tbuckley/cabot-search huggingface dataset:
Final results of first European phase II trial of intravenous cetuximab (Cet) and hepatic artery infusion of irinotecan, 5-fluorouracil, and oxaliplatin in patients (pts) with unresectable liver metastases from <i>wt</i> KRAS colorectal cancer (LM-CRC) after systemic treatment failure (OPTILIV, NCT00852228).
Authors: Francis Levi, Valerie Boige, Mohamed Hebbar, Denis Smith, Céline Lepère, C. Focan, Rosine Guimbaud, Carlos Carvalho, Salvatore Tumolo, Pasquale Innominato, Yves Ajavon, Stéphanie Truant, Denis Castaing, Thierry de Baere, Francis Kunstlinger, Abdoulaye Karaboué, Mohamed Bouchahda, Philippe Rougier, Rene Adam, Michel Ducreux
Journal: Journal of Clinical Oncology (2013)

466 Background: Multiple, large and bilateral LM-CRC can be downsized with chemotherapy (chemo) and resected with curative intent in ~15% pts (Adam et al. 2004). The complete resection rate (R0+R1) may be increased with Cet addition, triplet chemotherapy, chronomodulated delivery (Chrono) and hepatic artery infusion (HAI) (Bouchahda et al. 2009; Kemeny et al. 2009; Garufi et al. 2010; Goere et al. 2010). Purpose: To increase the R0+R1 rate from 15% to 30% in pts with unresectable KRAS wt LM-CRC despite failure of 1-3 prior chemo protocols. Methods: 64 pts received iv Cet (500 mg/m²) and Chrono (18 pts) or conventional (Conv, 46 pts) HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 weeks. Liver surgery was performed according to q6wks multidisciplinary meetings. Results: There were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2). Liver lesions were bilateral in 50 pts (78.1%), with a median of 10 metastases (1-50) and largest diameter of 52 mm (15-172). Five courses (1-13) were given to 61 pts (3 never treated), as 3-4 th line for 35 pts (54.6%). Grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain (26%), fatigue (18%) and diarrhea (16%). Tumor response (RECIST) was achieved in 28 pts (2 CR, 26 PR), with an objective response rate of 46% [95%CL, 33-58]. Disease control rate was 95% [90-100]. The main endpoint was met, with R0-R1 resections in 19/61 pts, for an overall complete macroscopic resection rate of 28% [17-39]. R0+R1 resections were performed in 33.3% Chrono pts and 25.6% Conv pts, with worse initial prognosis for the Chrono pts (&gt;6 segments involved, 50% vs 9%; &gt; 9 metastases, 75% vs 27%). Median progression-free and overall survival were 8.7 months [6.9-10.5], and 25.7 months [14.2-37.2] respectively. Conclusions: The combination of intravenous Cet and triplet hepatic artery infusion safely doubled the expected rate of complete resections of LM-CRC, despite prior failure of systemic chemo. This most effective treatment option now deserves upfront testing. Clinical trial information: NCT00852228.
Chemoradiation followed by adjuvant hysterectomy for the treatment of stage IB-2 cervical cancer: 10-year experience.
Authors: G. E. Bigsby, R. W. Holloway, S. Ahmad, M. D. Sombeck, G. Ebra, N. J. Finkler
Journal: Journal of Clinical Oncology (2010)

