Performance of the Decipher Genomic Classifier in High-Risk Men After Prostatectomy to Predict Development of Metastatic Disease
Authors: Daniel E. Spratt, Kasra Yousefi, Samineh Deheshi, Ashley E. Ross, Robert B. Den, Edward M. Schaeffer, Bruce J. Trock, Jingbin Zhang, Andrew G. Glass, Adam P. Dicker, Firas Abdollah, Shuang G. Zhao, Lucia L.C. Lam, Marguerite du Plessis, Voleak Choeurng, Zaid Haddad, Christine Buerki, Elai Davicioni, Sheila Weinmann, Stephen J. Freedland, Eric A. Klein, R. Jeffrey Karnes, Felix Y. Feng
Journal: Journal of Clinical Oncology (2017)

Purpose To perform the first meta-analysis of the performance of the genomic classifier test, Decipher, in men with prostate cancer postprostatectomy. Methods MEDLINE, EMBASE, and the Decipher genomic resource information database were searched for published reports between 2011 and 2016 of men treated by prostatectomy that assessed the benefit of the Decipher test. Multivariable Cox proportional hazards models fit to individual patient data were performed; meta-analyses were conducted by pooling the study-specific hazard ratios (HRs) using random-effects modeling. Extent of heterogeneity between studies was determined with the I2 test. Results Five studies (975 total patients, and 855 patients with individual patient-level data) were eligible for analysis, with a median follow-up of 8 years. Of the total cohort, 60.9%, 22.6%, and 16.5% of patients were classified by Decipher as low, intermediate, and high risk, respectively. The 10-year cumulative incidence metastases rates were 5.5%, 15.0%, and 26.7% ( P < .001), respectively, for the three risk classifications. Pooling the study-specific Decipher HRs across the five studies resulted in an HR of 1.52 (95% CI, 1.39 to 1.67; I2 = 0%) per 0.1 unit. In multivariable analysis of individual patient data, adjusting for clinicopathologic variables, Decipher remained a statistically significant predictor of metastasis (HR, 1.30; 95% CI, 1.14 to 1.47; P < .001) per 0.1 unit. The C-index for 10-year distant metastasis of the clinical model alone was 0.76; this increased to 0.81 with inclusion of Decipher. Conclusion The genomic classifier test, Decipher, can independently improve prognostication of patients postprostatectomy, as well as within nearly all clinicopathologic, demographic, and treatment subgroups. Future study of how to best incorporate genomic testing in clinical decision-making and subsequent treatment recommendations is warranted.
Stem cell rescue from irradiation of multifocal bone disease combined with high-dose chemotherapy and reduced intensity conditioned haplodisparate stem cell transplantation in advanced pediatric sarcomas: Update of MetaEICESS 2007.
Authors: Stefan Burdach, Uwe Thiel, Angela Wawer, Irene Teichert von Luettichau, Hans-Jochem Kolb, Marc Steinborn, Barbara Roeper, Thomas Klingebiel, Ewa Koscielniak, Uta Dirksen, Herbert Juergens
Journal: Journal of Clinical Oncology (2014)

e21021 Background: Advanced pediatric sarcomas are associated with poor prognosis. They include Ewing’s sarcomas (ES), metastatic to more than one bone or early relapse as well as stage IV rhabdomyosarcomas (RMS). We assessed toxicity, relapse free survival (RFS) and overall survival (OS) of eight ES and RMS patients treated with the MetaEICESS 2007 protocol. Methods: From 2007 to 2013 six ES and two RMS patients were enrolled. Four ES patients had multifocal disease (≥ three bones/organs or marrow at diagnosis) and two due to early relapse (<24 months after diagnosis). Two RMS patients were in stage IV. The protocol comprised (1) VIDE induction-chemotherapy; (2) local consolidation total-body MRI/PET directed and stem cell rescue supported irradiation of the primary tumor as well as all metastases with simultaneous chemotherapy, facultative surgery; (3) systemic consolidation with tandem high-dose chemotherapy with autologous stem cell transplantation and reduced intensity conditioning and haplodisparate stem cell transplantation (allo-SCT). Results: 5/8 (0.625) patients as compared to <0.10 (historic controls) are surviving at a median of 31 months after diagnosis. 4/8 patients survive in CR and 1/8 survives in stable disease. Seven patients reached complete remission (CR) before allo-SCT, three of whom relapsed thereafter. Four patients with relapsed or progressive disease after allo-SCT received donor lymphocyte infusions (DLI), of whom one showed ongoing remission after one year, one has stable disease for >48 months after transplant and 30 months after relapse; two patients progressed. 1/8 patients had to be retransplanted after initial graft rejection, 3/8 patients suffered ADV reactivation, 3/8 patients developed acute- and 1/8 developed chronic GvHD. Median RFS after allo-SCT was 18 months (range 0-50+ months) and median OS was 24 months (range 5-50+). Conclusions: The MetaEICESS 2007 protocol is a feasible and promising option for patients with advanced pediatric sarcomas. A larger cohort is mandatory to verify OS or RFS improvements over current protocols.
Variable clinical response of hypereosinophilic syndromes (HES) to current therapeutic options
Authors: S. Mitra, P. T. Murphy, J. R. O’Donnell
Journal: Journal of Clinical Oncology (2006)

