tbuckley/cabot-search huggingface dataset:
Safety profile of 152 consecutive image-guided lung and liver tumor biopsies for molecular profiling (IMPACT-SG).
Authors: Ning Mao Kam, Daniel Shao-Weng Tan, Mar Khin Pwint, Bien Soo Tan, Leong Sum, Chow Wei Too, Karthikeyan Damodharan, Chau Hsien Matthew Ng, Wai Meng David Tai, Angela Takano, Wan-Teck Lim, Xin Ying Yew, Win Aung Zaw, Gek San Tan, Alvin ST Lim, Eng-Huat Tan, Kiat Hon Lim, Apoorva Gogna
Journal: Journal of Clinical Oncology (2015)

e22134 Background: Research biopsies play a critical role in facilitating biomarker driven clinical trials. The increasing requirement to perform comprehensive molecular analyses necessitates procurement of adequate amount of tissue. This study aims to examine the safety of multiple needle passes performed during research biopsies. Methods: We reviewed consecutive patients (pt) undergoing biopsies for molecular profiling or as part of a clinical trial (IMPACT-SG). Depending on location of pulmonary lesions, either a transbronchial (n = 29, 21G) or percutaneous (perc) biopsy (n = 86) using coaxial needle technique (17G outer; 18G cutting; 22G chiba) was performed. We collated variables such as lesion size, location, depth and number of needle passes, as well as procedure-related complications including pneumothorax and bleeding. Logistics regression analysis was employed to determine factors associated with complications. Results: Between Nov 11 and Nov 14, 152 pt underwent core and/or fine needle biopsy of the lung (n = 115) or liver (n = 37). The median number of needle passes during perc lung and liver biopsies were 6 (range 2-14) and 5 (range 3-10) respectively. There were no procedure-related deaths. 22 pt (25.6%) had pneumothorax after perc image-guided lung biopsy, of which 4 (4.6%) required chest tube placement. Post-biopsy, 10 pt (11.6%) developed pulmonary haemorrhage and 6 (7%) had hemoptysis. Using multivariate logistic regression analysis, greater lesion depth was found to be an independent risk factor for pulmonary haemorrhage (p = 0.016). Post perc image-guided liver biopsy, bleeding occurred in 10 pt (27%). None required further intervention. Performing fine needle aspiration during liver biopsies was significantly associated with post procedure bleeding (p = 0.026). Other variables did not show a significant effect on hemoptysis, bleeding, or pneumothorax. Using simple linear regression analysis, performing more needle passes during biopsies did not correlate with increased complication rates. Conclusions: Our findings suggest that performing multiple needle passes during perc image-guided lung and liver biopsies is safe with acceptable morbidity.
Cost-effectiveness analysis of eribulin (E) versus treatment of physician’s choice (TPC) in patients (pts) with pretreated metastatic breast cancer (MBC).
