bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival outcomes in patients undergoing neoadjuvant chemotherapy for upper tract urothelial cell carcinoma.
Authors: Porten Sima P. , Siefker-Radtke Arlene O. , Kamat Ashish M. , Dinney Colin P.N. , Matin Surena F. 
Published: February 2017

311 Background: High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged at surgery and has uniformly poor survival rates. Neoadjuvant chemotherapy (NAC) may provide an avenue to improve clinical outcomes in these patients prior to loss of renal function after nephroureterectomy. Methods: We performed a retrospective review of patients with high risk UTUC who received NAC followed by surgical extirpation from 2004 to 2008, a time period during which NAC was uniformly offered to patients. The study group was then compared to a historical cohort of similar risk patients who underwent initial surgical treatment from 1993-2004. Results: Of the 120 patients, 31 patients with high-risk cN0 disease received NAC, 76 had initial surgery, and 13 had surgical consolidation of clinically involved lymph nodes after chemotherapy. Those receiving NAC had an improved OS and DSS (p=0.018 and p=0.0005, respectively). The 3 and 5 year DSS for cN0 patients receiving NAC was 90% and 90% (OS 87% and 80% respectively) with median follow up of 64 months. The 3 and 5 year DSS and OS for the historical group was 70% and 62%, with median follow up of 87 months. The two groups had similar demographics and clinical features, except for a higher proportion of sessile tumor architecture in the NAC group (p=0.021). Full dose cisplatin or high dose ifosfamide based chemotherapy was given to 22 (71%) patients, while 4 (13%) received a modified dose of cisplatin, and 5 (16%) received a nephron sparing combination. Pathologic downstaging to <=pT1N0 was significantly associated with NAC (65% vs 26% initial, p=0.004). The 13 patients with node positive disease at presentation received NAC followed by surgical consolidation with median OS 78 months. The 3 and 5 year DSS was 77% and 67% (OS 69% and 60% respectively). Conclusions: Neoadjuvant chemotherapy improves survival in patients with UTUC compared with historical expectations. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy especially considering the limitations of administering curative cisplatin-based chemotherapy after nephrectomy.
Quality of life (QoL) among patients with renal cell carcinoma (RCC) treated with pazopanib versus sunitinib in the COMPARZ study.
Authors: Cella David , Hackshaw Michelle Denise , Diaz Jose , Huang Chun , Deen Keith C. , Crescenzo Rocco , Motzer Robert John 
Published: February 2017

346 Background: Pazopanib and sunitinib are targeted therapies associated with particular treatment-related side effects that may affect patients’ QoL. COMPARZ was a randomized, open-label, parallel group, phase III study of pazopanib vs. sunitinib in 1,110 subjects with advanced RCC who had not received prior systemic therapy. The study demonstrated pazopanib is non-inferior to sunitinib with respect to progression-free survival. The study also confirmed the differentiated safety profiles of the two drugs. Methods: QoL endpoints were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19), the Cancer Therapy Satisfaction Questionnaire (CTSQ), and a Supplementary Quality of Life Questionnaire (SQLQ). Research to validate the SQLQ is currently ongoing. Each instrument was administered at baseline (except CTSQ) and then day 28 of every cycle. Changes in mean scores over time were analyzed and compared using a repeated measures analysis of covariance. Comparisons were pre-specified at the first 6 months of treatment as this time was expected to be a key interval during which tolerability issues may have occurred. Results: During the first 6 months, treatment differences in change from baseline for 11 of the 14 QoL domains studied were statistically significant (p < 0.05), all of which favored pazopanib. Further analysis up to 12 months of treatment, showed the treatment differences observed for fatigue scores increased over time with pazopanib improving and sunitinib remaining relatively flat. The difference in limitations due to foot soreness between the two treatments also progressively increased with time over 12 months favoring pazopanib. Conclusions: In this study, better patient-reported QoL scores for pazopanib indicate subjects experienced less worsening of fatigue, as well as mouth/throat, hands, and feet soreness, and fewer limitations due to soreness, while on pazopanib compared with sunitinib. The differences observed are likely to be clinically meaningful. The FACIT-F and SQLQ results are also highly consistent with the previously-reported PISCES study.
Inhibition of tumor growth in a VEGFR TKI-resistant model of renal cell carcinoma using dalantercept combined with sunitinib.
Authors: Bhatt Rupal Satish , Wang Xiaoen , Solban Nicolas , Wei Lin , Signoretti Sabina , Alsop David , Alimzhanov Marat , Pearsall Scott , Atkins Michael B. , Kumar Ravi , Sherman Matthew L. , Mier James Walter 
Published: February 2017