16527 The term Hypereosinophilic syndrome (HES) refers to a heterogeneous group of disorders characterised by marked blood (&gt;1500/cu mm) and tissue eosinophilia resulting in end organ damage.Several visceral complications like cardiomyopathies and cerebrovascular accidents are common. Treatment of HES includes corticosteroids,chemotherapeutic agents (hydroxyurea, cyclophosphamide, vincristine), interferon-alpha. Newer treatment modalities,including tyrosine kinase inhibitors (eg Imatinib) and monoclonal anti IL5 antibodies are now available. We report a case series of patients with HES which demonstrate the variable clinical response to above therapeutic options. Case 1: A 43 year old man who presented with a right lacunar infarct had a eosinophil count of 1200/cu mm. No cause was found. He also had Mitral valve endocarditis. Following initial treatment with Methylprednisolone, the eosinophil count came down to 3500/cu mm, but the eosinophilia persisted. He was given a trial of Imatinib. In 2 months time his eosinophilia resolved. However, he was negative for FILIPI-PDGFRa. Case 2: A 37 year old lady with history of Splenectomy (due to trauma) presented with a eosinophil count of 2660/cu mm. Result of the FILIPI-PDGFRa was equivocal. There was no response to Imatinib. A trial of Prednisolone (1 mg/Kg) was ineffective. She did not respond to Interferon-alpha. However when given a combination of Prednisolone (0.5 mg/kg) and Interferon-alfa, her counts were normal in a month. Case 3: A 63 year old man with history of Atrial Fibrillation had persistent eosinophilia (&gt;1500/cu mm). His serum Tryptase was raised but he was negative for FILIPI-PDGFRa. A trial of Imatinib failed He responded partially to high dose of Hydroxyurea. Prednisolone, Interferon-alpha or a combination of both are future options for him. Case 4: A 80 year old man with background history of Alzheimer’s Disease was found to have persistent unexplained eosinophilia. He had no complains of joint symptoms but his ANF was positive in low titres. A bone marrow showed no evidence of lymphoma or a myeloproliferative disorder. Karyotype was normal. He was given a trial of Hydroxyurea to which he responded in two weeks. Thus, response of HES patients to treatment is variable often unpredictable. No significant financial relationships to disclose.
High-density SNP array analysis of <i>TP53</i> p.R337H mutation carriers.
Authors: Diego Davila Paskulin, Juliana Giacomazzi, Ichiro Nakachi, Marileila Varella-Garcia, Patricia Ashton-Prolla
Journal: Journal of Clinical Oncology (2014)

e12500 Background: Germline mutations in TP53 are the underlying defect of Li-Fraumeni Syndrome (LFS), an autosomal dominant disorder characterized by predisposition to multiple early-onset cancers. A germline mutation at codon 337 (c.G1010A, p.R337H), which is present in about 0.3% of the population of Southern Brazil, has been associated with breast cancer, adrenocortical tumors in adults, choroid plexus carcinoma in children, and Li-Fraumeni/Li-Fraumeni-like syndromes. Structural and functional studies have demonstrated that the p.R337H protein displays a pH-dependence, rendering the protein inactive only under conditions of increased intracellular pH, and the majority of the time behaves normally, which could explain its lower overall malignant potential. Methods: In this study, we analyzed the genomic alterations present in eight patients carrying the TP53 p.R337H mutation using high density single-nucleotide polymorphism-array (SNP) genotyping arrays to discover new imbalanced regions associated with p.R337H. Fluorescence in situ Hybridization (FISH) was used to validate these regions in adrenocortical and breast carcinoma patient specimens. Results: SNP data analysis allowed us to detect chromosomal segments of copy neutral loss of heterozygosity (CN-LOH) in addition to copy number alterations. Our results show copy number gains in 12p13.3-12p11.23, 16p13.3-16q24.3, amplifications in 1q24.2-1q25.3, deletions in 2p25.3-2q37.3 and 17p13.1 and CN-LOH in 11p15.5-p11.2 and 17p13.1 in TP53 p.R337H mutation carriers. When analyzing a p.R337H homozygous patient and its carrier parents, we identified a CN-LOH of 4.2Mb encompassing the TP53 region on 17p13.1. We inferred that this area encompasses the TP53 p.R337H haplotypic block. FISH analyses validated copy number gains in 12p13.33-p11.12, amplifications in 1q21.1-q44 and deletions in 11p15.5-p11.2. Conclusions: This is the first study that used high density SNP arrays to identify copy number chances in TP53 p.R337H patients. The investigated chromosomal regions, in particular those with CN-LOH, point out to new chromosomal regions associated with LFS patients carrying the TP53 p.R337H mutation.
Ureteroscopy-assisted Percutaneous Kidney Access Made Easy: First Clinical Experience with a Novel Navigation System Using Electromagnetic Guidance (IDEAL Stage 1)
Authors: Estevao Lima, Pedro L. Rodrigues, Paulo Mota, Nuno Carvalho, Emanuel Dias, Jorge Correia-Pinto, Riccardo Autorino, João L. Vilaça
Journal: European Urology (2017)
High-resolution peripheral quantitative computed tomography (HR-pQCT) to detect compartmental bone loss on androgen deprivation therapy (ADT): A feasibility study.
Authors: Rahul Raj Aggarwal, Tammy J. Rodvelt, Dora Tao, Jeffrey Hough, Miles Thomas, Brian Ma, Li Zhang, Sharmila Majumdar
Journal: Journal of Clinical Oncology (2017)

