tbuckley/cabot-search huggingface dataset:
Effect of anti-inflammatory therapy in patients with metastatic renal cell carcinoma on clinical response
Authors: A. Reichle, J. Grassinger, K. Bross, J. Wilke, T. Suedhoff, A. Berand, W. Wieland, R. Andreesen
Journal: Journal of Clinical Oncology (2006)

14500 Background: Interaction among signalling networks from tumor and neighbouring stroma cells in complex disease traits is poorly understood. Methods: Two consecutive multi-centre phase II trials were designed (case calculation according response rate, T. Chen two stage design) to prove the hypothesis, whether the activation of presumably complementary receptor-triggered transcriptional cascades (via pioglitazone, and interferon alpha, IFNa) could result in synergistic clinical effects. Therapy in both trials consisted of low-dose capecitabine 1 g/m 2 twice daily po for 14 days, every 3 weeks, day 1+, and rofecoxib 25 mg daily, day 1+ (from 11/04 etoricoxib 60 mg daily instead) plus pioglitazone 60 mg daily, day 1+. In study II low-dose IFNa 4.5 MU sc three times a week, week 1+, was added until disease progression. Results: Eighteen, and 33 patients (pts, 31 eligible for analysis), respectively, with clear cell carcinoma, progressive disease, and ECOG 0–2 were enrolled between 2/02 to 2/03 and 4/03 to 4/05, respectively. Mean Bradley score in both trials was not significantly different, 4.1(I)/4.9(II), however, the rate of previous systemic treatments 33%/19%. Objective response (48%) was exclusively observed in study II (PR 35%, CR 13%), and paralleled by a strong CRP response (after 4 weeks on treatment) in all 29 pts with elevated CRP levels (93%) (study I: no significant CRP response): CRP values decreased from mean 41.3 mg/l, range 8.1 to 221, to 5.1 mg/l, range 2.1 to 15.6, p = 0.005. Stable disease &gt; 2 months (mos) occurred in 50%/48%. Median progression-free survival could be more than doubled from a median of 4.7 mos (95% CI, 1.0 to 10.4) to 11.5 mos (6.8 to 16.2) in study II, p = 0.0000. Median overall survival of population II has not been reached, yet. Toxicities &gt; WHO grade II were reported (study I/II): Hand-foot syndrome (3/3), diarrhoea (2/2), depression (0/1), pneumonia (0/1). Conclusions: (1) Clinical results of anti-inflammatory/angiostatic therapy compare with available immuno-therapies. (2) Improved outcome with additive IFNa argues for a synergistic drug interaction. (3) Control of tumor-associated inflammation is an important therapeutic principle in metastatic clear cell carcinoma. No significant financial relationships to disclose.
Abstract 16339: Heparin Bridging in Atrial Fibrillation Patients After Temporary Interruption of Warfarin: Evidence From Meta-analysis
Authors: Karam Ayoub, Ramez Nairooz, Ahmed Almomani, Meera Marji, Maria Pino, Waddah Maskoun
Journal: Circulation (2015)

Background: Patients with atrial fibrillation often require temporary interruption of warfarin for procedures. However, the efficacy of periprocedural heparin bridging in clinical practice is still unclear. Methods: We searched the literature for trials that compared heparin bridging to no bridging in atrial fibrillation patients for whom warfarin was temporarily interrupted. The incidence of all-cause mortality, thromboembolism, and major and all bleeding was included, and meta-analysis was performed. Results: A total of 11,924 patients with atrial fibrillation were included in 4 observational studies and 1 randomized trial. Mean CHADS2 score for the no heparin bridging group is 2.26 vs heparin bridging 2.26. At 30 days and up to 3 months, no bridging group in comparison to bridging group did not show any significant difference in mortality (odds ratio (OR), 1.22; 95% confidence interval (CI), 0.04-37.43; P = 0.91) or thromboembolism (OR, 0.69; 95% CI, 0.12-4.05; P = 0.68), but no bridging group showed significantly less major bleeding (OR, 0.43; 95% CI, 0.21-0.86; P = 0.02) and less all bleeding (OR, 0.43; 95% CI, 0.24-0.79; P = 0.007). Conclusion: Among atrial fibrillation patients anticoagulated with warfarin with an intermediate CHADS2 score requiring temporary interruption of warfarin for a procedure, periprocedural bridging with heparin was associated more with major and all bleeding when compared to no bridging, with no significant difference in mortality and thromboembolism.