5117 Background: To determine outcomes of patients (pts) with stage IB-2 cervical carcinoma (CC) treated with concurrent chemoradiation (CRT) followed by extrafascial total abdominal hysterectomy (TAH) with common iliac and para-aortic lymphadenectomy (PAL). Methods: We reviewed 69 pts with stage IB-2 CC who were treated with CRT followed by TAH/PAL from 01/99 to 01/09. All pre-treatment CAT scans were negative for para-aortic (PA) lymphadenopathy. Brachytherapy was limited to 1,500-1,800 cGy. Results: Mean age was 46.7 ± 10.7 yr, BMI 29.5 ± 6 kg/m2, tumor size 5.4 ± 1.2 cm, operative time 62 ± 15 min, EBL 187 ± 103 mL, LOS 3.1 ± 1.0 days, and node counts 6.3 ± 2.9. Tumor histologies were: squamous=55, adenocarcinoma = 11, adenosquamous = 3. There were 6 (9%) radiation external beam and 23 (33%) brachytherapy protocol violations. All pts had a complete response to CRT prior to TAH. Complete pathologic responses were confirmed in 34 (49%) pts. At surgery, 11 (16%) pts had (+) PA nodes and 5/11 (45%) had persistent disease following additional CRT. Ten (91%) of (+) PA node pts died. 7/58 (12%) PA node (-) pts developed recurrent disease (mean PFI 31.6 months, range 6-110). In total, 16 (23%) pts relapsed with 2 (3%) pelvic sidewall and 14 (20%) distant sites. Of the 14 distal relapses, 11 had (+) PA nodes at surgery. Eleven (16%) pts had treatment-related complications and 5 (7%) required reoperation. Mean F/U time was 62 months (range 13-125). There are 53 (77%) alive including 2 pts with disease. Three pts (4%) died of other causes and were free of CC. The 5-year disease-specific OS was 79% and PFS was 70%. Conclusions: Adjuvant hysterectomy following CRT for stage IB-2 CC resulted in excellent pelvic control, no pelvic exenterations, and acceptable morbidity. Persistent central disease found at TAH had no effect on PFS or OS. Conversely, PA metastasis was rarely cured with additional therapy. No significant financial relationships to disclose.
Interaction of combination taxane/NSAID treatment and hyperthermia <i>in vitro</i>
Authors: A. P. Barnes, B. E. Miller, G. L. Kucera
Journal: Journal of Clinical Oncology (2005)

5158 Background: Inhibition of the COX-2 enzyme has become a new and controversial target for combination chemotherapy in recent years. Equally as disputed is the effectiveness of hyperthermic chemotherapy as a treatment for ovarian cancer. The purpose of this study is two-fold 1) determine if the addition of NSAID to taxane chemotherapy enhances cytotoxicity 2) determine if the addition of hyperthermia to this combination treatment has an added effect. Methods: The human ovarian carcinoma cell line, 2008, were seeded in 96-well plates and allowed to attach. Following temperature equilibration in a CO2 incubator for 30 minutes at 37, 41 or 43°C, cells were treated with docetaxel (DTX) or paclitaxel (PTX) (1.25–160 nM) in the presence and absence of NS-398 (NS) or sulindac sulfide (SS) (1–40 μM). The plates were returned to their respective temperature for 1 hour. Cytotoxicity was measured by a CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay. Cellular proliferation was measured at 72 hours by a plate reader at 490 nm. Cell death was reported as the percent of control cells at each temperature. Synergy was established by determining the Combination Index using CalcuSyn software. Statistical significance was analyzed using a Student’s t-test. Results: The combination taxane/NSAID treatment caused a dose-dependent enhancement of taxane induced cytotoxicity and was synergistic over a range of taxane doses. DTX/NS, DTX/SS, and PTX/NS resulted in dose-dependent cytotoxicity enhancement and decreased the IC50 value by approximately 2.0, 3.3 and 1.5-fold, respectively; however, PTX/SS did not result in any enhanced cytotoxicity. There was no observed difference in IC50 values when cells were treated with taxane alone or in combination with NSAIDs under hyperthermic conditions. Conclusions: The addition of a NSAID enhances taxane induced cytotoxicity; however, DTX is more sensitive to NSAID enhanced cytotoxicity than PTX. Hyperthermia did not enhance taxane’s cytotoxicity either alone or in combination with NSAIDs in ovarian cancer cells. If these results are confirmed, the combination of hyperthermia and taxane therapy may not be indicated; however, the combination with NSAIDs may offer some treatment advantages. No significant financial relationships to disclose.
Advanced tissue-based image analysis techniques integrated with biomarker-morphometric multiplex immunofluorescence to provide prostate cancer risk stratification models post-surgery.
Authors: Michael Donovan, Faisal M Khan, Richard Scott, Jack Zeineh, Giovanni Koll, Nataliya Gladoun, Elizabeth Charytonowicz, Gerardo Fernandez
Journal: Journal of Clinical Oncology (2016)