209 Background: ADT causes bone loss, yet standard bone density (DXA) measurements do not distinguish cortical vs. trabecular bone loss and are falsely elevated in patients (pts) with sclerotic metastases, potentially underestimating fracture risk. HR-pQCT of the tibia and radius is a validated method to assess compartmental bone density and architecture that may overcome these limitations. Methods: Cross-sectional study of prostate cancer pts who underwent HR-pQCT (Scanco XtremeCT) of the radius and tibia and DXA scans within 6 months of initiating ADT. The relationship between HR-pQCT and relevant clinical variables was assessed using Spearman’s rank correlation method. Results: 22 pts were enrolled. Median baseline characteristics included: age = 64.5 (range 53-90), serum testosterone (T) level = 17 ng/dL (6-978), and interval between ADT start and HR-pQCT = 1.6 months (0-5.7). 5 pts (23%) were osteopenic as assessed by DXA. The correlation between HR-pQCT and clinical variables in shown in the Table. Of 12 pts with bone metastases, 7 (58%) had DXA L-spine and/or hip t-scores &gt; 2 standard deviations above mean for 30 year-old male. In contrast, all 7 pts had HR-pQCT measurements within the expected range based on age, sex, and serum T. Conclusions: HR-pQCT to assess bone loss in prostate cancer pts on ADT is feasible. Radial trabecular bone volume and density are correlated with relevant clinical variables including ADT duration and serum T. In pts with bone metastases, HR-pQCT may provide more accurate means to estimate BMD and determine fracture risk. Longitudinal studies in pts on ADT with paired HR-pQCT scans are ongoing. Clinical trial information: NCT02168062. [Table: see text]
Preliminary analysis of FOLFIRI regimen with or without bevacizumab as second-line systemic therapy in patients with metastatic gastroenteropancreatic neuroendocrine carcinoma.
Authors: Xiaoying Zhao, Chen Chen Wang, Wen Zhang, Xiaodong Zhu, Weijian Guo, Zhi-Yu Chen
Journal: Journal of Clinical Oncology (2017)

469 Background: Patients with gastroenterpancreatic neuroendocrine carcinomas (NECs) have a very poor prognosis. And the role of the second-line therapy remains unknown. Methods: We retrospectively analyzed 11 patients with gastroenteropancreatic NEC after failure of first-line chemotherapy in the last two years in our cancer center. Data examined included clinical and pathological characteristics at the time of diagnosis, efficacy and safety. Results: Median age was 51 (17-64) years old. Most were male (81.8%). Tumor origin included pancreas (6pts, 54.5%), colon-rectum (3pts, 27.3%), one stomach and one liver. Metastatic disease was evident at diagnosis in all patients (liver metastases: 100%, celiac lymph nodes: 72.7%, bone: 18.2%, pleural effusion and peritoneal metastasis: 18.2%). Median Ki-67 index was 80%. Etoposide-cisplatin combinations as first line chemotherapy were administered in 8 (72.7%) patients and 2 (18.2%) capecitabine based regimen and 1(9.1%) gemcitabine with nab-paclitaxel. All patients received the FOLFIRI regimen with a median number of 8 (3-36) courses. Three patients (27.3%) had partial response, 4 (36.4%) stable disease, and 4 (36.4 %%) tumor progression. But in 6 patients received the FOLFIRI plus bevacizumab, disease control rate was 66.7%, 3 (50.0%) partial response, 1(16.7%) stable disease. The median PFS in all 11 pts was 3.77 (1.77-24.07) months, in 6pts with bevacizumab was 4.77(1.83-24.07) months. The most severe toxicities was grade 3 neutropenia (27.2%), the other adverse effects were mild to moderate, including mild anemia, transient transferase elevation and proteinuria. Conclusions: FOLFIRI regimen is a potentially effective and safe chemotherapy given as second-line in patients with NEC. Additional anti-VEGF therapy with bevacizumab may improve the disease control and PFS time.
Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study
Authors: Youn H Kim, Sean Whittaker, Steven M Horwitz, Madeleine Duvic, Reinhard Dummer, Julia J Scarisbrick, Pietro Quaglino, Pier Luigi Zinzani, Pascal Wolter, Yinghui Wang, Maria Corinna Palanca-Wessels, Erin Zagadailov, William L Trepicchio, Yi Liu, Meredith Little, H Miles Prince
Journal: Blood (2016)
Platinum-gemcitabine-bevacizumab (PGA) for platinum-resistant/refractory recurrent ovarian cancer.
Authors: Jiaxin Niu, Madappa N. Kundranda, Glen J. Weiss, John H. Farley
Journal: Journal of Clinical Oncology (2015)

