tbuckley/cabot-search huggingface dataset:
Real-life patterns of use and effectiveness of sunitinib in patients with metastatic renal cell carcinoma: The SANTORIN study.
Authors: Alain Ravaud, Stephane Culine, Angela Grelaud, Christine Chevreau, Stephanie Lamarque, Aurelie Balestra, Marie-Agnes Bernard, Nicholas Moore, Pernelle Noize, Jacques-Olivier Bay, Annie Fourrier-Réglat
Journal: Journal of Clinical Oncology (2013)

400 Background: Until 2006, treatment options for metastatic renal cell carcinoma (mRCC) were limited to cytokine therapy and surgery. Sunitinib, an oral antiangiogenic agent, received European marketing authorisation in Jan 2007 for first-line treatment in advanced and/or mRCC. The SANTORIN study was designed to describe patterns of use and estimate survival outcomes in mRCC patients treated with sunitinib in a real-life setting. Methods: SANTORIN was an observational cohort conducted in 36 French centres including patients initiating first-line treatment with sunitinib from Jan 2008-Apr 2010, followed 2 years after treatment onset. Treatment characteristics, response (evaluated by investigator based on RECIST criteria) and survival outcomes were collected from medical files. Overall and progression-free survival (OS and PFS) results were estimated using Kaplan-Meier method. Results: Characteristics of the 302 included patients were: mean age 64.3 years; male 73.2%; clear-cell histological component 83.1%; ECOG ≥2 9.9%, prior nephrectomy 85.4%. Baseline sunitinib dose was 50 mg/day for 83.4% of patients. The median duration of first-line treatment was 10.7 months (median number of cycles: 6). Dose reduction occurred in 65.2% of patients. Reasons for discontinuation of first-line treatment were progressive disease (61.1%), death (31.2%), adverse events (6.8%), and other reasons (1.0%). OS was 70.8% at 1 year (95%CI [65.3;75.5]) and 49.5% at 2 years [43.7;55.0]. Median OS was 23.6 months [19.9;27.4] (not reached in patients with clear-cell component). PFS was 38.2% at 1 year [32.7;43.7] and 16.4% at 2 years [12.5;20.9]. Median PFS was 8.4 months [7.6;9.9] (9.5 months [8.1;11.0] in patients with clear-cell component). Overall best response was 31.1% (2.3% complete, 28.8% partial), 40.1% had stable and 18.5% progressive disease. Conclusions: Despite certain differences regarding severity of cancer, these results demonstrated that effectiveness of sunitinib in mRCC is close to efficacy reported in the pivotal clinical trial (median OS: 26.4 months [95% CI 23.0 ; 32.9], median PFS: 11.0 months [11.0 ; 13.0]), especially in patients with clear-cell component.
Romanian experimental research on boron neutron capture therapy (BNCT) in liver tumors.
Authors: L. Minea, A. Rodica Maricela, I. Gruia, X. Bacinschi, I. Isacu, A. Tarlea, M. Nedelcu
Journal: Journal of Clinical Oncology (2010)