370 Background: Antagonists of VEGF/VEGFR pathway have demonstrated clinical utility in patients with metastatic renal cell carcinoma (RCC); however, the therapeutic responses tend to be short-lived. Thus, there is a need for new treatments to overcome the acquired resistance to the current standards of care. Methods: We have used a murine xenograft model of RCC to study the relationship of the bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) superfamily pathways and the VEGF pathways. Additionally, we have studied the effects of BMP9/10 inhibition on RCC tumor growth and performed MRI based tumor blood flow analyses to study antiangiogenic activity of the treatments. To explore the role of BMP9/10/ALK1 signaling in resistance to VEGFR inhibition, we used dalantercept (human ALK1-Fc fusion protein) as a ligand trap for BMP9 and 10. Results: We have found evidence of upregulation of BMP10 in A498 RCC xenograft tumors that have developed resistance to sunitinib. In tumors that had developed resistance to sunitinib, addition of ALK1-Fc to sunitinib led to prolonged tumor stabilization compared to either agent alone. Imaging of tumors revealed that addition of ALK1-Fc to sunitinib prevented the resumption in blood flow that is generally seen with continued sunitinib. Conclusions: These murine xenograft model data demonstrate that inhibition of ALK1 receptor pathway in combination with inhibition of VEGFR pathway may be a useful strategy for the treatment of RCC. A phase II randomized study of dalantercept in combination with axitinib in patients with metastatic RCC after progression on VEGFR/TKI therapy is ongoing.
Defining the molecular tumor margin regions of clear cell renal carcinoma tissues by MALDI-MS imaging of lipid and glycan species.
Authors: Drake Richard , Powers Thomas , Jones Ellen , Mehta Anand , Lance Raymond S. , Troyer Dean A. 
Published: February 2017

421 Background: The frequent tumor recurrence associated with clear cell renal cell carcinoma (ccRCC) suggests that there are underlying molecular processes present in the remaining tissue following nephrectomy that are not identified through conventional histopathological techniques. At the molecular level, transcript, metabolomic, and protein expression patterns have indicated a striking Warburg Effect profile in ccRCC tissues, with major affects on sugar and lipid metabolism. Our group has been applying MALDI mass spectrometry imaging approaches to uniquely profile lipids and glycans associated with disease progression directly in frozen tissue slides. Methods: Frozen ccRCC tissues with tumor, non-tumor adjacent, and tumor margin regions were selected by a pathologist. Lipid profiles from fresh-frozen tissue slides coated in DHB matrix were obtained on a dual source Bruker Solarix 70 FTICR mass spectrometer. Glycans were imaged in a similar fashion in ethanol-washed tissues using on-tissue protein N glycanase F digestion to release surface N-glycans. Detected lipid and glycan ion intensities were converted to a color pixel scale for creating an image of individual peaks, linked directly to the histopathology of the tissue. Results: Five groups of lipid and N-glycan species were identified following MALDI tissue imaging, those present in the immediate margin area of non-tumor tissue adjacent to tumor; only in non-tumor regions; only in tumor regions; primarily in tumor regions but extended beyond the margin; and present throughout the tissue. Specific lipid and glycan species associated with margin and tumor regions are being correlated with disease progression and pathology data. Conclusions: Analysis of the periphery of the tumor tissue and the normal parenchyma or capsule regions at this biomolecule level may better define the metastatic potential of the tumor as compared to analysis of the central tumor region. This approach has the potential to not only improve prognostic assessment and treatment choices, but also to inform on the underlying biology of ccRCC metastasis and new rational targets for therapeutic intervention.
The initial biopsy Gleason score as a predictive marker for docetaxel survival benefit in patients with prostate cancer: Data from the TAX 327 study.
Authors: van Soest Robert , de Morrée Ellen , Shen Liji , Tannock Ian , Eisenberger Mario A. , De Wit Ronald 
Published: February 2017

