tbuckley/cabot-search huggingface dataset:
Overall response rate (ORR) as a potential surrogate for progression-free survival (PFS): A meta-analysis of metastatic non-small cell lung cancer (mNSCLC) trials submitted to the U.S. Food and Drug Administration (FDA).
Authors: Gideon Michael Blumenthal, Stella Karuri, Sean Khozin, Dickran Kazandjian, Hui Zhang, Lijun Zhang, Shenghui Tang, Rajeshwari Sridhara, Patricia Keegan, Richard Pazdur
Journal: Journal of Clinical Oncology (2014)

8012 Background: Targeted therapies (TT) administered as single agents in molecularly defined mNSCLC subsets are yielding high ORR. Improvements in PFS of large magnitude with favorable benefit-risk have served as the basis of drug approval in mNSCLC. The relationship between ORR with PFS or Overall Survival (OS) in mNSCLC is not established. Therefore, we conducted a meta-analysis of mNSCLC trials submitted to the FDA, including 3 trials of TT in molecularly enriched populations with high ORR. Methods: We identified 15 trials of 12,534 patients (median N = 698) of 9 experimental agents (tyrosine kinase inhibitor = 5, chemotherapy = 2, monoclonal antibody = 2) submitted for treatment of mNSCLC in initial or supplemental New Drug or Biologics License Applications since 2003. Criteria for inclusion of the trials in this analysis were: randomized, active-controlled, multicenter, N ≥ 150. Three trials tested TT in defined populations (EGFR mutant = 2, ALK+ = 1). The estimated PFS hazard ratio (HR- ratio of hazard of treatment versus hazard of control group) and OS HR versus the estimated odds ratio (OR) of ORR (ratio of odds of response in controls to odds of response in treatment) on the log-scale was calculated. Weighted least square (WLS) regression analyses (weight equal to the number of patients) were performed on log-transformed effects. Results: For the PFS HR vs. ORR OR analysis, the R2 = 0.89, the slope of the WLS = 0.41 (95% CI: 0.32, 0.49). For the OS HR vs. ORR OR analysis, R2 = 0.12, slope = 0.05 (95% CI: -0.03, 0.13). Using trials ≥ 500 patients (n=12), R2 = 0.50, slope = 0.16 (95% CI: 0.04, 0.3). For the OS HR vs. PFS HR analysis, R2 = 0.1, slope = 0.1 (95% CI: -0.1, 0.3). Using trials with ≥ 500 patients, R2 = 0.39, slope = 0.32 (95% CI: 0.04, 0.6). Conclusions: On a trial level, the meta-analysis of randomized, active-controlled trials indicates a strong correlation between ORR and PFS. A correlation between ORR or PFS and OS is not established and may be confounded by cross-over in the TT trials. At the trial level, a TT in a molecularly defined subset of mNSCLC with a large magnitude of effect on ORR will likely have a large effect on PFS.
Synergistic activity of vertical combinations of agents targeting multiple steps along the RAF/MEK/ERK cascade as a therapeutic strategy in human tumors.
Authors: Ursula Cesta Incani, Anais Del Curatolo, Cristina Di Sanza, Italia Falcone, Francesco Cognetti, Ludovica Ciuffreda, Michele Milella
Journal: Journal of Clinical Oncology (2012)