47 Background: We have previously validated the importance of utilizing the intact tissue section and quantitative biomarker strategies for developing prognostic prostate cancer outcome models. We sought to further expand upon these constructs by applying next-gen advanced image analysis tools using multiplex immunofluorescence (IF) integrated with clinical variables on an independent cohort. Methods: Utilizing a 686 patient radical prostatectomy tissue microarray population with median 8 years follow-up from Roswell Park Cancer Institute, NY, we selected an initial subset of 98 patients to construct a training model; applying multiplex immunofluorescence with CK-18 (epithelial cells), CK 5/6 (basal cells), androgen receptor (AR), Ki67, AMACR and DAPI (nuclear marker). Images were captured with an Nikon i90 microscope equipped with a CRI multiplex camera, a Bayesian probabilistic approach was used to derive features that reflect tumor grade and co-locate - quantify IF biomarker expression within various glandular sub-types. Multivariate models were constructed to predict disease progression (i.e., clinical failure (CF) = PSA rise post-adjuvant therapy, or metastasis, or death) with c-index (CI) to estimate performance. Results: A 98 patient with the following clinical features: mean PSA 6.6 ng/mL, prostatectomy Gleason score, PGS 6, 34%; &gt;/=PGS 7, 55%; LN+ 2%, +SM 19%; + ECE 49% ; + SVI 3%. CFevent rate 13%. Two models (i.e., +/- LN status) employing 47 features with 7 clinical variables (e.g., PSA and Gleason) had comparable outcomes, CI 0.84. The number one feature selected in both models was an imaging feature reflecting prostate cancer gland architecture and differentiation. Combined AR levels with gland phenotype and CK-18 composition characterized a relevant phenotype dependent upon feature inclusion in the model generated. Conclusions: We have established the importance of utilizing the intact tissue section when developing accurate prognostic prostate cancer models. Additional studies with expanded training and test patient cohorts are underway to confirm and validate these initial findings.
The significance of protocol biopsy after intravesical BCG treatment in patients with non-muscle–invasive bladder cancer.
Authors: Satoru Maruyama, Nobuo Shinohara, Norihiro Murahashi, Hidetaka Suzuki, Ryuji Matsumoto, Tomoshige Akino, Naoto Miyajima, Kunihiko Tsuchiya, Takashige Abe, Katsuya Nonomura
Journal: Journal of Clinical Oncology (2014)

356 Background: Currently, there are few well-validated data of the optimal schedule of follow-up after BCG intravesical instillation. The objective of the study were to elucidate the ability of conventional exams (cystoscopy, urine cytology) to diagnose presence of carcinoma and the significance of protocol biopsy after BCG intravesical treatment in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Methods: The study included patients treated with BCG intravesical treatment. From January 2002 to October 2012, we retrospectively reviewed a total of 72 patients (61 men and 11 women). The median age was 72 years (range 47-84). The pathological stages were Tis in 4 patients (6%), Ta in 29 (40%) and T1 in 39 (54%) (T1 with CIS in 30 [42%]). Tumors were multifocal in 56 (78%) and second TUR had been performed in 53 (74%) patients. We investigated the prognosis and accuracy of tumor existence by conventional exams referring with the protocol biopsy. A protocol biopsy was performed within 5 to 9 months after the final TUR. CTCAE v4.0 was used to grade adverse events. Results: Of 72 patients, we performed protocol biopsy in 62 patients and 9 (15%) had cancer. The conventional methods had a sensitivity of 78%, specificity of 81%, positive predictive value of 41% and negative predictive value of 96% in diagnosing cancer. Although three (5%) had grade2 adverse events, there were no grade 3 or greater adverse events. Of 53 patients with no cancer in protocol biopsy, 8 (8%) patients experienced a recurrence but 51patients (96%) were alive with no evidence of disease. Of 9 patients pointed out cancer in protocol biopsy, 7patients (78%) had no evidence of disease recurrence at last follow-up. The 5-year recurrence-free survival rate and overall survival rate were 77% and 95%, respectively. Conclusions: To the best of our knowledge, this is the first report of the ability of conventional exams for follow-up after BCG treatment. Our findings revealed that conventional exams were limited for meticulous follow-up, so that the protocol biopsy will be recommended to obtain the better survival in high-risk NMIBC patients.
A Correction to the Research Article Titled: “Lineage Structure of the Human Antibody Repertoire in Response to Influenza Vaccination” by N. Jiang, J. He, J. A. Weinstein, L. Penland, S. Sasaki, X.-S. He, C. L. Dekker, N.-Y. Zheng, M. Huang, M. Sullivan, P. C. Wilson, H. B. Greenberg, M. M. Davis, D. S. Fisher, S. R. Quake
Journal: Science Translational Medicine (2013)
Lessons from the other side of clinical trial accrual: Screen failures at the Josephine Ford Cancer Center/Henry Ford Health System in 2010.
Authors: D. Wang, T. Pearce, V. Cobani, M. Zekaj, N. Adams, A. Williamson, C. Harkness
Journal: Journal of Clinical Oncology (2011)