44 Background: The TAX 327 study was conducted in 1,006 men with metastatic castration-resistant prostate cancer (mCRPC) who were randomized to receive 3-weekly docetaxel (D3), weekly docetaxel (D1) or 3-weekly mitoxantrone (M), each with prednisone. Survival and symptom control were superior following D3 as compared to M. In this post-hoc analysis we aimed to identify factors that could characterize subgroups of patients who obtained the greatest benefit from the use of D3 as compared to M. Methods: The TAX 327 database was used to investigate if patients with poorly differentiated tumors (Gleason 7-10) at diagnosis had greater benefit from D3 as compared to M, than patients with better differentiated tumors (Gleason ≤6). Using a Cox model, we compared overall survival (OS) between the treatment groups within each subgroup of Gleason score. Results: Baseline characteristics known to predict OS including visceral metastasis and time from first hormonal treatment to the start of chemotherapy were well balanced between patient groups, except for an imbalance in the small group of patients with impaired Karnofsky performance score (PS) (see table). The TAX 327 data showed that the OS benefit of D3 versus M is greater in patients with high grade tumors (median OS 18.9 vs 14.5 months) than in patients with low grade tumors (median OS 21.6 vs 20.7 months). Conclusions: The survival benefit obtained with docetaxel as compared to mitoxantrone is greater in patients with high Gleason score tumors. Although this finding is hypothesis-generating and needs confirmation in other trials, it may provide additional guidance in treatment decisions regarding the use of chemotherapy as first line treatment for patients with mCRPC. [Table: see text]
Effect of pazopanib on myeloid-derived suppressor cells and T-cell function in patients with metastatic renal cell carcinoma.
Authors: Khurana Kiranpreet K. , Rayman Pat A. , Elson Paul , Rini Brian I. , Finke James 
Published: February 2017

455 Background: Tyrosine kinase inhibitors have been shown to have an effect on T cell function. Sunitinib decreases immunosuppression in patients with metastatic renal cell carcinoma (mRCC) as seen by a reduction in myeloid derived suppressor cells (MDSC) that inhibit T cell function. The effect of pazopanib on immune function is unknown. Methods: Peripheral blood mononuclear cells from 21 patients with mRCC treated with pazopanib were thawed for cycle 1 day 1, cycle 1 day 28, cycle 2 day 28, and cycle 4 day 28. Total MDSC and neutrophilic, monocytic, and lineage-negative MDSC subsets were measured by flow cytometry. T cell response was measured by interferon-gamma production after in vitro stimulation by anti-CD3/anti-CD28 beads. Pre-treatment cycle 1 day 1 levels were compared to cycle 4 day 28. Results: In mRCC patients, MDSCs comprise 4.7 % (median, range 1.7-32.9 %) of the peripheral blood mononuclear cells pre-treatment. Neutrophilic MDSC subset is the most prevalent at 2.0 % (median, range 0.3-30.4 %). Monocytic MDSCs comprise 1.5 % (median, range 0.4-5.3 %), and lineage-negative MDSCs comprise only 0.15 % (median, range 0.01-1.03 %). We found that pazopanib does not significantly decrease the percentage of MDSCs (total or subpopulations) over time with the exception of a modest decrease in the lineage-negative MDSC subset (p = 0.08). In terms of T cell function, pre-treatment level of CD3+ interferon-gamma was found to be 10.6 % (median, range 1.3-22.3 %). In contrast, pazopanib significantly increased CD3+ interferon-gamma level over time to 18.1 % (median, range 3.0-25.0 %), p = 0.03. Conclusions: Our study shows that pazopanib does not significantly reduce MDSC levels in patients with mRCC. However, pazopanib improves T cell function over time, as seen by a significant increase in CD3+ interferon-gamma production.
CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).
Authors: Venook Alan P. , Niedzwiecki Donna , Lenz Heinz-Josef , Innocenti Federico , Mahoney Michelle R. , O'Neil Bert H. , Shaw James Edward , Polite Blase N. , Hochster Howard S. , Atkins James Norman , Goldberg Richard M. , Mayer Robert J. , Schilsky Richard L. , Bertagnolli Monica M. , Blanke Charles David ,   Cancer and Leukemia Group B (Alliance), SWOG, and ECOG
Published: February 2017