Authors: Alberto J. Montero, Kiran Kumar Venkata Raja Avancha, Stefan Gluck, Gilberto de Lima Lopes
Journal: Journal of Clinical Oncology (2012)

e16525 Background: Eribulin was FDA approved in 2010 for pts previously receiving &gt;2 prior chemotherapeutic regimens for MBC. This approval was based on the phase 3 trial (EMBRACE) which demonstrated that E significantly improved median overall survival (OS) relative to different TPC by 2.5 months [HR 0.81; p=0.041]. Methods: The aim of this study was to assess the cost-effectiveness of E versus the 3 most commonly selected TPC in EMBRACE. We also evaluated the cost effectiveness of E compared to other approved drugs for MBC. We created a decision-analytical model using clinical data from the EMBRACE trial. Health utilities were derived from the published literature. Costs for drug acquisition, physician visits, and laboratory tests were obtained from Medicare Services Drug Payment Table and Physician Fee Schedule and are represented in 2011 USD. Life-years saved (LY), Quality-adjusted life years (QALY), and Incremental Cost Effectiveness Ratio (ICER) were calculated using the EMBRACE median OS data. TPC cost was calculated with 3 most commonly used drugs: vinorelbine (V), gemcitabine (G), and capecitabine (X), comprising 60% of pts in the TPC arm. Other drugs analyzed included liposomal doxorubicin (D), nab-paclitaxel (A), and ixabepilone (I). Greater GCSF use with E vs. TPF was also accounted for in our model. Results: E added 0.208 LY and 0.119 QALY with an incremental cost over TPC of $24,035; and therefore a cost of $115,369/LY and an ICER of $201,790/QALY. The main drivers of the model were drug acquisition cost, OS, and health utility values. The results of the model were robust in sensitivity analyses. Because of the very low cost of V and G, we looked at the cost-effectiveness of E relative to several other drugs commonly used in this setting, but used in fewer pts in the pivotal trial. Relative to ixabepilone, liposomal doxorubicin, nab-paclitaxel, and capecitabine the ICER for E was $85,130, $98,538, $119,029, and $154,591, respectively. Conclusions: Using commonly accepted willingness-to-pay thresholds, E appears to be cost effective in the treatment of MBC relative to D, A, X, and I; with marginal cost effectiveness for less expensive drugs such as V and G.
Treatment outcome and recovery from peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer (JFMC41-1001-C2: JOIN Trial).
Authors: Dai Manaka, Masahito Kotaka, Katsunori Shinozaki, Tetsuo Touyama, Takanori Matsui, Kiyoshi Ishigure, Junichi Hasegawa, Keiji Inoue, Yoshinori Munemoto, Akinori Takagane, Hiroshi Ishikawa, Hideyuki Ishida, Yutaka Ogata, Koji Oba, Koichi Goto, Junichi Sakamoto, Shigetoyo Saji, Atsushi Ohtsu, Toshiaki Watanabe, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2017)

703 Background: The JOIN Trial investigated safety and efficacy of modified FOLFOX6 (mFOLFOX6) in Japanese patients (pts) with stage II/III colon cancer. In the initial safety report, incidence of ≥ grade 3 (G3) peripheral sensory neuropathy (PSN) was 5.8% during treatment. Methods: Twelve cycles of mFOLFOX6 were given to pts with the following criteria: stage II/III curatively resected colon cancer; ECOG Performance Status (PS) of 0–1; age, ≥ 20 years; and adequate organ function. We report the treatment outcome results, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery from PSN during 3-year follow-up. Results: From November 2010 to March 2012, 882 pts were enrolled. In the efficacy group (N = 864; median follow-up, 3 years), pt characteristics were as follows: median age, 64 years; male, 53.8%; PS 0, 93.8%; stage II/IIIA/IIIB/IIIC (TNM), 18.5/7.3/52.5/21.6%; and lymph nodes examined, &lt; 12/ &gt; 12/unknown: 17.2/82.5/0.2%, respectively. Three-year DFS, RFS, and OS were 76.1, 77.3, and 92.7%, respectively. Favorable 3-year DFS, RFS, and OS were 92.1, 92.8, and 97.4% in stage II patients; 76.4, 77.9, and 93.8% in stage IIIA/B; and 61.6, 62.7, and 85.9% in stage IIIC, respectively. The main recurrent sites were liver (7.6%), lung (7.3%), and lymph nodes (5.2%). In multivariate Cox regression analysis, tumor histology, venous invasion, and lymph node metastatic ratio were statistically significant prognostic factors for DFS, RFS, and OS. Cumulative incidence of PSN during treatment was 47.8% in G1, 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 and G2 residual PSN after 3 years was observed in 21.0% of pts (18.7%, G1; 2.3%, G2). Conclusions: Efficacy and safety of adjuvant mFOLFOX6 in pts with stage II/III colon cancer can be confirmed. Most pts successfully recovered from G3 PSN related to oxaliplatin, but G1 and G2 PSN was irreversible in one-fifth of pts at the 3-year follow-up. Clinical trial information: UMIN000004443.