e16624 Background: Clinical trials are a critical approach of pharmaceutical development and a bridge that connects between scientific advances and clinical applications. It also provides us with more safe and effective cancer therapy. A definition of screen failure is that a potential subject never gets enrolled into the trial through a screening process for various reasons. An assumed screen failure rate (SFR) has been at a national level of 80%. Methods: The screen logs from 794 patients who were considered for clinical trials at the Josephine Ford Cancer Center (JFCC) in year 2010 were reviewed. A 2-stage screening process was begun by a case manager (registered nurse) from the Clinical Trials Office (CTO). A screen log was manually created for each patient and eligibilities specified by a particular protocol were checked from patient’s electronic medical records (EMRs). Once patients passed first stage, a visit was scheduled as a screening visit where the patient was interviewed and examined by an investigator and the case manager with an informed consent offered to any eligible patients (second stage). Results: Of 794 patients screened for clinical trials in year 2010, 192 patients were enrolled to 63 active trials at JFCC. We had 602 of 794 (75.8%) patients failed the screening process. Among 220 patients screened for phase I trials, the screen failure rate (SFR) was slightly higher (78.2%). The major causes of screen failures were: not consented but choosing off-protocol therapies (48.4%), poor performance/inadequate organ functions or laboratory parameters/estimated < 12-week life expectancy (40.8%), lack of a specific biomarker or lack of archived tumor tissues (8.4%), closed cohort enrollment (2.4%). Conclusions: Screen failure rate is an important benchmark of clinical trial operations. A high screen failure rate will not only increase the cost of a clinical trial at the expenses of either the sponsor or the participating site, but also may prolong accrual period. In order to decrease the screen failures, several factors have been identified and may be modified in our practice, which will be discussed in more details.
Factors associated with recurrence in lymph node-negative gastric adenocarcinoma: Results from the U.S. Gastric Cancer Collaborative.
Authors: Linda X. Jin, Malcolm Hart Squires, George A. Poultsides, Konstantinos Ioannis Votanopoulos, Sharon M. Weber, Mark Bloomston, Timothy M. Pawlik, William G. Hawkins, David Linehan, Steven M. Strasberg, Alexandra W. Archer, Kenneth Cardona, Clifford Suhyun Cho, David A. Kooby, Edward Allen Levine, Emily Winslow, Neil Saunders, Gaya Spolverato, Shishir Kumar Maithel, Ryan C. Fields
Journal: Journal of Clinical Oncology (2014)

80 Background: Lymph node (LN) status is a predictor of recurrence after gastrectomy for gastric adenocarcinoma. Clinicopathologic predictors of recurrence in patients with node-negative disease are less well established. Methods: Patients who underwent surgery with curative intent for gastric adenocarcinoma from between 2000-2012 from participating institutions of the U.S. Gastric Cancer Collaborative were analyzed. Patients who died within 30 days of surgery were excluded. Univariate (UV) and multivariate (MV) analysis of clinicopathologic factors was associated with recurrence was performed. Results: Nine-hundred sixty-five patients from seven institutions were included in the analysis. Three-hundred forty-five (36%) had LN- disease, of whom 63 (18%) had disease recurrence after a median follow-up of 24 months. The most common patterns of recurrence were: peritoneal alone (44%), liver (22%), or combined liver/peritoneal (9%). This distribution did not differ significantly from LN+ disease. UV analysis identified tumor size, linitis plastica, diffuse histology, poor differentiation, signet ring histology, T stage ≥3, perineural invasion, and lymphvascular invasion as risk factors for recurrence (Table). On MV analysis, T stage≥3 (OR 3.6, 95% CI=1.7-7.5) and poorly differentiated histology (OR 2.4, 95% CI=1.2-4.9) were independent predictors of recurrence. Conclusions: Despite the presence of negative lymph nodes, patients with T stage ≥3 and poorly differentiated histology are at high risk of recurrence after gastrectomy for adenocarcinoma of the stomach. These factors, along with other patient and treatment-related variables, may be used to select patients who may benefit from more aggressive adjuvant therapy and to guide subsequent monitoring for disease recurrence. [Table: see text]
Marked improvement in bone mineral density (BMD) for patients (pts) with monoclonal gammopathy of undetermined significance (MGUS) using zoledronic acid (ZOL)
Authors: J. R. Berenson, O. Yellin, R. V. Boccia, M. S. Flam, S. Wong, O. Batuman, M. M. Moezi, D. V. Woytowitz, H. L. Duvivier, Y. Nassir, R. Swift
Journal: Journal of Clinical Oncology (2008)