e21111 Background: BNCT is based on the nuclear reaction following irradiation of Boron-10 (B-10) with low-energy neutrons and on the selective delivery of B-10 to tumor cells, which can lead to selective irradiation. Our objective was to develop a preclinical model for the BNCT in animals with experimental hepatoma with Romanian nuclear facilities. Methods: We use nuclear reactor TRIGA-ACPR to realize the experimental irradiation. The experimental models were RS1 hepatoma-bearing rats. We induce the RS-1 hepatoma by 2-acetylaminofluorene administration in rats' food. We injected intravenously Bor-Phenil-Alanin (BPA) solution in 5% fructose. We measure the BPA level into the tumor at 1, 3 and 6 hours after injection. The rats were irradiated 3 hours after B delivery for 1 or 2 hours. We evaluate the biologic effects of the BNCT using blood and tumor samples, which were obtained 2 hours after end of irradiation. We measured cytotoxic effects of BNCT by measuring apoptosis using flow-citometry and by measuring oxidative stress using biochemical tests (MDA and SH). We also measure apoptosis after bevacizumab administration. Results: The BPA was selectively accumulated at the tumor level, with a maximum level at 3 hours after administration. At the liver level we observed an increase of apoptosis rate both at one hour and 2 hours of irradiation (70.42% and 72.98%) compare to apoptosis rate in basal condition which was 27.8%. At the tumor level the number of apoptotic cells was unsignificant for one-hour irradiation and was 34.35% for 2 hours irradiation, compare to the initial value (11.48%). The MDA (8.64 μmoli/100 mL vs 7.18 μmoli/100 mL) and SH (253 μmoli/L vs 440 μmoli/L) levels in the tumor tissue were higher after irradiation, suggesting that the cytotoxic oxidative reactions were initiated. We also observed an increased level of apoptotic cells after 2 doses of 5 mg/kgc bevacizumab before BNCT irradiation. Conclusions: The BPA level into tumor tissue was maximum after 3 hours from the administration. The apoptotic level into the tumor was higher for a 2 hours irradiation. The association between antiangiogenic agents and BNCT deserve further research. Our experiment creates the premises for clinical research on BNCT in Romania. No significant financial relationships to disclose.
Fourteen-year results of a non-randomized comparison between a second conservative treatment and mastectomy for locally recurrent breast cancer
Authors: B. Guix, J. A. Lejarcegui, J. I. Tello, G. Zanon, P. Hugo, J. M. Del-Campo, D. Rubio, L. Marques, P. Palombo
Journal: Journal of Clinical Oncology (2005)

711 Aim of the study: To report the long term results obtained in a prospective group of patients (pts) treated for local recurrence after conservative treatment of breast cancer treated by a second conservative surgery or by total mastectomy. Methods: Between 12/1990 and 04/2003, 81 patients with <3cm, low-risk local recurrence after conservative treatment for breast cancer were offered total mastectomy. 44 of them refused it and were treated by a second lumpectomy followed by HDR brachytherapy implant to the tumor bed plus a 3 cm margin. 30 Gy in 12 fractions in 5 days were given. Patients treated by mastectomy had no further radiotherapy treatment. Postmenopausal patients with negative receptors had no systemic treatment. The rest of the patients had chemo or hormonal treatment. No patient was lost for follow-up. Results: All patients completed treatment. During the 14-year, 1-year minimum follow-up, in the 2nd conservative group there were 8 pts who had regional (2 pts) or distant metastases (6 pts) as their first site of failure. 3 of them experienced a differed local recurrence and 1 died from the disease. In the total mastectomy group, there were 2 local recurrences, 1 regional recurrence and 5 distant metastases as first site of failure. One patient died from the disease. Actuarial results at 14-year for 2nd conservative and total mastectomy were respectively: local control 84.2% - 71.7%; disease free survival 65.4%–63.8%; and survival 90.7% and 88.2%. Cosmetic results were satisfactory in 89.4% treated conservatively. No patient experienced arm edema or grade 3–4 early or late complications. Between the 14 pts that were followed-up for at least 10-years, 13 of them were with their breast still in place. Conclusions: Second conservative treatment by HDR brachytherapy was a safe and effective method of treatment for small-size, low-risk, local recurrence after local excision in conservatively treated patients. The good results achieved justifies the initiation of randomized trials exploring its use as standard treatment in selected patients with low-risk recurrent breast tumors. No significant financial relationships to disclose.
Grading financial toxicity based upon its impact on health-related quality of life (HRQol).
Authors: Jonas A. De Souza, Brisa Aschebrook-Kilfoy, Raymon Grogan, Bonnie J. Yap, Christopher Daugherty, David Cella
Journal: Journal of Clinical Oncology (2016)