Effect of the load versus capacity unbalance on the sensitivity of malignant pleural mesothelioma cells to proteasome inhibitors.
Authors: Genny Jocolle', Gianmauro Numico, Fulvia Cerutti, Oliva Laura, Simone Cenci, Giovanni Donati, Paolo Cascio
Journal: Journal of Clinical Oncology (2013)

e18522 Background: Malignant Pleural Mesothelioma (MPM) is an aggressive cancer that originates from the mesothelium of the pleural cavities. Due to its resistance to all chemotherapies available, news therapies against MPM are urgently needed. Bortezomib is a potent Proteasome Inhibitors (PI) that induces apoptosis in different cancers and it was recently approved for treatment of Multiple Myeloma (MM). Since in MM an unbalance between a reduced proteasomal activity (capacity) and an increased proteins degradation (load) was shown to determine apoptotic sensitivity to PI, we challenged this paradigm also in MPM. Methods: Four different MPM (MM98, REN, MMB, MSTO) and a normal (TERT) pleural lines were treated with increasing doses (from 1 to 1000 nM) of Bortezomib and after 24h apoptosis was assessed by flow cytometric analysis of AnnexinV and propidium iodide positive cells. Levels of polyubiquitinated proteins were evaluated by immunofluorescence microscopy and western blotting with the specific monoclonal Ab Fk2 (BIOMOL International). The three main proteasome activities were measured in continuoin cellular extracts at 37°C with a Carry Eclipse spectrofluorometer (Varian, Palo Alto) by means of specific fluorogenic substrates (Suc-LLVY-amc, Bz-VGR-amc, Suc-YVAD-amc). Results: The sensitivity towards Bortezomib greatly differs between the 5 pleural lines analyzed. Specifically the EC 50 value was higher for the TERT line (130 nM) while for MPM lines ranged between 17 nM (MM98) and 71 nM (MSTO). Importantly, for all the 5 lines analyzed enhanced sensitivity to Bortezomib perfectly correlates with increased levels of ubiquitinated proteins and reduced proteasome specific activity. Conclusions: Our results prove that MPM lines are significantly more sensitive towards the pro-apoptotic effect of Bortezomib than normal pleural cells. Moreover, as in MM, also in MPM PI-sensitivity stems from an unbalance of the load/capacity ratio. Our data, therefore, establish a rationale for the use of Bortezomib (and new second generation PI) in MPM and indicate that combinatorial therapies with other drugs active on the proteostasis network (like HSP inhibitors) might be highly effective against this cancer.
The receptor for urokinase-type plasminogen activator and urokinase is translocated from two distinct intracellular compartments to the plasma membrane on stimulation of human neutrophils
Authors: T Plesner, M Ploug, V Ellis, E Ronne, G Hoyer-Hansen, M Wittrup, TL Pedersen, T Tscherning, K Dano, NE Hansen
Journal: Blood (1994)
Feasibility of intensive post-Induction therapy incorporating clofarabine (CLOF) in the very high risk (VHR) stratum of patients with newly diagnosed high risk B-lymphoblastic leukemia (HR B-ALL): Children’s Oncology Group AALL1131.