e13572 Background: BRAF-selective kinase inhibitors have potent antitumor effects in mutant BRAF(V600E) tumors; however, in BRAF-wt cells, they paradoxically activate MEK/ERK. In addition, MEK blockade may induce compensatory signaling through both upstream pathway elements (RAF) and parallel pathways (PI3K/AKT/mTOR). Methods: We set out to define molecular and functional effects of single and combined BRAF (GSK2118436A, BRAF-I) and MEK (GSK1120212B, MEK-I) inhibition, using WB analysis to dissect signaling and a fixed dose-ratio experimental design to assess functional synergism by conservative isobologram analysis. Results: In A549 lung adenocarcinoma (KRAS G12S), BRAF-I (10 μM) induces hyperphosphorylation of CRAF, MEK, ERK, and p90RSK, while MEK-I (10 nM), alone or in combination with BRAF-I, potently offsets MAPK activation. Combined BRAF-I and MEK-I suppress malignant growth and survival at 72 h with highly synergistic effects in the A549 (lung, KRAS G12S), H1299 (lung, NRAS), HCT116 (colon, KRAS G13D), and MIAPACA (pancreatic, KRAS G12V) models, with combination indexes (CI), ranging from 1.37 to 0.12. Conversely, in other lung cancer models (H460, Calu-1, Calu-3) the combination of BRAF-I and MEK-I produced modestly additive to highly antagonistic antitumor effects. In BRAF-mutant melanoma and colon carcinoma models (M14 and HT29), there was no paradoxical activation of the MEK/ERK module in response to BRAF-I and both BRAF-I and MEK-I had pronounced growth inhibitory effects as single agents, but were frankly antagonistic in combination. Similarly, the pan-RAF inhibitor RAF265 did not cause MAPK activation and did not result in synergistic growth inhibition when combined with the MEK-I in the A549 and MIAPACA cell lines. Conclusions: Overall, our data indicate that combined inhibition of multiple signaling elements along the RAF/MEK/ERK pathway results in strongly synergistic growth inhibition, particularly in tumors with RAS mutations. Additional studies to better define genetic determinants of sensitivity/resistance and molecular mechanisms of therapeutic synergism of combined BRAF-I and MEK-I are currently ongoing.
Trends and variations in the use of adjuvant immunotherapy for stage III melanoma in the U.S. population.
Authors: Teresa J. Nasabzadeh, Huei-Ting Tsai, Eshetu Tefera, Suraj S. Venna, Arnold L. Potosky, Michael B. Atkins, Sekwon Jang
Journal: Journal of Clinical Oncology (2013)

9077 Background: High dose Interferon alfa-2b (IFN), an adjuvant immunotherapy for patients (pts) with stage III melanoma, was the only approved treatment option in the US from 1995-2011. There is limited information on how high dose IFN has been disseminated to eligible pts in general clinical practice, and whether variations exist in its adoption according to non-clinical factors. Methods: We obtained data on 34,208 pts diagnosed between 1998-2010 with stage III melanoma from the National Cancer Data Base (NCDB). IFN treatment was abstracted as immunotherapy. We investigated the use of immunotherapy according to pt demographic, socioeconomic, and clinical variables. We conducted multiple logistic regression analysis to examine the effect of these variables on the receipt of immunotherapy. Results: 62% of pts in our study population were male, 88% were Caucasian and 31% were over age 65. Overall, 27% of the pts received immunotherapy. There was no significant trend in its adoption between year 1998 and 2010. After adjustment for clinical variables, age at diagnosis, facility type, and geographic region are predictors strongly associated with use of immunotherapy. Only 16% of pts aged 65-74 and 3% over 75 received immunotherapy compared to 42% of those ages less than 45 (adjusted ORs 0.44 [0.32-0.59], 0.05 [0.04-0.14), respectively). Also 24% of pts treated at a comprehensive community cancer program received immunotherapy compared to 30% of those treated at an academic/research program (OR, 0.71 [0.51-0.99]). The frequency of immunotherapy was 25% in the Atlantic region and 17% in the Western region compared to 33% in Northeast (ORs 0.42 [0.18-0.99], 0.31 [0.13-0.74], respectively). Median household income, insurance type and comorbidity were not associated with adoption of immunotherapy after adjustment for all other variables. Conclusions: Less than one-third of all eligible patients received adjuvant immunotherapy in US general practice over the past decade. There is significant variation in its adoption according to non-clinical factors. Further exploration of the reasons for these variations and whether they are linked to important patient outcomes is needed.
Impact of Remission Status on Outcomes in AML Patients ≥ 60 Years of Age after Allogeneic Stem Cell Transplantation
Authors: Pavan Bhamidipati, Young Se Han, John F. DiPersio, Keith E. Stockerl-Goldstein, Jingxia Liu, Geoffrey L. Uy, Peter Westervelt, Ravi Vij, Mark A. Schroeder, Camille N. Abboud, Amanda F. Cashen, Nusayba A Bagegni, Rizwan Romee
Journal: Blood (2014)
Multivariate analysis of determinant factors in adjuvant chemotherapy (AC) utilization in patients with stage II colon cancer (CC): Analysis of the National Cancer Database (NCDB).
Authors: Donny V. Huynh, Shiva Kumar Reddy Mukkamalla, Ponnandai Sadasivan Somasundar, Ritesh Rathore
Journal: Journal of Clinical Oncology (2017)