LBA3 Background: Irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6), combined with bevacizumab (BV) or cetuximab (CET), are first-line treatments for metastatic adenocarcinoma of the colon or rectum (MCRC). The optimal antibody combination is unknown. Methods: Patients (pts) with KRAS wild-type (wt)(codons 12 and 13) MCRC and performance status 0-1 received FOLFIRI or mFOLFOX6 (MD/pt choice at enrollment) and randomized to either CET 400 mg/m2 X 1, then 250 mg/m2 qw or BV 5 mg/kg q2w. The original study included unselected MCRC pts receiving FOLFIRI or mFOLFOX6 and randomized to CET, BV, or both. After 1,420 pts accrued the study amended as follows: only pts with KRAS wt tumors (codon 12 and 13) were included and the combination CET + BV arm was deleted. Rx continued until progression, death, unacceptable toxicity, curative surgery; treatment holidays of 4 wks permitted. Subsequent Rx not mandated. Accrual goal was 1,142 pts. One° endpoint was overall survival (OS). Results: Between November 2005 and March 2012, 3,058 unselected pts enrolled, 2,334 KRAS wt pts randomized; final N =1137 (333 pre-amend eligible retrospective KRAS test, 804 post-amend), median f/u = 24 mos; Median age – 59 y; 61% male. Chemo/BV – 559; chemo/CET – 578. FOLFIRI = 26.6%, mFOLFOX6 = 73.4%. OS analysis planned at 849 events; efficacy futility boundary crossed at 10th interim analysis on 1/29/14. OS - chemo/BV v. chemo/CET = 29.04 (25.66 - 31.21) v. 29.93 (27.56 - 31.21) mos; HR = 0.92 (0.78, 1.09) (p value = 0.34). PFS (by investigator): chemo/BV v. chemo/CET: 10.84 (9.86 - 11.4) v. 10.45 (9.66 - 11.33) mos. There were 94 pts free of disease following surgery, median f/u 40 mos (range 8.0 - 86.0). Outcomes similar by gender. On-study toxicity and deaths as expected. Analyses underway: Expanded RAS, FOLFOX v. FOLFIRI, subsequent therapies, long-term survivors, correlates. Conclusions: Chemo/CET and chemo/BV equivalent in OS in pts KRAS wt (codons 12 + 13) MCRC; either is appropriate in first line. Overall OS of 29 + mos and 8% long-term survivors confirms progress in MCRC. The preference for FOLFOX limits chemotherapy comparison. Expanded RAS and other molecular and clinical analyses may identify subsets of pts who get more or less benefit from specific regimens. Clinical trial information: NCT00265850.
HPV-targeted tumor-infiltrating lymphocytes for cervical cancer.
Authors: Hinrichs Christian S. , Stevanovic Sanja , Draper Lindsey , Somerville Robert , Wunderlich John , Restifo Nicholas P. , Sherry Richard , Giao Phan Q , Kammula Udai S. , Yang James C. , Rosenberg Steven A. 
Published: February 2017

LBA3008 Background: Adoptive T-cell therapy (ACT) is a promising cancer treatment modality with potentially broad application. It is not known if ACT can mediate regression of carcinomas, the most common solid tumors in humans. We studied carcinoma of the uterine cervix, a virally induced malignancy that constitutively expresses the HPV E6 and E7 oncoproteins, as a model cancer to test if ACT can mediate regression of an epithelial malignancy. Methods: We initiated a clinical trial to treat metastatic HPV+ cancers with tumor-infiltrating lymphocytes (TIL) selected for HPV E6- and E7-reactivity (HPV-TIL). Patients from the cervical cancer cohort are reported here. HPV-TIL infusion was preceded b y non-myeloablative conditioning and followed by high-dose bolus aldesleukin. HPV-reactivity was assessed by ELISPOT, IFN-gamma production, and CD137 expression assays. Results: Nine patients were treated on the study. They received a median of 81 x 109 T cells (range 33 to 159 x 109) as a single infusion. The infused cells possessed reactivity against high-risk HPV E6 and/or E7 in 6/8 patients. The two patients with no HPV reactivity did not respond to treatment. 3/6 patients with HPV reactivity demonstrated objective tumor responses by RECIST (1 PR and 2 CR). One patient had a 39% best response. Two patients with widespread metastases had complete tumor responses that are ongoing 18 and 11 months after treatment. One patient with a complete response had a chemotherapy-refractory HPV-16+ squamous cell carcinoma and the other a chemoradiation-refractory HPV-18+ adenocarcinoma. Both patients demonstrated prolonged repopulation with HPV-reactive T cells following treatment. Increased frequencies of HPV-specific T cells were detectable after 13 months in one patient and 6 months in the other. Two patients with HPV-reactive TIL that did not respond to treatment did not display repopulation with HPV-reactive T cells. Conclusions: HPV-TIL can mediate durable, complete regression of metastatic cervical cancer. Continued investigation of HPV-TIL for cervical cancer, and possibly other HPV+ malignancies, is warranted. Cellular therapy can mediate complete regression of an epithelial malignancy. Clinical trial information: NCT01585428.
A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT).
Authors: Schlumberger Martin , Tahara Makoto , Wirth Lori J. , Robinson Bruce , Brose Marcia S. , Elisei Rossella , Dutcus Corina E. , de las Heras Begoña , Zhu Junming , Habra Mouhammed Amir , Newbold Kate , Shah Manisha H. , Hoff Ana O. , Gianoukakis Andrew G , Kiyota Naomi , Taylor Matthew Hiram , Kim Sung-Bae , Krzyzanowska Monika K , Sherman Steven I. 
Published: February 2017