Authors: Michael Burke, Meenakshi Devidas, Si Chen, Lia Gore, Eric Larsen, Joanne M. Hilden, Mignon L. Loh, Naomi J. Winick, William L. Carroll, Elizabeth A. Raetz, Stephen Hunger, Wanda L. Salzer
Journal: Journal of Clinical Oncology (2015)

10007 Background: Four-year disease free survival (DFS) for patients with B-ALL classified as VHR is approximately 70%. Strategies to improve DFS with intensive post-Induction therapy using fractionated cyclophosphamide (CPM), etoposide (ETOP) and CLOF were evaluated on AALL1131. Methods: AALL1131 enrolled patients 1-30 years old with newly diagnosed HR B-ALL. The VHR subset was randomly assigned post-Induction to the Control Arm (CA) with modified BFM CPM + fractionated cytarabine + mercaptopurine, Experimental Arm 1 (Exp1) with CPM + ETOP, or Experimental Arm 2 (Exp2) with CLOF (30 mg/m2x 5 days) + CPM + ETOP during Part 2 of Consolidation (CON) and Delayed Intensification. All arms included identical doses of vincristine and pegaspargase. Results: The rates of Grade 4/5 infection and Grade 3/4 pancreatitis were significantly increased in Exp2 compared to CA and Exp1 (Table). The dose of CLOF was subsequently reduced from 30 to 20 mg/m2x 5 days and myeloid growth factor was required following CLOF administration. Despite these changes, 3/39 patients developed Grade 4 infections and one of these patients later developed a Grade 5 toxicity [acute kidney injury (AKI)] attributed to CLOF versus no Grade 4/5 infections on CA (n = 20) or Exp1 (n = 47). Four patients on Exp2 had prolonged cytopenias > 60 days during the 28 day CON Part 2 versus none on CA or Exp1. Two of the Exp2 patients failed to recover counts, one had Grade 5 AKI on day 92 and one was removed from protocol therapy on day 92. Conclusions: CLOF as administered with CPM/ETOP on Exp2 showed greater toxicity and was not considered feasible due to infectious toxicities and prolonged cytopenias. Exp2 was permanently closed to accrual in September 2014. Clinical trial information: NCT01406756.Toxicities: CON part 2 CLOF (30 mg/m2 x 5 days) Toxicity CA(N = 26) Exp 1(N = 49) Exp 2(N = 50) p Gr4/5 Infection 1 Gr 4 1 Gr 4 12 Gr 4 (11) Gr 5 (1) 0.0017 Gr3/4 Pancreatitis 0 0 5 0.0238 Gr3/4 AKI 0 0 2 0.3517 CLOF (20 mg/m2 x 5 days) Toxicity CA(N = 20) Exp 1(N = 47) Exp 2(N = 39) p Gr4/5 Infection 0 0 3 (7.7%) 0.14 Gr3/4 Pancreatitis 0 (0%) 1 (2.1%) 1 (2.6%) 1.00 Gr3/4/5 AKI 0 (0%) 0 (0%) 1 (2.6%)* 0.56 *Also listed as a Gr 4 infection.
Modified FOLFIRINOX regimen in advanced biliary tract adenocarcinoma.
Authors: Amit Rauthan, Poonam Patil
Journal: Journal of Clinical Oncology (2017)

484 Background: The treatment of advanced biliary tract adenocarcinoma is based on chemotherapy with Gemcitabine with Cisplatin or Oxaliplatin in various combinations. After seeing the high efficacy of FOLFIRINOX regimen in advanced pancreatic cancers, we studied the efficacy and safety of a modified FOLFIRINOX regimen in advanced biliary tract adenocarcinoma. Methods: We retrospectively reviewed patient with advanced biliary tract adenocarcinoma who were treated with modified FOLFIRINOX regimen from April 2013 to March 2016 in a tertiary hospital. The schedule of modified FOLFIRINOX was - Oxaliplatin 85 mg/m 2 , Irinotecan 150 mg/ m 2 , Leucovorin 400 mg/m 2 , and 5 fluorouracil 2400 mg/m 2 given as a 46-hour continuous infusion, every 2 weeks. All patients received primary prophylactic growth factors. The objective was to evaluate the efficacy and safety of FOLFIRINOX regimen. Results: 20 patients with untreated advanced biliary tract adenocarcinoma were enrolled. The median age was 55 (range 31 to 66 years). All patients had good performance status. 2 patients had a complete response (10%), 8 patients had a partial response (40%), 5 patients had stable disease (25%) and 5 patients had progression (25%). The median progression free survival was 6 months and the median overall survival was 10 months. The major toxicities were grade 3/4 neutropenia (30%), oral mucositis (20%), fatigue (20%) and neuropathy (10%). Dose reduction was required in 30% patients. Conclusions: A modified FOLFIRINOX regimen is an effective regimen in good performance status patients with advanced biliary tract adenocarcinoma. Dose modifications are required to reduce toxicity of the regimen. It needs to be further studied in a phase 3 study in comparison to Gemcitabine based regimens.