16 Background: Financial toxicity (FTox) is an important symptom. We hypothesized that FTox can be graded based on statistically significant and clinically meaningful changes in HRQoL. Methods: FTox was assessed by the COST (COmprehensive Score for financial Toxicity) in 2 sets of cancer patients (pts). Set 1(S1): pts with Stage IV cancers on chemotherapy. Gradations of FTox were determined by ROC analyses based on conventions for clinically meaningful small (0.2), medium (0.5) and large (0.8) effect sizes (e.s.) for the FACT-G HRQoL instrument. Demographics, income, mood disorders (POMS), and symptoms (EORTC QLQ-C30) were collected. We computed η 2 (Eta squared) to estimate the magnitude of the variability in HRQoL explained by specific symptoms. Set 2 (S2): pts and survivors with thyroid cancer within 3 years of diagnosis. In S2, HRQoL was assessed by the thyroid-specific City of Hope HRQoL measure. Results: A total of 600 cancer pts were assessed (233 in the S1 and 367 in the S2). S1: the median COST value was 23 (range 0-44). ROC curve analyses produced 4 COST grades (G): G0 ≥ 26 (99 pts, 42%); G1: ≥ 14-26 (71 pts, 31%); G2: &gt; 0-14 (58 pts, 25%); and G3: = 0 (5 pts, 2%). Pts with G0 had no impact of FTox on their HRQoL. Absolute e.s. decreases in FACT-G by grade compared to G0 were: G1, 0.59 (95% CI: 0.27 – 0.90); G2, 0.92 (CI: 0.59 – 1.26); G3, 1.77 (CI: 0.83 – 2.70). In multivariate analyses, mood explained 22% (CI 13-31%) of the variability in FACT-G; FTox, 7.6% (CI 2.2-15%); fatigue, 5.6% (CI 1.1-12%); pain, 3.6% (CI 0.3-9.6%); and loss of appetite, 3.4%(CI 0.3-9.3%). VS: applying the COST thresholds to S2, we had: G0: 154 pts (42%); G1: 126 (34%); G2: 84 (23%); and G3: 3(1%). The decreases in HRQoL measured in e.s. were: G1: 0.84 (CI: 0.68 – 1.00); G2: 1.88 (CI: 1.67 – 2.09); G3: 2.99 (CI: 2.29 – 3.68). The association between HRQoL and FTox was significant in multivariate models in both sets (p &lt; 0.001). Conclusions: We developed and validated a FTox grading system in 2 different set of patients. This grading was anchored on independent and clinically meaningful changes in HRQoL attributable to FTox. FTox is a meaningful event that can be objectively measured, and should be included in the assessment of patient-centered outcomes.
Predicting survival in metastatic RCC on sunitinib using MASS criteria: Evaluation of a large multicentered prospective phase III trial.
Authors: Andrew D. Smith, Haowei Zhang, Frederico Souza, Manohar Roda, Alan Penman
Journal: Journal of Clinical Oncology (2013)

407 Background: The objective of this study is to predict progression-free survival (PFS) and overall survival (OS) in metastatic RCC on sunitinib therapy using initial post-therapy CT imaging changes as a biomarker. Methods: An IRB-approved HIPAA-compliant analysis of CT imaging and survival data from 213 randomly selected patients on sunitinib therapy from a prospective phase III trial of metastatic RCC treated with sunitinib (N=375) versus interferon-alpha (N=375) was performed. Up to 5 target lesions were identified, and response per RECIST 1.1, Choi Criteria, Modified Choi Criteria, and MASS Criteria were made in comparison with the baseline images, while blinded to clinical data. Imaging responses on the first post-therapy CT were associated with PFS and OS by log-rank test, descriptive statistics, and cox proportional hazards models. Results: All criteria had predictive capacity for PFS and OS (log-rank p &lt; 0.0004 each). Only hazard ratios (HRs) of the best and worst response for Modified-Choi (0.60/2.60) and MASS Criteria (0.46/14.8) were both significantly different from the middle category for predicting PFS (p = 0.002/p = 0.008 and p &lt; 0.001/p &lt; 0.001). Only HRs of the best and worst response for RECIST (0.46/9.78) and MASS Criteria (0.56/7.18) were both significantly different from the middle category for predicting OS (p = 0.007/p &lt; 0.001 and p = 0.001/ p &lt;0.001). The overall accuracy for detecting a good clinic outcome (PFS &gt; 250 days) was 51% for RECIST, 62% for Choi Criteria, 67% for Modified Choi Criteria, and 76% for MASS Criteria. The overall accuracy for detecting a poor clinical outcome (PFS&lt;250 days) was 58% for RECIST, 57% for Choi Criteria, 58% for Modified Choi Criteria, and 58% for MASS Criteria. Conclusions: MASS Criteria had the best overall accuracy for predicting PFS and OS in metastatic RCC on sunitinib therapy.
68Ga-DOTATATE PET/CT in Nonneuroendocrine Tumors
Authors: Lilian Yuri Itaya Yamaga, Jairo Wagner, Marcelo Buarque de Gusmão Funari
Journal: Clinical Nuclear Medicine (2017)

