tbuckley/cabot-search huggingface dataset:
Efficacy of cetuximab-based second-line therapy in patients with metastatic head and neck squamous cell carcinoma (HNSCC) which progressed on gefitinib-based first-line therapy
Authors: J. C. Mosley, B. Ganz, T. Rachocki, J. Ley, D. Seckfort, D. Morgensztern, D. I. Kuperman, D. R. Adkins
Journal: Journal of Clinical Oncology (2008)

6075 Background: The pathobiology of HNSCC depends, in part, on the epidermal growth factor receptor (EGFR). In HNSCC cell lines and xenograft models, tyrosine kinase (TKI) and monoclonal antibody inhibitors of EGFR had additive and apparent independent effects in controlling the proliferation of HNSCC. Cetuximab and gefitinib each have anti-tumor activity in pts with HNSCC; however, it is not known if tumor resistance to a TKI EGFR inhibitor conveys cross-resistance to a monoclonal antibody EGFR inhibitor. Methods: In a retrospective study of pts with metastatic HNSCC, we sought to determine the tumor response (by RECIST criteria) rate to a second line regimen of cetuximab (400 mg/m2 loading dose then 250 mg/m2/wk) and carboplatin (AUC 5 q3wks) in pts whose disease had progressed on gefitinib (250 mg orally daily) and docetaxel on ECOG protocol 1302. Results: Of the 22 pts enrolled at this institution onto ECOG 1302 protocol from 2/05–7/07, we identified 5 treated with cetuximab and carboplatin as second line therapy after disease progression on gefitinib and docetaxel. Best tumor response to gefitinib and docetaxel was partial (PR) in 2, stable (SD) in 1, and progression (PROG) in 2. Best tumor response to second line therapy with cetuximab and carboplatin was PR in 1, SD in 1, and PROG in 3. Relationship of tumor response to therapies is shown below (Table). Conclusions: This limited data set suggests: 1) Prior tumor progression on gefitinib/docetaxel does not predict for failure to respond to second line therapy with cetuximab/carboplatin, and 2) A potential favorable effect of prior tumor response to an oral EGFR TKI in predicting subsequent tumor response to a monoclonal antibody EGFR inhibitor. Expected tumor response rate to single agent carboplatin is 10% suggesting that the response rate (2 of 6) to cetuximab/carboplatin seen in our patients was at least in part due to cetuximab. Relationship of Tumor Response to Therapies Patient Best Tumor Response to First Line Therapy (Gefitinib/Docetaxel) Best Tumor Response to Second Line Therapy (Cetuximab/Carboplatin) 1 PR SD 2 PR PR 3 SD PROG 4 PROG PROG 5 PROG PROG Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abraxis, Bristol-Myers Squibb, Cytogen, ImClone, sanofi-aventis Abraxis
Implications prognostics of methylation 14-3-3 sigma promoter in peripheral blood cell DNA with nodal involvement status and tumor size for breast cancer patients.
Authors: Joaquina Martínez-Galán, Cynthia S. González Rivas, Julia Ruiz Vozmediano, Pedro Ballesteros, Juan Ramón Delgado, Sandra Ríos, M. Isabel Núñez, Jesus Lopez-Peñalver, Blanca Torres-Torres
Journal: Journal of Clinical Oncology (2012)

33 Background: Expression of 14-3-3 σ is a tumor suppressor gene induced in response to DNA damage, and has been implicated in G2/M cell cycle arrest by p53. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. To correlation methylation levels of promoter 14-3-3σ with association prognostic factors in breast cancer. Methods: This is a prospective study we quantified methylation levels of promoter 14-3-3σ gene in 107 women with breast cancer and 108 control subjects by Real Time QMS-PCR SYBR green and analyzed association with prognostics factor in breast cancer. Results: Median age was 58 years (32-88); 69% were postmenopausal women. Nodal involvement N0; 63%,N1;30%,N2;7%), tumor size (T1;58%,T2;35%,T3;4%,T4;4%) and grade G1; 20%,G2;37%,G3;30%). The methylation of 14-3-3σ were 60% of sporadic breast cancer patients and were 34% of normal breast (p=0.0047). The methylation of 14-3-3σ gene in serum was markedly related with T3-4 stage (p&lt;0.05),nodal positive status (p&lt;0.05) and poor outcome. With a median follow up 6 years we saw more probability of developing distance metastasis in patients with methylation 14-3-3σ (p&gt;0.05). Conclusions: Hypermethylation of the 14-3-3σ a promoter is an early and frequent event in breast neoplastic transformation, leading to the suggestion that silencing of 14-3-3σ may be an important event in tumor progression and particularly in breast carcinogenesis.Therefore, it is possible that loss of σ expression contributes to malignant transformation by impairing the G 2 cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Perhaps in the detection of CpG methylation of 14-3-3σ may be used for diagnostic and prognostic purposes.
Value of multimodality MRI and MR-guided biopsy at inclusion in an active surveillance protocol for prostate cancer.
Authors: Diederik Meindert Somford, Caroline M. Hoeks, Roderick C. van den Bergh, Henk Vergunst, Inge M van Oort, Geert A. Smits, Jorg R. Oddens, Christina A Hulsbergen - van de Kaa, Chris H. Bangma, J. Alfred Witjes, Jelle O. Barentsz
Journal: Journal of Clinical Oncology (2012)