e16534 Background: Synergism between gemcitabine and platinum is known clinically. Bevacizumab in combination with single-agent chemotherapy has demonstrated significant clinical activity in platinum-resistant recurrent ovarian cancer in the AURELIA study. However, the efficacy of platinum-gemcitabine-bevacizumab has not been investigated in the platinum-resistant population. Methods: A retrospective chart review was conducted in all patients with platinum-resistant/refractory ovarian cancer treated with triplet combination therapy containing gemcitabine plus bevacizumab and a platinum agent between July 2011 and December 2013. Results: A total of 13 patients with platinum-resistant/refractory ovarian cancer that were treated with triplet combination therapy were identified. 10 patients responded biochemically to the therapy. Of the biochemical responders, 1 patient achieved radiographic CR that was maintained for 22 months (8%), 6 patients achieved PR for a median of 7 months (46%), 3 had SD for > 4 months (23%), and 3 patients had PD (23%) by RECIST 1.1 criteria. The regimen was well-tolerated. Most patients received carboplatin (AUC of 5 every 3 weeks), gemcitabine (1000 mg/m2 every 3 weeks), and bevacizumab (15 mg/kg every 3 weeks). 4 patients received cisplatin and 2 patients received oxaliplatin. A total of 5 patients (38%) experienced 1 episode of grade (G) 3 toxicities, and no G4 or G5 toxicity was reported. Of these five patients, 2 patients (both had central venous catheter via the internal jugular vein) developed thrombosis in the internal jugular vein (G3), requiring discontinuation of bevacizumab. Interestingly, carboplatin was discontinued due to allergic reaction in 2 patients who are responding to the regimen, and both patients developed PD with continuation on gemcitabine and bevacizumab, suggesting a synergistic role for platinum in this three-drug combination. Conclusions: Combination of platinum-gemcitabine-bevacizumab (PGA) appears to be safe and very active against platinum-resistant/refractory ovarian cancer and merits further evaluation prospectively. A randomized phase II study (NCT01936974) is currently under way to confirm this important finding.
Natural tolerance development in cow's milk allergic children: IgE and IgG4 epitope binding
Authors: J. C. Caubet, J. Lin, B. Ahrens, G. Gimenez, L. Bardina, B. Niggemann, H. A. Sampson, K. Beyer
Journal: Allergy (2017)

Although most of cow's milk (CM) allergic children will outgrow their allergy, the pathomechanism of the natural development of tolerance remains poorly understood. It has been suggested that the balance between milk-specific IgE and IgG4 plays a major role.We aimed to investigate differences in IgE and IgG4 antibody binding to CM epitopes between patients with persistent CM allergy (CMA) and those that naturally became tolerant.Sera from 35 children with proven CMA (median age at inclusion of 10 months) were analyzed retrospectively; 22 patients have become tolerant (median age at tolerance acquisition of 51 months) during the study period as confirmed by a negative oral food challenge. IgE and IgG4 binding to sequential epitopes derived from five major CM proteins were measured with a peptide microarray-based immunoassay.At baselines, greater intensity and broader diversity of IgE and IgG4 binding have been found in children with persistent CMA beyond 5 years of age compared to patients with transient CMA. Moreover, children with transient CMA had IgE and IgG4 antibodies that more often recognized the same epitopes, compared to those with persistent CMA. From baseline to the time of tolerance development, both IgE and IgG4 binding intensity decreased significantly, particularly in areas of α-s- and β-casein (P<.01, false discovery rate [FDR]<.1). Interestingly, differences between IgE and IgG4 binding intensity to CM peptides decreased when the patients became tolerant.Our results suggest that the overlap between IgE and IgG4 might be important in natural tolerance acquisition. Further studies are needed to confirm our data and can eventually lead to development of more targeted treatment of food allergy.