PET-CT with somatostatin analogs labeled with Ga is increasingly recognized as the best imaging modality for the evaluation of well-differentiated neuroendocrine tumors (NETs). However, somatostatin receptor (SSR) is not an exclusive marker for NET. A variety of tumors other than NETs express SSR, leading to a significant risk of false-positive PET/CT results. We illustrate false-positive Ga-DOTATATE PET/CT findings due to high uptake by non-Hodgkin lymphoma, metastatic meningioma, breast cancer, thyroid adenoma, and papillary carcinoma. Although Ga-DOTATATE is a noteworthy tracer for oncological application, pathological conditions with overexpression of SSR should be recognized to prevent misinterpretation of PET/CT images.
Hypertonic saline in patients with primary ciliary dyskinesia: on the road to evidence-based treatment for a rare lung disease
Authors: Claudia E. Kuehni, Myrofora Goutaki, Helene E. Kobbernagel
Journal: European Respiratory Journal (2017)

The study of Paff et al. [1], published in this issue of the European Respiratory Journal on Rare Disease Day 2017, describes the first randomised clinical trial of inhaled hypertonic saline on quality of life and other outcomes in patients with primary ciliary dyskinesia (PCD). Although the results were negative, the study is a major step towards evidence-based treatment of PCD. Participation in clinical studies should be an essential part of routine care for patients with rare lung diseases <http://ow.ly/WfAm307Tqsg> C.E. Kuehni is a participant in the European Union's Seventh Framework Programme under EG-GA No. 35404 BESTCILIA: Better Experimental Screening and Treatment for Primary Ciliary Dyskinesia. All authors participate in the network of COST Action BEAT-PCD: Better Experimental Approaches to Treat PCD (BM 1407); C.E. Kuehni and M. Goutaki were members of the ERS PCD Taskforce for PCD Diagnostics (ERS TF-2014-04). C.E. Kuehni receives funding from the Swiss National Science Foundation (32003B_162820). The views expressed in this manuscript do not reflect official views of these collaborations. We thank Christopher Ritter (Institute of Social and Preventive Medicine, University of Bern, Switzerland) for proofreading and editorial contributions.
Very small nuclear circulating tumor cell (vsnCTC) as a putative biomarker for visceral metastasis in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Jie-Fu Chen, Hao Ho, Elisabeth Hodara, Ann Go, Alexander Ureno, Elizabeth Taryn Kaufman, Margarit Sievert, Leland Wk Chung, Zunfu Ke, Hsian-Rong Tseng, Edwin M. Posadas
Journal: Journal of Clinical Oncology (2016)