105 Background: To prevent overtreatment of insignificant and/or low-risk prostate carcinoma in the PSA screening era, active surveillance is emerging as a treatment strategy for selected patients. In our series we aim to establish whether MRI could aid in correct risk assessment for these patients within the framework of the Prostate Cancer Research International Active Surveillance (PRIAS) study. Methods: We included patients in our protocol based on contemporary criteria for active surveillance: - Diagnosis of prostate cancer by TRUS-guided biopsy. - PSA ≤10 ng/mL, PSA density &lt;0.2 ng/mL/mL - Clinical stage ≤ T2 - Gleason score (GS) ≤3+3=6 - ≤ 2 biopsy cores with cancer All patients underwent multimodality MRI of the prostate, including T2-weighted, diffusion-weighted and dynamic contrast-enhanced MR sequences. When a tumor-suspicious region (TSR) could be identified a targeted MR-guided biopsy (MRGB) was performed to obtain pathology. Patients were referred for definitive treatment in case of GS &gt; 3+3=6 upon MRGB or T3 stage at MRI. Results: In 48 of 49 included patients at least one TSR was identified, with a median of 2 TSRs (range1-4) per patient. MRGB was obtained from every TSR, with a median of 4 MRGBs taken per patient. Five patients had a GS &gt;3+3=6 upon MRGB and were excluded. Three patients were excluded due to suspicion of T3 stage on MRI. Five patient were excluded upon physician’s discretion due to multifocal prostate cancer upon MRGB. Combined multimodality MRI/MRGB in our active surveillance cohort thus excluded 27% (13/49) of patients who were incorrectly stratified as low-risk prostate carcinoma by contemporary criteria. Conclusions: Application of multimodality MRI and MRGB in an active surveillance protocol improves risk stratification, adding onto contemporary PSA and TRUS-guided biopsy criteria for low-risk prostate cancer. This approach might increase safety and reliability of active surveillance for prostate cancer and deserves ongoing prospective evaluation.
OP0107 Does Metabolic Syndrome or its Individual Components Affect Pain and Function in Knee Osteoarthritis Women?
Authors: S. Talbi, H. Azzouzi, N. Aradoini, F.F. Lazrak, S. Keita, M. Errasfa, F.E. Abourazzak, T. Harzy
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Current studies and research support the role of metabolic syndrome (Mets) in knee osteoarthritis (KOA). However, few studies have focused on its impact on KOA parameters <h3>Objectives</h3> The aim of this study was to investigate if metabolic syndrome or its individual components affect the intensity of pain, functional disability, and radiographic severity in KOA women. <h3>Methods</h3> We conducted a cross sectional study including confirmed radiographic knee osteoarthritis according to Kellgren and Lawrence scale, with and without MetS according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The two groups were compared for pain Visual Analogue Scale (VAS), Lequesne index, Womac function, and radiological grade after adjusting for significant covariates. Multiple regression analysis was used to identify the independent effects of each specific component for metabolic syndrome on knee osteoarthritis parameters. <h3>Results</h3> One hundred thirty women were included. The mean age was 56,68±8,07 [34-75] years, and the mean BMI was 32,54±2,92 [23-37] kg/m<sup>2</sup>. The prevalence of metabolic syndrome was 48,5%. Women with and without MetS had similar KOA parameters. Multiple regression analyses showed, after adjusting for all covariates, that hyperglycemia had a positive impact on pain (p=0,009), waist circumference was positively associated with Lequesne index (p=0,04), high triglycerides level was significantly associated with increased pain (p=0,04) and higher Lequesne score (p=0,05), and Systolic blood pressure was positively correlated with Lequesne index (p=0,01). <h3>Conclusions</h3> In addition to weight reduction, appropriate treatment of MetS needs to become an important management strategy for knee pain and functional impairment. <h3>Disclosure of Interest</h3> None declared
Prognostic impact of baseline LDH on survival independent of tumor burden in advanced melanoma: Results of phase III trial of oblimersen-dacarbazine (OBL-DTIC) vs DTIC
Authors: E. M. Gilles, A. Y. Bedikian, S. S. Agarwala, J. Wu, L. M. Itri, A. M. Eggermont
Journal: Journal of Clinical Oncology (2008)