Randomized phase II study of S-1 monotherapy versus gemcitabine plus S-1 in gemcitabine-refractory advanced pancreatic cancer.
Authors: Makoto Ueno, Shinichi Ohkawa, Noritoshi Kobayashi, Kazuya Sugimori, Yoshiaki Kawaguchi, Satoshi Kobayashi, Masataka Taguri, Takeharu Yamanaka, Tetsuya Mine
Journal: Journal of Clinical Oncology (2017)

429 Background: Gemcitabine is one of the standard chemotherapeutic agents for pancreatic cancer in a first-line setting. In a second-line setting, there are various unmet needs. After gemcitabine chemotherapy, S-1 is mainly used and sometimes gemcitabine plus S-1 (GS) is used. Cytotoxic effect of gemcitabine had been reported to have the potential to be enhanced when used with fluorouracil. This randomized study aimed to evaluate the efficacy and safety of gemcitabine plus S-1 in gemcitabine-refractory advanced pancreatic cancer. Methods: This phase II study consisted of patients (pts) who were randomly allocated into the GS group (gemcitabine 1,000 mg/m 2 on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle) or the S-1 group (S-1 80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle) at a 1:1 ratio. The primary endpoint was the evaluation of progression-free survival (PFS). The sample size of 90 pts was chosen based on the randomized phase II selection design reported by Simon et al.(1985). The design suggests a correct selection probability of 75% with two-sided significance level of 0.10 if median PFS is 3.3 mo and 2.0 mo in GS and S-1 groups. Results: From Jan 2012 to March 2015, randomized 51 pts were examined (GS: 26, S-1: 25). This study was discontinued due to slow accrual. The median PFS of GS group was 2.0 mo while the S-1 group was 2.1 mo. The hazard ratio was 1.06 [95%CI 0.60-1.86]; (p=0.844). The median survival times were 3.8 mo in GS group and 5.5 mo in S-1 group, respectively. The hazard ratio was 1.02 [95%CI 0.57-1.81]; (p=0.96). The response rates were 4.2% and 4.3%. The disease control rates were 33.4% and 30.4%. Although bone marrow suppression is higher in GS group, the toxicities were manageable in both groups. Grade 3/4 toxicities (GS/S-1 %) included: neutropenia, 53.8/8; hemoglobin, 30.8/28.0; thrombocytopenia, 7.7/4.0; nausea, 0/8.0; anorexia 11.5/16.0, fatigue 7.7/0 and diarrhea, 3.8/4.0. Conclusions: Gemcitabine plus S-1 is not more effective than S-1 in gemcitabine-refractory advanced pancreatic cancer. Clinical trial information: 000007173.
Clinicopathologic and molecular associations of PIK3CA and PTEN mutation in colorectal cancer.