64 Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) who develop visceral metastasis (VM) have a poorer clinical outcome in comparison to those without VM. Their clinical course is aggressive and culminates in organ failure as this process is often discovered late in the disease course. There are no existing tests that identify men at risk for VM. Our team has identified an association between the presence of very small nuclear circulating tumor cells (vsnCTCs) and VM. We hypothesized that vsnCTC that can predict the development of VM and monitor the response to anticancer treatment. Methods: In our database we identified mCRPC patients who had progressed through next generation hormonal maneuvers such as abiraterone, enzalutamide, or an equivalent drug. Serial blood specimens were used for vsnCTC enumeration using published methods. The vsnCTC counts were related to the presence and development of VM as well as the response to anticancer treatment. Results: Blood specimens were identified from 28 patients who met the eligibility criteria; 16/28 patients presented with VM and 12/28 had bone-only disease at their first CTC enumeration. Five out of 12 non-VM patients developed VM during follow-up, and vsnCTCs were detected 86-196 days prior to radiographic detection of VM (true positive); 3/12 had vsnCTCs detected but no VM was found by the time of analysis (false positive). None of the vsnCTC(-) patients developed VM. vsnCTCs were detected in 21/21 VM patients compared to 3/12 non-VM patients. Reduction of vsnCTC count occurred at initiation of anticancer treatment; transition from vsnCTC(-) to vsnCTC(+) was seen prior to progression under the treatment. Conclusions: vsnCTC is associated with the presence of VM and is a potential biomarker for predicting the development of VM and monitoring the treatment response in mCRPC. Transition from vsnCTC(-) to vsnCTC(+) was associated with the development of VM and progression under the treatment.
S-1 in combination with docetaxel and oxaliplatin (DOS) every 2 weeks (DOS<sub>2w</sub>) or every 3 weeks (DOS<sub>3w</sub>) in patients with advanced gastro-esophageal adenocarcinoma (aGEA): Final results of 2 parallel phase I studies.
Authors: Camilla Qvortrup, Jon Kroll Bjerregaard, Per Pfeiffer
Journal: Journal of Clinical Oncology (2016)

153 Background: S-1 in combination with cisplatin is one of several accepted doublets, but triplet combinations with docetaxel (D) increase efficacy and substitution with oxaliplatin (O) and oral fluoropyrimidines (S-1) ease the administration. Based on our recent phase I study, we wanted to establish a recommended dose (RD) for an every 3 week regimen (DOS 3w ) but inspired by promising data from the GATE study, we also sought for an every second week regimen (DOS 2w ). Therefore we designed this dose-finding study which present the first experience with the combination of D+O+S-1 (DOS) in Caucasian patients (Clinical trial ID: 2011-003471-11). Methods: All pts had chemo-naïve aGEA. We used a standard 3+3 phase I design. DOS 2w (dose levels 1A-4A) was given with escalating doses of D (30 to 50 mg/m 2 day 1) and S-1 (2x30 to 2x35 mg/m 2 /day - days 1-7) with a fixed dose of O (70 mg/m 2 day 1) every 2 weeks for a maximum of 9 cycles. DOS 3w (dose levels 1B-3B) was given with escalating doses of D (40 to 60 mg/m 2 day 1) and fixed doses of O (100 mg/m 2 day 1) and S-1 (2x25 mg/m 2 /day - days 1-14 every 3 weeks) for a maximum of 6 cycles. After the planned number of DOS, S-1 maintenance therapy (2x30 mg/m 2 days 1-14 every 3 weeks) was administered until PD or toxicity. Toxicity was evaluated according to NCIC-CTC 4.0. Dose-limiting toxicity (DLT) was evaluated after the first course of DOS and defined as non-hematological toxicity grade ≥ 3 or febrile neutropenia. RD was defined as the highest level at which less than 2/6 of pts experienced a DLT. Once RD was established, this level was expanded to at least 6 pts. Results: From Oct. 2013 to Mar. 2015, 18 and 16 patients received DOS 2w and DOS 3w , respectively. Median age was 63 years (49-78). DLTs in both cohorts were febrile neutropenia. Response rates were 56% and 57% and OS were 13.8 and 11.6 months, respectively. Conclusions: We recommend DOS 2w at dose level 3A (D 40 mg/m 2 day 1; O 70 mg/m 2 day 1 and S-1 2x35 mg/m 2 /day orally days 1-7 every 2 weeks) and DOS 3w at dose level 2B (D 50 mg/m 2 day 1; O 100 mg/m 2 day 1 and S-1 2x25 mg/m 2 /day orally days 1-14 every 3 weeks). Both regimens are well-tolerated in an out-patient setting. Clinical trial information: 2011-003471-11.
Salvage chemotherapy with paclitaxel, gemcitabine, and nedaplatin (TGN) for cisplatin refractory heavily treated germ cell tumors.
Authors: T. Nakamura, Y. Kimura, K. Mikami, F. Hongo, T. Shiraishi, N. Takaha, T. Miki
Journal: Journal of Clinical Oncology (2011)