20007 Background: Baseline serum LDH is an important prognostic factor in advanced melanoma. In a randomized Phase 3 trial of OBL-DTIC vs DTIC (N=771) (Bedikian et al, J Clin Oncol, 2006), multiple endpoints significantly favored OBL-DTIC, with a trend toward improved survival (P=0.077). Analysis revealed an interaction between treatment and LDH (Keilholz et al, ASCO 2007). LDH values were highly predictive of survival (LDH <0.8 x ULN: hazard ratio=0.64; P<0.001). It is commonly accepted that LDH is reflective of tumor burden. We assessed the database to determine whether our conclusion based on LDH levels could be explained by tumor burden. Methods: The hazard ratios for survival as a function of LDH and of tumor size were independently determined using a moving- average technique. The distribution of baseline LDH values across disease sites (as defined by protocol stratification) was also determined. Results: Above the ULN, LDH exerted no effect on survival (HR ∼1). Within the normal range, LDH was strongly predictive of survival. Below the ULN, baseline LDH exerted a monotonic, continuous, and strong impact. LDH was weakly correlated with disease site. There was no obvious pattern relating tumor size to treatment effect. LDH predicted OBL efficacy, but tumor size did not. Conclusions: Baseline LDH exquisitely predicts OBL effect in melanoma that is independent of tumor burden, and elevated LDH probably reflects aggressive tumor biology. A randomized study of OBL-DTIC in pts with low LDH (the AGENDA Trial) is ongoing. It is important to screen all pts for baseline LDH, as even those with large tumor burden and/or visceral disease can benefit from OBL treatment if LDH is low. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genta Incorporated Genta Incorporated Genta Incorporated Genta Incorporated
Ifosfamide neurotoxicity is related to previous cisplatin treatment for pediatric solid tumors.
Authors: C B Pratt, M P Goren, W H Meyer, B Singh, R K Dodge
Journal: Journal of Clinical Oncology (1990)

Neurotoxicity developed in 22 of 97 children and adolescents with malignant solid tumors treated within a phase II ifosfamide protocol. The occurrence of neurotoxicity was related to previous cumulative dosages of cisplatin. One third of the patients who had received more than 600 mg/m2 of cisplatin developed this complication. The relative risk increased 3.2-fold with previous cisplatin dosages above 301 to 600 mg/m2, and 4.1-fold with dosages of 601 to 1,340 mg/m2. The increased risk of neurotoxicity in patients who had received more than 600 mg/m2 of cisplatin may be related to either a decreased clearance of ifosfamide itself or of the drug's active metabolites.
Selective agnostic monoclonal antibodies to the TRAIL receptors R1 and R2 induce cell death and potentiate the effect of chemotherapy and bortezomib in primary and cultured lymphoma cells
Authors: G. V. Georgakis, Y. Li, H. Robin, M. Andreeff, O. Susan, V. Albert, A. Younes
Journal: Journal of Clinical Oncology (2004)