Authors: Fiona Lee Day, Jayesh Desai, Robert N Jorissen, Peter Gibbs, Dmitri Mouradov, Shan Li, Oliver Sieber
Journal: Journal of Clinical Oncology (2012)

3623 Background: The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been implicated in the development of colorectal cancer (CRC), however a systematic analysis of pathway members and their association with clinical, pathological and other molecular features has been lacking. Methods: We determined the prevalence of PIK3CA (exons 9, 20) mutations in a large cohort (n=1092) of community-based patients (pts) with stage I-IV CRCs. A subset (n=744, 68%) were also tested for mutation in PTEN (exons 3,4,5,6,7,8), PTEN LOH and CIMP. All tumors were characterised for MSI, KRAS and BRAF mutations, and annotated for clinico-pathologic features and patient outcomes in a prospectively-recorded database. Detected novel PIK3CA exon-specific correlates were further explored in a combined analysis integrating the data of other published cohorts (total n=3677). Results: PIK3CA mutations occurred in 11.6% of primary tumors and were associated with older pt age (p=0.009), proximal site (p&lt;0.001), lower lymphovascular invasion (p=0.018) and KRAS mutation (p&lt;0.001), but not with gender, tumor stage or differentiation. Direct comparison of PIK3CA exon 9 and 20 mutations in the combined analysis (mixed effect logistic regression) finds both at increased frequency in KRAS-mutant tumors (p=0.098 for difference); however PIK3CA exon 20 mutations uniquely correlated with BRAF mutation (p=0.002 for difference), MSI (p&lt;0.001) and CIMP-high status (p=0.031). PTEN mutations were present in 5.8% of tumors and associated with proximal site (p=0.013), mucinous histology (p=0.013), MSI (p&lt;0.001), CIMP-high (p&lt;0.001), and BRAF mutation (p&lt;0.001). There was a trend toward mutation of both PIK3CA and PTEN and strong selection for two hits to PTEN (mut/mut or mut/LOH, p&lt;0.001). In our cohort neither PIK3CA or PTEN mutation were associated with pt survival outcomes. Conclusions: In CRC, common mutations in the PI3K signaling pathway are universally associated with proximal site, however display unique gene- and exon-specific associations with tumor histology, MSI, CIMP, KRAS and BRAF mutation. These need to be considered when exploring targeted therapeutic options for pts with CRC.
Performance of a validated urine exosome gene expression assay to predict high-grade prostate cancer utilizing the International Society of Urological Pathology (ISUP) 2014 grading system.
Authors: Michael Donovan, Phillipp Torkler, Johan Skog, Mikkel Noerholm, Peter Carroll
Journal: Journal of Clinical Oncology (2017)

49 Background: Overdetection and overtreatment of indolent prostate cancer (PCa) remains a significant health issue requiring noninvasive assays to guide the prostate biopsy decision process. We demonstrated that a urine exosome gene expression assay (ExoDx P rostate ( I ntelliScore) (EPI) discriminates GS 7 PCa from GS 6 and benign disease, potentially reducing the number of unnecessary biopsies. The International Society of Urological Pathology (ISUP) proposed a prognostic PCa grading system to accurately reflect the biology of PCa; ISUP separates GS 7 PCa into group 2 (GS 3+4) and group 3 (GS 4+3). We sought to evaluate the performance of the EPI test according to the newly proposed ISUP system. Methods: The 519 patient validation cohort was re-annotated using ISUP and assessed benign (B) +/- ISUP 1 and B+ISUP 1+2 (GS 3+3, GS 3+4) from ISUP 3-5 (GS &gt;= 4+3). We used validated / adjusted cut-points to assess performance with the AUC, sensitivity, specificity and NPV. In addition, we investigated the association of the EPI score with the benign biopsies (BB) and ISUP groups in the combined training and test cohort (n=774). Results: Applying the adjusted cut point (EPI 20) on the 519 ISUP cohort discriminated benign biopsies (BB) + ISUP 1 from &gt;/=ISUP 2, 37% of biopsies avoided, NPV of 90%, equivalent to Gleason grading. Utilizing either the validated (15.6) or adjusted cut points on BB+ISUP 1+ 2 vs. &gt;/=ISUP 3 (dominant pattern 4), 26% vs 37% biopsies avoided, with an improved NPV 98%. In the combined training / test cohort, higher EPI scores were significantly associated with ISUP categories. In this analysis EPI in BB vs. all ISUP groups (p&lt;0.0001); BB+ISUP 1 vs. &gt;/= ISUP2 (p&lt;0.0001) and BB+ISUP 1+2 vs. &gt;/=ISUP3 (p&lt;0.0001); supporting accurate discrimination in high grade PCa. Conclusions: The EPI test is a noninvasive, first-catch non-DRE gene expression assay that accurately discriminates low-grade from high-grade PCa in both ISUP as well as Gleason score based grading systems. The test has the potential to reduce the number of unnecessary biopsies and performs equally well in contemporary approaches to PCa stratification.