Differential expression of LKB1, PD-L1, and PD-L2 in KRAS-mutant non-small cell lung cancer in never-smokers.
Authors: Antonio Calles, Xiaoyun Liao, Lynette M. Sholl, Mohit Butaney, Scott J. Rodig, Gordon James Freeman, Christine A. Lydon, Geoffrey R. Oxnard, David Michael Jackman, Pasi A. Janne
Journal: Journal of Clinical Oncology (2014)

8032 Background: KRAS mutation is the most common oncogenic alteration in lung adenocarcinoma and is detected in smokers and up to 15% of never smokers. The tumor suppressor LKB1 is commonly mutated in NSCLC and LKB1 mutations occur concurrently in 30% of KRAS mutant NSCLC. In murine models, KRAS mutant tumors with concurrent LKB1 loss did not respond to docetaxel/selumetinib treatment. Immune checkpoint blockade by anti-PD-1/PD-L1 monoclonal antibodies (MoAb) is being clinically evaluated. Clinical responses to these agents correlate with PD-L1 expression and smoking status. We aimed to determine the expression of LKB1, PD-L1 and PD-L2 in KRAS mutant NSCLC from smokers (KS) and never smokers (KNS). Methods: We evaluated the clinical and molecular characteristics of KRAS mutant NSCLC patients (pts) using an institutional database. We examined LKB1, PD-L1, PD-L2 tumor expression by immunohistochemistry (IHC). IHC was performed using the murine MoAbs Ley37D/G6 (LKB1), 9A11 (PD-L1) and 9E5 (PD-L2). LKB1 staining was scored as intact or lost, with any degree of expression qualifying as intact, PD-L1 positive if >5% of cells were stained and PD-L2 positive if >10%. Results: Between 8/09 and 1/14 we identified 514 KRAS mutant NSCLC pts (stage I 22%/II 10%/III 19%/IV 49%) of which 39 were never smokers (incidence 7.6%) We analyzed 114 pts with available tissue using IHC (30 KNS and 84 KS). LKB1 loss was detected in 29% of cases (95%CI, 21-38%) and was significantly less frequent in KNS pts (KS 34% vs KNS 13%; P= 0.035). KRAS transversion mutations were more frequent in KS vs KNS pts (78% vs 37%; P= 0.0001). LKB1 staining was intact in 95% of KNS pts with transition mutations. Pts with LKB1 loss had more metastatic sites and brain involvement (47% vs 24%, P= 0.0472). PD-L1 was expressed in 19% of KRAS mutant cases and PD-L2 in 45% and were inversely correlated (r=-0.86, P <0.0001). PD-L1/PD-L2 expression was not related to either LKB1 status or type of KRAS mutation. PD-L1/PD-L2 IHC 3+ vs 1+/2+ staining was more frequent in KS vs KNS pts (50% vs 20%; 40% vs 13% respectively). Conclusions: KRAS mutant NSCLC is a heterogeneous disease. Our findings may have implications for choosing KRAS mutant pts for ongoing trials of MEK and PD-1/PD-L1 inhibitors.
Three year results of a prospective study on focal salvage HDR prostate brachytherapy for local recurrence after external beam radiotherapy (XRT).