6595 Bacground: TRAIL is a death protein that has a promising anti-cancer activity. Recent studies demonstrated that agonisitic antibodies to the TRAIL death receptors R1 and R2 can mimick the activity of TRAIL protein, and therefore may be of therapeutic value. The activity of these novel antibodies have been previously examined in primary lymphoma specimens. Methods: We evaluated the in vitro activity of two fully human agonistic monoclonal antibodies to the TRAIL death receptors R1 (HGS-ETR1) and R2 (HGS-ETR2) in 5 lymphoma cell lines and 27 primary lymphoid malignancy samples. Results: Although R1 and R2 receptors proteins were expressed in the majority of the samples as determined by Western blot, the surface receptor expression in the same sample frequently did not correlate with receptor protein expression suggesting that not all the receptors are present on the surface. Both ETR1 and ETR2 inhibited cell prolifeation and induced apoptosis in a dose and time dependent manner. However, ETR1 and ETR2 were not equally effective in different samples, and their activity did not correlate with the level of surface receptor expression. When the analysis is restricted to the 13 cases of primary non-Hodgkin's lymphoma samples, ETR1 induced at least 10% cell death in 62% of the samples, while ETR2 was effective in 77% of the samples. In the 14 primary chronic lymphocytic leukemia samples, ETR1 was effective in 71% of the samples, while ETR2 was effective in 64% of the samples. In some cases, ETR1 and ETR2 synergized with bortezomib (Velcade) and doxorubicin chemotherapy. However, this synergistic activity was not observed in all samples. Conclusions: We conclude that ETR1 and ETR2 monoclonal antibodies to the TRAIL death receptors R1 and R2 can induce cell death in a wide variety of cultured and primary tumor cells of lymphoid orgin origin. This preclinical data provide the basis for evaluating these novel antibodies for the treatment of patients with lymphoma and chronic lymphocytic leukemia. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Human Genome Sciences
The impact of lymph node status on clinical outcomes following accelerated partial breast irradiation.
Authors: C. Shah, J. B. Wilkinson, M. Wallace, F. A. Vicini
Journal: Journal of Clinical Oncology (2011)

107 Background: Currently, node-positive patients are considered unsuitable for APBI per the ASTRO guidelines with limited data on outcomes of node-positive patients following APBI. Methods: 510 patients with early-stage breast cancer received accelerated partial breast irradiation (APBI) between April 1993 and November 2010. Of these, 39 were lymph node positive with 10 patients having N1mi disease (median size of mets = 0.82 mm) and 29 patients having N1 disease (61.5% had 1 node positive [median size of mets = 2.5 mm], 30.8% had 2 nodes positive [median size of mets = 8.0 mm], and 7.7% had 3 nodes positive [median size of mets = 20 mm]). Patient, clinical, and pathologic factors were analyzed and compared for the node-negative (N0) and node-positive (N+) cohorts including age, tumor size, receptor status, margin status, adjuvant hormone therapy, adjuvant chemotherapy, and length of follow-up. Results: N+ patients were younger (p=0.04), had larger tumors (p&lt;0.001), and were more likely to receive chemotherapy (p&lt;0.001). Median follow-up was 5.3 years for N0 patients and 5.9 years for N+ patients (p=0.06). At 5 years, no differences were seen in the 5-year actuarial rates of LR (2.2% v. 2.6%, p=0.86), AR (0% v. 0%, p=0.69), DFS (90.0% v. 88.0%, p=0.79), CSS (98.0% v. 90.0%, p=0.06), or OS (91.0 v. 84.0%, p=0.65) while higher rates of RR (0% v. 6.1%, p&lt;0.001) and DM (2.2% v. 8.9%, p=0.005) were noted in N+ patients. A total of 10 LRs occurred in the N0 patients and 1 LR in the N+ patients at a median of 2.6 and 1.5 years respectively. Both RR that developed in N+ patients were within the supraclavicular fossa at a median of 2.8 years. Univariate analysis of LR was performed and age (p=0.31), tumor size (p=0.48), ER status (p=0.13), PR status (p=0.34), T-stage (p=0.48), chemotherapy (p=0.41), APBI technique (p=0.80), and nodal status (p=0.86) were not associated with LR while there was a trend for the association of LR with close/positive margins (p=0.07), and failure to receive adjuvant hormonal therapy (p=0.06). No variables were associated with any type of AR. Conclusions: No difference was seen in the rates of local recurrence or axillary failure between node-negative and node-positive following APBI with 5-years of follow-up.
Efficacy and toxicity of treatment with the anti-CTLA-4 antibody Ipilimumab in patients with metastatic melanoma who have progressed on anti-PD-1 therapy.
Authors: Prashanth Prithviraj, Grant A. McArthur, Victoria Atkinson, Phillip Parente, Miles Cameron Andrews, Sagun Parakh, Jonathan S. Cebon, Oliver Klein
Journal: Journal of Clinical Oncology (2015)