e15089 Background: Only 20-30% of patients with cisplatin (CDDP) refractory germ cell tumor (GCT) will remain continuously disease free with salvage chemotherapy. The present study investigated the chemotherapy with paclitaxel (PTX) in combination with gemcitabine (GEM) and nedaplatin (CDGP), which is a derivative of CDDP, as salvage chemotherapy for CDDP refractory GCT. Methods: Between Jan 2003 and Dec 2010, 16 patients with CDDP refractory GCT were enrolled. All patients were male, with mean age 33 (range: 19-51). Median number of previous chemotherapy was 12 (range: 9-26) cycles. The combination chemotherapy consisted of PTX: 210 mg/m2 on day 1, CDGP 100 mg/m2 on day 2 and GEM: 1000mg/m2 on day 1 and 8 every three weeks. Results: A median of 4 cycles (range: 2-10) of TGN therapy was administered to 16 patients. Grade 3/4 toxicities were reported as follows: neutropenia: 100%, thrombocytopenia: 92%, anemia: 71%. No treatment related death was observed. Response rate was 56.3% (CR: 0 %, PRm-: 25%, PRm+: 31.3%, NC: 0%, PD: 43.7%). Unfortunately, no patients achieved a no evidence of disease status with a median duration of follow-up of 15 months (2-80 months). Six patients (37.5%) remain alive with disease. However, 10 patients (62.5%) died of the disease. Conclusions: This study demonstrates that combination chemotherapy with PTX, GEM and CDGP showed moderate anticancer activity for patients with CDDP refractory GCT without severe adverse events. These findings suggest that TGN therapy might be one of the options of salvage chemotherapy for CDDP refractory GCT and may be assessed as second or third line therapy.
Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC).
Authors: Andrea Borghese Apolo, Young H. Lee, Fabiola Cecchi, Piyush K. Agarwal, Howard L. Parnes, Kattie Khadar, Amelia Summerell, James L. Gulley, Kathryn Compton, William Douglas Figg, William L. Dahut, Donald P. Bottaro
Journal: Journal of Clinical Oncology (2013)

4543 Background: Mounting evidence supports Met as a therapeutic target in urothelial cancer (UC). Activated Met can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in UC pathogenesis. Cabozantinib inhibits VEGFR2 and Met pathways. In this study, we assessed shed Met (sMet) levels in the urine and serum of UC patients (pts) and cabozantinib’s effects on HGF-driven UC cell growth and invasion. Methods: sMet levels in serum and urine samples from 31 pts with UC (23 metastatic, 8 muscle-invasive) were correlated with stage, presence of visceral metastases and urinary source. The effects of cabozantinib on 4 human UC-derived cell lines were studied in vitro. Intact RT4, TCC-SUP, T24M2 and T24M3 cells at 80% confluence were serum deprived 16 h, then left untreated or treated with hepatocyte growth factor (HGF) and/or cabozantinib prior to analysis of Met, phospho- (p)Met, pAkt, Akt, pMAPK and MAPK by immunoassay or immunoblotting. Cabozantinib effects on basal and HGF-induced UC cell invasion, proliferation and soft agar growth were measured. Results: Median serum Met levels were modestly higher in pts with metastatic versus muscle-invasive disease. Urinary Met levels were clearly higher in pts with visceral metastasis (P=0.0111) and in urine from ileal conduits and neobladders compared to normally voided urine, regardless of stage (P=0.0489). Met content in UC cell lines was low in RT4 and higher in T24M2, T24M3 and TCC-SUP. Basal pMet content was universally low, increased significantly by HGF and this was reversed by cabozantinib. HGF-driven increases in pAkt/Akt and pMAPK/MAPK in all 4 cell lines were reversed by cabozantinib, as were HGF-enhanced UC cell invasion, proliferation and anchorage independent growth. Conclusions: Median urinary sMet is significantly higher in pts with visceral metastasis and in specimens from ileal conduits and neobladders relative to normally voided urine. UC cell Met content in culture increased with disease grade; HGF stimulated activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; cabozantinib effectively reversed these HGF-driven effects. These data support evaluation of cabozantinib in pts with metastatic UC.