Authors: Hans T. Chung, Laura D'alimonte, Andrew Loblaw, Ananth Ravi, Melanie Davidson, Matthew Wronski, Masoom A. Haider, Gerard Morton
Journal: Journal of Clinical Oncology (2017)

e558 Background: Salvage options for those with local recurrence after XRT include surgery, brachytherapy, cryotherapy or high-frequency ultrasound. However, the risk of significant complications (e.g. fistula, incontinence, bladder neck contracture), is not insignificant. The sensitivity of multiparametric MRI in detecting viable cancer within the prostate is now more than 70%. The objectives of this pilot study are to explore the toxicities, QOL and efficacy of focal salvage HDR brachytherapy in patients with MRI-visible biopsy-confirmed local recurrence. Methods: Eligible patients included: multiparametric 3T MRI-visible biopsy-confirmed local recurrence &gt; 30 months after XRT, negative metastatic workup, IPSS &lt; 15, post-XRT PSA &lt; 10ng/mL, prostate volume ≤ 50cc. The ultrasound-based HDR brachytherapy prescription dose was 27Gy divided over two implants separated by 1 week to the target volume (TV) with dose constraints to the urethra and rectum. Follow-up PSA, IPSS, EPIC QOL and CTCAE v4.0 toxicities were collected. Results: 15 patients (mean age 73 years) were enrolled in the study. Median follow up was 30 months (12-42). At initial presentation, there were 5, 8 and 2 low-, intermediate- and high-risk disease, and initial XRT dose was 70-78Gy. The Gleason score of the local recurrence was 6, 7 and 8-10 in 1, 7 and 6, respectively, and not classified in 1 patient. The pre-HDR median PSA was 4.13 (1.30 – 9.29). The median size of the recurrence on MRI was 9mm (7-20), TV 6.1cc (2.2-16.1), TV V100 96.3%, TV D90 110.9%, urethral D10 64.5% and rectal D10 36.0%. No acute/late GU/GI grade 3-5 toxicities, nor urinary retention, were observed. The most common acute toxicity was frequency and nocturia. Median IPSS at baseline, 1-, 3-, 6-, 12-, 18-, 24-months was 4, 8, 5, 5, 8 and 5 (p = 0.72). Three year PSA failure free rate was 71%. There was no significant change in EPIC domains. Conclusions: Early toxicity, QOL and PSA failure-freedata suggests that focal salvage HDR brachytherapy is well tolerated and effective. Clinical trial information: NCT01583920.
Survival benefit and cost of autologous hematopoietic stem cell transplantation (Auto HSCT) in elderly patients with multiple myeloma (MM) using the SEER-Medicare database.
Authors: Gunjan L. Shah, Aaron Winn, Pei-Jung Lin, Andreas Kirschmer Klein, Kellie A. Sprague, Rachel J. Buchsbaum, Joshua T Cohen, Kenneth B Miller, Raymond Comenzo, Susan Kenyon Parsons
Journal: Journal of Clinical Oncology (2014)

8517 Background: Medicare coverage for Auto HSCT for MM began in 10/2000. By 2009, MM was the leading indication for this treatment (CIBMTR, 2011). The survival benefit and cost implications of the rise in Auto HSCT are not well described in this population. Using SEER-Medicare data, we explored these implications for MM patients (pts) age 66+ by comparing them with pts not undergoing Auto HSCT. Methods: We used auto HSCT-specific ICD-9 or HCPCS codes to identify pts as having an Auto HSCT. We restricted the sample to pts age 66+ at time of MM diagnosis and used propensity score matching to create a cohort not receiving Auto HSCT. We calculated costs and survival for the first 100 days (d), year (yr), 3 yrs, and 5 yrs post-diagnosis using Kaplan-Meier curves stratified by patients receiving a transplant. We inflation-adjusted cost data to 2009 US dollars, using the medical care component of the Consumer Price Index. Patients were followed for up to 9 years. Results: We identified 10,832 pts diagnosed with MM from 1/2000 to 1/2008. Of these, 267 received Auto HSCT. We created a matched “control” sample of 267 pts not having Auto HSCT (c-statistic 0.83). The samples had a median age at diagnosis of 69.8 yrs, with 60% males and 90% Caucasians. The Charleson comorbidity index (CCI) was 0 for 62% of the Auto HSCT and 67% of the control pts (p=0.52), with the rest having a CCI of 1+. Median time to transplant was 250d. Median survival increased from 822 to 1,705 days with Auto HSCT (p=<0.001). Overall survival (OS) with Auto HSCT was higher at all time points: 99 vs 87% at 100d (p=<0.001); 95 vs 71% at 1 yr (p=<0.001); 73 vs 45% at 3 yr (p=<0.001); and 48 vs 30% at 5 yr (p=<0.001). Mean cost post diagnosis was $301,000 vs 124,000 with a life year gain of 2 years with Auto HSCT. The incremental cost-effectiveness ratio was $88,500/life year. Conclusions: Auto HSCT significantly increases OS in elderly patients with MM. While the cost of treating the transplanted patients was higher, the incremental cost effectiveness ratio is below the commonly accepted threshold for cancer treatment. Components of cost will be presented to describe the impact of novel agents.
Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas: Final results.
Authors: Andrew David Norden, David Schiff, Manmeet Singh Ahluwalia, Glenn Jay Lesser, Lakshmi Nayak, Eudocia Quant Lee, Mikael L. Rinne, Alona Muzikansky, Jorg Dietrich, Benjamin Purow, Katrina H. Smith, Sarah C. Gaffey, Christine Sceppa McCluskey, Keith L. Ligon, David A. Reardon, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2014)

2053 Background: Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanibis an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/β, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to prior anti-VEGF therapy. Methods: This was an open-label, phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab. The primary endpoint was PFS6 in the bevacizumab-naive arm (arm A) and PFS3 in the post-bevacizumab arm (arm B). A Simon two-stage design was employed. Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Results: Twenty-two patients enrolled in Arm A and 14 in Arm B. Accrual to both arms was stopped after the first stage due to futility. Arm A included 12 GBMs (55%), 13 patients with one prior regimen (59%), and median age 54 years (range 28-75). Arm B included 10 GBMs (71%), one patient with one prior regimen (7%), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0%, median PFS 28 days (95% CI: 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0%, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). In Arm A (AG only), PFS6 was 0% and median PFS 28 days (27-68). In Arm B (AG only), PFS3 was 0% and median PFS 28 days (7-56). Rare grade >3 toxicities included transaminase elevation, hypophosphatemia, hypertension, intracranial hemorrhage, and abdominal pain. Two participants died during therapy, one from thromboembolism and one from colon perforation. Conclusions: Nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy. Clinical trial information: NCT01380782.
Effectiveness of a screening intervention to identify clinical-trial-eligible patients.
Authors: Leo Chen, Janice Grant, Hagen F. Kennecke
Journal: Journal of Clinical Oncology (2012)

6069 Background: Advancements in cancer therapy require clinical trials, but only 3% of all cancer patients (CP) participate in trials causing many studies to be delayed or fail to complete. Literature indicates that accrual to clinical trials is primarily driven by MD related factors. The objective of this study was to evaluate whether the screening and identification of potentially eligible patients (PEP) for specific clinical trials would lead to an increased rate of accrual (RA). Methods: During a 4 month period, the charts of CP attending the outpatient clinics of 12 MDs were reviewed to determine eligibility for 21 phase II-IV trials for CP with BR, GI, GU, GY, or LG cancer. Trials were included if they had been open for ≥ 4 months and would remain open ≥ 8 months from the start of the intervention. A screening coordinator with minimal clinical background reviewed the electronic record of new and followup CP to determine eligibility according to protocol specified criteria. PEP were identified for medical oncologist by attaching notices to CP charts. Participating MDs were surveyed regarding the helpfulness and accuracy of the forms. A negative-binomial regression model was used to compare RA and find 95% CI for relative rates. Results: Between May 1 to August 31, 2011 a total of 2,098 charts were screened for eligibility for 21 trials, and 120 PEP were identified. Of these, 15 were randomized to the referred study, 4 to a different study, and 4 CP were offered but declined the referred study. Four month RA for included trials were 61 before, 73 during and 51 after the intervention. Relative rates adjusted for MD bookings were 0.85 (95% CI: 0.67, 1.06, p = 0.15) before and 0.70 (95% CI: 0.54, 0.90, p &lt; 0.005) after, relative to during the intervention. 33 completed questionnaires were received: 22 (67%) were helpful and 23 (70%) were accurate. Screening required a 1.0 Full Time Equivalent position during the period of the intervention. Conclusions: Manual screening of patient records to determine clinical trial eligibility is labor intensive and increases enrolment to specific clinical trials. Notifications were deemed mostly helpful and accurate by oncologists. Screening interventions should be considered to improve clinical trial accrual.