577 Background: Evidence from randomized controlled trials does not support routine use of AC for patients with stage II CC. Clinical guidelines recommend discussion of AC in patients with high-risk disease. In our study, we analyzed NCDB data to determine factors favoring the use of AC in this setting. Methods: NCDB data was extracted on a total of 45,098 patients from 2004 to 2009 with stage II CC. Descriptive characteristics were analyzed using Chi-square test and odds ratios were calculated using multiple logistic regression. Results: Frequency of AC was significantly different among patients belonging to different age groups, tumor laterality, grade, pathologic tumor status (pT), and clinical nodal status (cN) (Chi-square test; p &lt; 0.0001). Age distribution analysis revealed higher frequency of AC administration among patients of 18-64 years compared to those of 65-74 years and older, irrespective of single-agent or multi-agent regimens (p &lt; 0.0001). Multivariate analysis was performed using multiple logistic regression technique. The odds of AC administration increased with increasing pT status, worsening tumor grade, and inadequate lymph node dissection ( &lt; 12 lymph nodes evaluated) (p &lt; 0.0001). AC administration was also more likely with left sided primary tumors (p &lt; 0.0001). Conclusions: Using NCDB data, our analysis reveals conventional factors which are associated with AC administration in patients with resected stage II CC. Use of single-agent vs. multi-agent regimens did not differ, though elderly patients and those without left sided tumors were less likely to receive AC. Oncologists should be able to utilize these findings in discussions with stage II CC patients regarding the use of AC. [Table: see text]
ASPEN: A randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma.
Authors: Andrew J. Armstrong, Susan Halabi, Tim Eisen, Walter Michael Stadler, Robert R Jones, Ulka N. Vaishampayan, Jorge A. Garcia, Robert E. Hawkins, Christian K. Kollmannsberger, Christine Lusk, Samuel Broderick, Daniel J. George
Journal: Journal of Clinical Oncology (2013)

TPS4590 Background: Currently no level 1 evidence exists to guide therapeutic decisions in patients with metastatic non-clear cell renal cell carcinoma. Case series and retrospective analyses suggest that strategies targeting either the VEGF or mTOR/TORC1 pathways have clinical activity in papillary, chromophobe, or poorly differentiated histologic subtypes. Methods: We are conducting an international, randomized phase 2 trial of patients with metastatic non-clear cell RCC; either papillary, chromophobe, or undifferentiated histology; any Motzer risk group; and who have had no prior systemic therapy. All patients contribute tissue to an international biorepository for correlative genomic, genetic, and protein biomarker studies, along with companion longitudinal plasma and urine angiome studies. Patients are randomized to either everolimus or sunitinib (1:1) at FDA approved dosing until progression. The primary endpoint is progression free survival. Trial status: Seventy-three out of a planned 108 subjects have been enrolled at the time of abstract submission: median age 64, 59 white, 10 black, 4 unknown race, and includes 42 papillary and 31 chromophobe/undifferentiated histologies, 49 men and 22 women. Accrual is anticipated to be completed by December 2013. Accrual distribution by country is currently 43 (USA), 27 (UK), and 3 (Canada). The first DSMB meeting was conducted after 40 subjects completed at least 6 months of therapy and concluded that there were no unexpected safety signals and that the study should proceed. Tissue (primary, some metastatic, urine, plasma, whole blood) has been collected on all patients to date through the Duke Center for Human Genetics Biorepository. Clinical trial information: NCT01108445.
Outcome and prognostic factors in localized osteosarcoma with uniform chemotherapy protocol: A single-center experience of 234 cases.
Authors: Vijaya Murugan, Sameer Bakhshi, Shishir Rastogi, Shah Alam Khan
Journal: Journal of Clinical Oncology (2014)