8550 Background: MGUS patients have increased rates of bone resorption with a higher prevalence of osteopenia/osteoporosis than in the normal population. These pts also have an increased risk of fractures. ZOL has been shown to increase bone density among men with prostate cancer without metastatic bone disease when administered every 3 mos at 4 mg. The rationale for the use of ZOL for pts with osteopenia/osteoporosis in the setting of MGUS is based on these studies as well as the higher prevalence of bone loss and fracture risk in these patients. Methods: This open-label study evaluated the efficacy and safety of ZOL dosed at 4 mg every 6 mos for MGUS pts with significant bone loss. Eligible pts showed osteopenia/osteoporosis (T-score worse than -1) as verified by a DEXA scan and met criteria for MGUS. Pts with prior use of oral bisphosphonates (BIS) or fluorides for more than 3 mos within the last 2 yrs or prior use of intravenous (IV) BIS within the last 2 yrs were excluded. ZOL 4 mg was administered IV over 15 minutes at 0, 6, and 12 mos. To assess the efficacy of ZOL therapy, DEXA scans and skeletal surveys were conducted at screening and 1 mo after the final ZOL infusion (13 mos). Results: Fifty-four pts were enrolled with an average age of 68 (range, 50–91). The baseline L-spine T-scores ranged from -3.97 to -1.10 (mean = -2.21). At the final timepoint (13 mo), T-scores improved by an absolute value of +0.58 (range, -0.40 to +3.90 P = 0.0021) corresponding to a mean increase of 26% (range, -19% to 134%). Baseline T-scores in the hip ranged from -2.95 to -1.00 (mean = -1.89). T-scores rose by +0.26 (range, -0.60 to +2.00 P = 0.0020) which corresponds to +14% (range, -55% to +163%). No patient developed a new fracture. One patient developed chronic lymphocytic leukemia but no other patient showed progression to myeloma or another related B-cell disorder. No patient developed osteonecrosis of the jaw or a significant adverse renal event. Conclusions: This trial suggests that ZOL administered at 4 mg every 6 mos significantly improves bone mineral density in MGUS pts with bone loss (osteopenia/osteoporosis); and, thus, suggests that this is a safe and effective treatment to prevent the development of new fractures in this high risk population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis
Pragmatic approach to quality metrics development in cancer.
Authors: Donna Chung, Aniruddha Dwarakanath, Charlotte Williams, Kathy Pritchard-Jones, James Mountford, Astrid Mayer
Journal: Journal of Clinical Oncology (2013)

60 Background: London Cancer aims to use transparency of service and quality measures to drive improvement in cancer care in North and East London and surrounding areas, serving our population of 3.5m people. Whilst the on-going implementation of the National Outcome and Service Dataset for UK is expected to take 18 months we have chosen to develop quality measures with the teams accountable to deliver the service by using available data from a variety of existent sources and illustrate this in value scorecards tracking the patient pathway. Methods: Building on an engagement exercise with patients, clinicians and charities in 2011 to identify which outcomes mattered most to patients, a small set of key pathways metrics was identified for each site specific cancer pathway board to monitor their progress in implementing integrated cancer care. Metrics were selected only if (a) clinically useful, in line with the current work plan and improvement effort; (b) accessible on a recurrent basis and requiring minimal manual effort; (c) facilitate the understanding of the patient pathway; (d) align with London Cancer objectives in improving survival, patient experience, and access to innovation and clinical trials. Pathway boards were invited to contribute with the intention to provide a pathway metrics value scorecards on a quarterly basis. Results: The first set pathway metrics scorecards, with 31 metrics, were published by June 2013. Key items include adherence to established best practice (16), data completeness (6), survival (3), pathway efficiency (3), and patient experience (3). Conclusions: Pathway metrics are reported at a system level, reflecting the care for our local population, against measures that are important to them and will allow visibility of success. Whilst current pathway metric development is limited by the availability of meaningful data we aim to build on the existing metrics in an iterative fashion. For this we are working with stakeholders to improve data quality.