9059 Background: Immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies has demonstrated overall survival benefits in patients (pts) with metastatic melanoma (MM) compared to standard therapy. An early phase clinical trial suggests that combination therapy with an anti-CTLA-4 and anti-PD-1 antibody increases the response rate compared to single agent treatment however is associated with increased toxicity. Anti-PD-1 therapy demonstrated equal efficacy and toxicity in pts that progressed on or were naive to treatment with the anti-CTLA-4 antibody Ipilimumab. So far only very limited evidence exists regarding the efficacy and toxicity of Ipilimumab in pts that have progressed on treatment with an anti-PD-1 agent. Methods: We retrospectively identified ten pts with MM who received anti-PD-1 therapy (Nivolumab/Pembrolizumab) in a clinical trial and were subsequently treated with Ipilimumab. Ipilimumab was administered at a dose of 3mg/kg every three weeks for four cycles and response has been assessed by CT scan 4-6 weeks after the last dose. Results: The median time between the last dose of anti-PD-1 therapy and the commencement of Ipilimumab was 7 months. The median age of the patient cohort was 58 years with all pts having stage IV C disease and 4/10 pts had an elevated LDH on commencement of Ipilimumab therapy. 1/10 of pts achieved a partial remission as their best response to anti-PD-1 therapy with an additional 5/10 having stable disease. 4/10 of pts received all four doses of Ipilimumab. The follow up after the last dose of Ipilimumab has been more than three months. 1/10 of pts achieved a response to ipilimumab with another 1/10 having prolonged stable disease. 3/10 pts experienced grade3/4 immune related adverse events (irAE). Conclusions: Ipilimumab therapy can induce responses in pts who have failed treatment with an anti-PD-1 antibody. The response rate and clinical benefit rate appears similar compared to pts that have not received prior anti-PD-1 antibody therapy. Although cases of severe and unusual irAEs (eg pneumonitis) have been observed in our pts, an analysis of a larger patient cohort will be required to test the significance of these observations.
Family history of breast cancer (BC) and biological and clinicopathologic features in Uruguayan BC patients
Authors: C. Castillo, N. Artagaveytia, S. Mauriz, C. Meyer, G. Sena, G. Spera, L. Ubillos, F. Xavier, M. Aghazarian, R. Rodríguez
Journal: Journal of Clinical Oncology (2009)

e11622 Background: Hereditary BC can have a distinct phenotype and behavior in comparison to sporadic BC. The aim of the present study was to investigate if there is any difference in the age at diagnosis, disease extension and biological profile in BC patients (pts) with or without a significant family history of BC. Methods: We retrospectively reviewed clinical charts of BC pts, stage 0- III who had surgery between March 2006 and March 2008. We included pts with known estrogen receptor (ER), progesterone receptor (PR) and HER2 status. The family history was obtained from the clinical charts and confirmed by a telephone interview with a standardized questionnaire. A significant family history of BC was defined by the presence of one of the following criteria: (1) 3 or more BC cases among close relatives, at least one diagnosed before 50 years (2) 2 BC cases among close relatives, at least one diagnosed before 50 years and one of the following: bilateral BC, ovarian cancer diagnosed in the family, male BC, father´s inheritance, Ashkenazi Jewish ancestry Results: 435 pts were identified, with available data on ER/PR and HER2 status in 197 pts. Family history was evaluated in 136 pts (69%) and was classified as significant in 18 (13.2%). Between pts with and without a significant family history of BC cancer there were no difference in the proportion of pts &lt; 50 years old at diagnosis (0.36 vs. 0.39), T3/T4 tumours (0.08 vs. 0.11), axillary node positivity (0.55 vs 0.66), ER/PR+ (0.77 vs. 0.72), HER2 + (0.11 vs. 0.11) and triple negative tumors (0.19 vs 0.17). Conclusions: our data does not show any difference in the main prognostic and predictive factors between operable BC pts with and without a significant family history of BC. These findings are concordant with previous published data about a greater prevalence of BRCA2 mutations in Uruguayan families. No significant financial relationships to disclose.
The Relationship Between Anatomical and Functional Coronary Artery Disease Severity and Transmural Myocardial Blood Flow Distribution
Authors: Ibrahim Danad, Pieter G. Raijmakers, Hendrik J. Harms, Martijn W. Heymans, Niels van Royen, Adriaan A. Lammertsma, Mark Lubberink, Albert C. van Rossum, Paul Knaapen
Journal: Circulation (2013)

The Relationship Between Anatomical and Functional Coronary Artery Disease Severity and Transmural Myocardial Blood Flow Distribution