10540 Background: Data on outcome of localized Osteosarcoma (OS) treated with uniform protocol is limited from Asia. Methods: This is a single institutional review of patients treated between Jan 2004-Dec 2012, and evaluated on per protocol analysis. All patients received uniform chemotherapy protocol with cisplatin, doxorubicin as neo-adjuvant chemotherapy (NACT), followed by surgery and adjuvant chemotherapy (ACT) based on risk stratification. Results: 234 OS patients were treated with median age 17 years (range: 2–66), Male: Female: 2:1, tumor diameter 9 cm (range: 1-25) and symptom duration 4 months (range: 1-36). Sites of disease were extremities 93%, pelvis 2 % and head & neck 5%. Of them 218 (93.2%) received NACT and 16 (6.8%) underwent upfront surgery. Post-NACT, 4(1.7%) were in CR; 152(66%) in PR with ORR 67.7%. Of the 218 patients who received NACT, 198 (90.8%) underwent surgery (70.2%- Limb salvage, 29.8%-Amputation). On histological examination, 47(28.4%) achieved >90% tumor necrosis while 118(71.6%) achieved <90% tumor necrosis. Adjuvant chemotherapy was given to 198 (84.6%) patients with median of 5 cycles. At median follow-up of 68 months (range: 2–119), 5-year EFS, overall survival were 39.5%, 51.5% respectively. Multivariate analysis showed tumor site and tumor necrosis as significant risk factors for EFS and OS respectively. Conclusions: This is largest single institutional study of localized osteosarcoma from Asia which constituted 70% of entire cohort with delayed presentation. More than 2/3rdof patients had successful limb salvage chemotherapy after NACT. Extremities OS with post NACT tumor necrosis >90% had best outcome. Multivariate analysis. Variable EFS OS HR 95% CI P Value HR 95% CI P value Tumor site Extremities Head and neck, pelvis 2.45 1.30-4.50 0.01 ----- ------ ------ Necrosis >90% <90% 2.54 1.01-6.33 0.05
Patterns of toxicities and outcome in children versus adolescents/young adults (AYA) with metastatic rhabdomyosarcoma (RMS): A report from the Children’s Oncology Group (COG) Soft Tissue Sarcoma Committee.
Authors: Abha A. Gupta, Elizabeth Lyden, James Robert Anderson, Carola A. S. Arndt, David Anthony Rodeberg, Jeff M. Michalski, David Parham, William H. Meyer, Douglas S. Hawkins, Brenda Weigel
Journal: Journal of Clinical Oncology (2013)

10554 Background: Age at diagnosis is a prognostic factor in patients with RMS. We sought to determine whether AYA with metastatic alveolar (ARMS) or embryonal (ERMS) RMS had a different failure-free survival (FFS) compared to younger patients, and to identify treatment related factors that may be associated with outcome. Methods: COG ARST0431 patients were reviewed. The incidence of toxicities (AE, grade3/4 using CTCAEv3) by age was determined in 4 reporting periods (RP: wks 1-6; RP2:7-19; RP3: 20-34; RP4: 35-54). The AEs in younger patients (&lt;=13 years) were compared with those in AYA. Fisher’s exact test was used to compare differences between the groups. Results: Of 109 patients, 60 (55%) were AYA. In RP1, they were more likely to have nausea/vomiting (4.1 vs. 16.9%, p=0.06), pain (6.1 vs. 20.3%, p=0.05), and metabolic disturbances (4.1 vs. 20.3%, p=0.02) compared to younger patients. In RP4, older patients trended to have less infection (15.8 vs. 30.1, p=0.07). All other toxicities were similar between the two age cohorts in the other RPs. AYA were less likely to complete therapy (52 vs. 73%, p=0.03) and more likely (in RP 4) to have unplanned dose modifications (outside of protocol guidelines) (23 vs. 2.7%). Of patients that completed therapy, there was no age-related difference in the time to completion. As shown in the table, younger patients had better 3-yr FFS, driven by a lower FFS for AYA with ARMS. Conclusions: This evaluation suggests that AYA with RMS were less likely to complete therapy and experienced a higher prevalence of pain and nausea compared to younger patients; the role of reporting bias and reasons for treatment discontinuation need further study. Children were more likely than AYA to have infection. Inferior FFS was only seen in AYA with ARMS suggesting a clear need for novel therapies for these patients. This study may be underpowered to demonstrate significant differences in other toxicities or in FFS among ERMS patients. [Table: see text]
Time to Endovascular Thrombectomy for Acute Stroke—Reply
Authors: Jeffrey L. Saver, Mayank Goyal, Michael D. Hill
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Basal Cell and Squamous Cell Carcinoma in Persons Younger Than 40 Years—Reply
Journal: JAMA (2006)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Immune Responses to Novel Adenovirus Type 26 and Modified Vaccinia Virus Ankara–Vectored Ebola Vaccines at 1 Year
Authors: Rebecca L. Winslow, Iain D. Milligan, Merryn Voysey, Kerstin Luhn, Georgi Shukarev, Macaya Douoguih, Matthew D. Snape
Journal: JAMA (2017)