LBA6008 Background: Lenvatinib (LEN) is an oral tyrosine kinase inhibitor of the VEGFR1-3, FGFR1-4, PDGFRβ, RET, and KIT signaling networks. Based on efficacy results of the phase 2 study of patients (pts) with 131I-refractory differentiated thyroid cancer (RR-DTC), this phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) was developed. Methods: This randomized, double-blind, placebo (PBO)-controlled study enrolled pts with RR-DTC with documented disease progression within 13 months (mo). Pts were stratified by age (≤65, >65 years), region and ≤1 prior VEGFR-targeted therapies and randomized 2:1 to LEN or PBO (24mg/d, 28-d cycle). Upon progression, pts receiving PBO could crossover to open-label LEN. The primary endpoint was PFS assessed by Independent Radiologic Review; secondary endpoints included overall response rate (ORR; complete response [CR] + PR), overall survival (OS) and safety. Results: 392 pts (63.0 years median age; 51.0% male) were randomized. Pts on LEN had a significantly prolonged PFS vs PBO (hazard ratio 0.21, 95% confidence interval [CI] 0.14–0.31; P <.0001); median PFS was LEN: 18.3 mo (95% CI 15.1–not evaluable), PBO: 3.6 mo (95% CI 2.2–3.7). A LEN PFS benefit was observed in all predefined subgroups; median LEN PFS for pts with prior vs no prior VEGF-therapy was 15.1 mo (n=66) and 18.7 mo (n=195), respectively. Rates (n) of CRs were LEN: 1.5% (4), PBO: 0; PRs were LEN: 63.2% (165), PBO: 1.5% (2).Median exposure duration was LEN: 13.8 mo, PBO: 3.9 mo; median time to LEN response was 2.0 mo. Median OS has not been reached; deaths per arm were LEN: 71 (27.2%), PBO: 47 (35.9%). The 5 most common LEN treatment-related adverse events (TRAEs; any grade) were hypertension (68%), diarrhea (59%), appetite decreased (50%), weight loss (46%), nausea (41%). LEN grade ≥3 TRAEs (≥5%) were hypertension (42%), proteinuria (10%), weight loss (10%), diarrhea (8%), appetite decreased (5%). The dose was reduced in 78.5% of pts and discontinued due to adverse events (AEs) in 14.2% of pts. Conclusions: LEN significantly improved PFS compared with PBO in pts with progressive RR-DTC. There were no unexpected toxicities and AEs were manageable. Clinical trial information: NCT01321554.
Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL).
Authors: Ribas Antoni , Hodi F. Stephen , Kefford Richard , Hamid Omid , Daud Adil , Wolchok Jedd D. , Hwu Wen-Jen , Gangadhar Tara C. , Patnaik Amita , Joshua Anthony M. , Hersey Peter , Weber Jeffrey S. , Dronca Roxana Stefania , Zarour Hassane M. , Gergich Kevin , Li Xiaoyun (Nicole) , Iannone Robert , Kang Soonmo Peter , Ebbinghaus Scot , Robert Caroline 
Published: February 2017

LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. Methods: A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. Results: 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and >75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. Conclusions: MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. Clinical trial information: NCT01295827. [Table: see text]