Association of the 3'-untranslated region KRAS-variant with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
Authors: Joanne B. Weidhaas, Ju-Whei Lee, Robbert Slebos, Jason Howard, Jimena Perez, Jill Gilbert, Sunitha Nallur, Trupti Paranjape, Joaquin J. Garcia, Barbara Burtness, Arlene A. Forastiere, Christine H. Chung
Journal: Journal of Clinical Oncology (2013)

6016 Background: A germline mutation in let-7 complementary site 6 (LCS6) within the KRAS 3'-untranslated region (rs61764370, the KRAS-variant: TG/GG) is known to associate with poor outcome and drug resistance in various cancers compared to the wild type allele (TT). We examine the prognostic significance of the KRAS-variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods: The KRAS-variant was determined in 116 tumor DNA samples from HNSCC patients enrolled in 3 clinical trials and a tissue collection study using a previously validated PCR-based assay. Results: KRAS-variant status could be determined in 108/116 (93%) samples and an allele frequency of TG/GG was 28.7%. These results were correlated with patient demographics, p16/human papillomavirus (HPV) status and clinical outcome. There was no association between p16/HPV status and the KRAS-variant status (Fisher’s exact test, p=1.0). The KRAS-variant was associated with poor progression-free survival in patients treated with cisplatin+/-cetuximab (log-rank p=0.002) but this association was not observed in docetaxel/bortezomib treated patients (log-rank p=0.89). Conclusions: KRAS-variant is a potentially promising biomarker of poor prognosis and a predictive biomarker of cisplatin resistance in R/M HNSCC. Prospective validation is warranted. Clinical trial information: NCT00003809.
Phase II study of combination of hyperCVAD with ponatinib in frontline therapy of patients (pts) with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL).
Authors: Elias Jabbour, Hagop M. Kantarjian, Deborah A. Thomas, Farhad Ravandi, Jorge E. Cortes, Stefan Faderl, Naveen Pemmaraju, Tapan M. Kadia, Rebecca S. Garris, Guillermo Garcia-Manero, Gautam Borthakur, William G. Wierda, Susan Mary O'Brien
Journal: Journal of Clinical Oncology (2013)

7024 Background: Combination of chemotherapy with TKIs was evaluated and appears to be effective in Ph+-ALL. Ponatinib is a more potent inhibitor and suppresses the T315I clones, a common cause of relapse in pts with Ph+- ALL. Clinical trials of ponatinib have demonstrated its high activity and limited toxicity in pts with Ph+-leukemia failing 2-3 TKIs and in those with a T315I mutation. Combinations of chemotherapy regimens and ponatinib may be associated with better response rates and higher likelihood of eradication of MRD. Methods: In this phase II trial, pts with newly diagnosed Ph+ ALL receive ponatinib 45 mg po QD for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR receive maintenance with ponatinib 45 mg po QD and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring is conducted. Results: To date 20 pts with untreated Ph+ ALL have received a median of 6 cycles; 5 pts are receiving maintenance in CR. Median age is 49 years. Median WBC at diagnosis was 2.45 x 10 9 /L. All pts were in CR after 1 cycle. 