Vaccinia Virus Ankara-Vectored Ebola Vaccines at 1 YearThe Ebola virus vaccine strategies evaluated by the World Health Organization in response to the 2014-2016 outbreak in West Africa included a heterologous primary and booster vaccination schedule of the adenovirus type 26 vector vaccine encoding Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia virus Ankara vector vaccine, encoding glycoproteins from Ebola, Sudan, Marburg, and Tai Forest viruses nucleoprotein (MVA-BN-Filo).This schedule has been shown to induce immune responses that persist for 8 months after primary immunization, with 100% of vaccine recipients retaining Ebola virus glycoprotein-specific antibodies. 1 A vaccine that provides durable immune responses is important in maintaining sustained protection against disease, both during outbreaks and outside of an outbreak for at-risk populations, such as health care and aid workers in risk areas, individuals in areas experiencing low-grade endemic disease, 2 and contacts of Ebola survivors, given evidence of prolonged shedding of the virus from body fluids with the potential for transmission. 3,4e report the 1-year data for the study of the Ad26.ZEBOV and MVA-BN-Filo vaccines, 1 the longest duration follow-up for any heterologous primary and booster Ebola vaccine schedule to our knowledge.Methods | The single-center, randomized, placebo-controlled, observer-blind, phase 1 trial received approval from the National Research Ethics Service.Participants provided written Table.Ebola Antibody and T-Cell Responses Detected by ELISA, Interferon-γ ELISpot, and Intracellular Cytokine Staining at 1-Year Follow-up (Day 360) Prime on Day 1, Boost on Day 29 Prime on Day 1, Boost on Day 57 Prime on Day 1, Boost on Day 15: Ad26.ZEBOV, Then MVA-BN-Filo MVA-BN-Filo, Then Ad26.ZEBOV Ad26.ZEBOV, Then MVA
Phase II study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM).
Authors: David A. Reardon, Jorg Dietrich, Thomas Joseph Kaley, Hui Kong Gan, Gavin P Dunn, Timothy Francis Cloughesy, Michael Lim, Jennifer Leigh Clarke, Andrew J. Park, Linda S. Pan, Dominic W Lai, Joyson Joseph Karakunnel, Paul B. Robbins, Rajesh Narwal, Ralph Rudolph Venhaus
Journal: Journal of Clinical Oncology (2015)

TPS2077 Background: Programmed cell death ligand-1 (PD-L1) is widely expressed on antigen presenting cells (APC) and other immune cells. PD-L1 binds two important regulatory receptors on T-cells: programmed cell death-1 (PD-1) and CD80/B7. Targeting Programmed Death-1 (PD-1) and its ligand, PD-L1, have demonstrated promising anti-tumor activity among other challenging solid tumors and growing data implicates PD-1/PD-L1 signaling as a significant contributor to immunosuppression in glioblastoma (GBM). PD-1 is expressed by many GBM infiltrating lymphocytes while PD-L1 is expressed by 61-100% of GBM tumors. Furthermore, loss of the PTEN tumor suppressor gene, which occurs in 40-50% of GBM tumors, leads to increased transcription and expression of PD-L1 in GBM. These findings indicate that PD-L1 is an attractive and important therapeutic target in GBM. MEDI4736 (M), a human IgG1κ blocking monoclonal antibody against PD-L1, represents a compelling immune-mediated anti-tumor treatment for GBM. Methods: Phase II, multicenter, open-label study (NCT02336165) is evaluating the clinical efficacy and safety of M in GBM patients. Eligible patients include those who are newly diagnosed with unmethylated MGMT GBM scheduled for standard radiotherapy (Cohort A); Bevacizumab-naïve patients with recurrent GBM (Cohort B); and Bevacizumab-refractory patients with recurrent GBM (Cohort C). Cohort A patients will receive M at 10 mg/kg i.v. Q2W for up to 12 months beginning with standard radiotherapy. Cohort B will receive M at 10 mg/kg i.v. Q2W for up to 12 months as monotherapy. Cohort C will receive M at 10 mg/kg i.v. Q2W for up to 12 months in combination with continued bevacizumab at 10 mg/kg Q2W. Primary endpoints include overall survival (OS) at 12 months (cohort A), progression free survival rate at 6 months (PFS-6) (cohort B) and OS-6 (cohort C). Secondary endpoints are safety/tolerability, PFS, median OS, radiographic response, and quality of life (QoL) by EORTC QLQ-C30/BN20. Exploratory endpoints are patient neurologic function using the Neurologic Assessment in Neuro-Oncology (NANO) scale, as well as immuno-correlative biomarkers and pharmacokinetics. Clinical trial information: NCT02336165.