15 of the 17 pts (88%) known to be Ph+ by cytogenetic analysis at baseline achieved CCyR after 1 cycle; 1 had mCyR only and 1 had no cytogenetic analysis at CR, both of them achieved CCyR after cycles 2; 3 had a diploid karyotype at the start. To date, 17 pts (85%) have achieved MMR, of whom 11 (55%) have achieved CMR at a median of 10 weeks from initiation of treatment. MRD assessment by flow cytometry is negative in 18 (90%) pts at a median of 3 weeks. Median time to neutrophil and platelet recovery for cycle 1 was 18 and 22 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥3 toxicity included increase of LFT’s/hyperbilirubinemia in 8 pts, thrombosis in 3, skin rash in 2, pancreatitis in 1, and pericardial effusion in 1. With a median follow up of 6 months, 19 pts are alive and in CR; 1 pt died in CR from an unrelated cardiac event. 1 pt has undergone an allogeneic transplant. The 1-year PFS and OS rates were 100% and 95%, respectively. Conclusions: The combination of hyperCVAD with ponatinib is safe and highly effective in achieving molecular remissions in pts with Ph+ ALL. Clinical trial information: NCT01424982.
Primary CNS lymphoma; a review of the University of Michigan experience 2004-2013.
Authors: Aaron Gerald Mammoser, Shiao-Pei S. Weathers, Nicholas J. Seewald, Jeremy MG Taylor, Larry Junck
Journal: Journal of Clinical Oncology (2015)

e13012 Background: Evidence supports high dose methotrexate (HD-MTX), rituximab, and cytarabine treatment for newly diagnosed primary CNS lymphoma (PCNSL), but no regimen is standard. Since 2004, the University of Michigan treatment regimen has been 8 cycles of HD-MTX (8 g/m2), rituximab 375 mg/m2, vincristine 2 mg (cycles 1-5), cytarabine 1.5-3 g/m2 (cycles 4-8) with 6 cycles of temozolomide consolidation, 150-200 mg/m2 days 1-5 of 28. Radiation is reserved for patients without a complete response (CR). Methods: We conducted an IRB-approved review of all patients with newly diagnosed PCNSL treated at the University of Michigan from 1/1/04 – 12/31/2013. Patients with absent/inconclusive pathology, a history of high-grade systemic lymphoma, or organ transplant were excluded. Immunosuppression with no transplant history was allowed. No performance status cutoff was employed. All patients initiating treatment were included in the analysis. MRI was reviewed to determine overall response, date of complete response (CR), and date of progression. Survival endpoints were estimated from time of diagnosis, and were analyzed using PROC LIFETEST in SAS v9.4. Results: 57 patients, median age of 66 (range 43-85), were identified. 38 (67%) had CR at completion of HD-MTX. Median overall survival (mOS) was 5.25 years (95% CI 2.14, ∞). Median progression free survival (mPFS) was 1.94 years (1.41, ∞). In the CR group, mPFS was 6.02 years (1.89, ∞), 2-year PFS 65% (46,78), and 3-year PFS 53% (34,69). Also in the CR group, mOS was not reached, 2-year OS 83% (65,92), and 3-year OS 62% (43,77). Median follow up in the CR group was 3.87 years. Presently, 22 patients with CR, and 33 patients overall, are alive without progression. Conclusions: The University of Michigan PCNSL regimen shows response rates, response duration, and survival outcomes comparable to the more efficacious published regimens. Advantages of this regimen include use early in treatment of drugs with low passage across the blood-brain barrier, applicability to nearly all patients with CNS lymphoma, and avoidance of radiation with its attendant long-term toxicity. Strengths of this study include the large number of patients and inclusion of patients with a wide range of age and functional status.