tbuckley/cabot-search huggingface dataset:
Subgroups of survivors with distinct aggravating factors associated with chemotherapy-induced neuropathy (CIN) in the feet.
Authors: Judy Mastick, Grace Mausisa, Melissa Mazor, Steven M. Paul, Bruce A. Cooper, Betty Smoot, Kimberly Topp, Gary Abrams, Lee-may Chen, Margaret Chesney, Kord Kober, Yvette Conley, Jon Levine, Christine Miaskowski
Journal: Journal of Clinical Oncology (2017)

151 Background: CIN is the most prevalent neurologic complication of cancer treatment. Inter-individual variability exists in survivors’ reports of the factors that aggravate CIN in their feet. The purpose of this study was to identify groups of survivors with CIN in their feet based on distinct aggravating factors and evaluate for differences in demographic, clinical, symptom characteristics and quality of life (QOL) based on group membership. Methods: Cancer survivors (n = 403) who received a platinum and/or a taxane and rated their altered sensation/pain in their feet at &gt; 3 on 0-10 scale were enrolled and completed study questionnaires, including a list of 22 factors that could make pain worse. Medical records were reviewed and sensory and motor tests were done. Latent class analysis was used to identify groups of survivors based on the occurrence rates for aggravating factors. Differences among the groups were evaluated using parametric and nonparametric statistics. Results: Three groups were identified based on occurrence rates for aggravating factors in the feet (i.e., Activity and Temperature (40.2%), Activity (25.8%), Few Factors (34.0%)). No differences were found among the groups in demographic characteristics, or sensory (light touch, temperature, pain, vibration) and motor (Timed Up and Go, Fullerton Assessment of Balance) tests. Compared to the Few Factors group, the other two groups had higher BMI, worse foot pain, poorer functional status and sleep, more depressive symptoms, and lower QOL. Survivors who received a platinum compound were more likely to be in the Activity and Temperature group. Those that received a taxane compound were more likely to be in the Few Factors or Activity groups. Conclusions: Survivors who reported a higher occurrence of aggravating factors had a higher symptom burden and poorer QOL. Objective measures did not differ among the groups. Aggravating factors associated with the CTX received supports previous work in that the survivors who received platinum drugs noted cold temperatures aggravated their CIN. Findings suggest that subgroups of survivors can be identified based on their reports of CIN aggravating factors.
JAGUAR: A randomized phase II study of the AKT inhibitor ipatasertib (GDC-0068) versus placebo in combination with mFOLFOX6 chemotherapy in patients (pts) with locally advanced or metastatic HER2-negative gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Yung-Jue Bang, Yoon-Koo Kang, Maria Alsina, Zev A. Wainberg, Ian Chau, Jin Zhu, Wai Y. Chan, Premal H. Patel, Raymond D. Meng, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2014)

TPS4147 Background: Activation of PI3K/Akt signaling occurs in greater than 60% of G/GEJ cancers by decreased PTEN and/or mutations or amplifications of PIK3CA, and may contribute to chemoresistance. Pts with G/GEJ cancers that have PI3K/Akt activation have been reported to have poor prognosis and decreased overall survival. Ipatasertib (GDC-0068) is an oral, potent ATP-competitive small molecule inhibitor of all three isoforms of Akt that specifically targets cancer cells with activated Akt. In preclinical models, ipatasertib synergistically combines with fluorouracil (5-FU) and platinum chemotherapy. In Phase Ib clinical studies, the combination of ipatasertib and mFOLFOX6 chemotherapy is well-tolerated; the most commonly reported adverse events associated with ipatasertib are grade 1-2 diarrhea, nausea, vomiting, fatigue, and decreased appetite. RECIST responses and prolonged stable disease were seen with the combination, including pts with tumors having PI3K/Akt activation. Methods: JAGUAR is a randomized, double-blind, placebo-controlled, global Phase II study in pts with previously untreated locally advanced or metastatic G/GEJ cancers. Approximately 120 patients with measurable HER2-negative or HER2-unknown G/GEJ cancer will be randomized (1:1) to receive mFOLFOX6 plus ipatasertib or mFOLFOX6 plus placebo. Patients will be stratified by PTEN status. A maximum of 8 cycles of mFOLFOX6 are permitted, and ipatasertib or placebo in combination with 5-FU and leucovorin will be continued until disease progression or intolerable toxicity. The primary endpoint is progression free survival. Additional endpoints include overall survival, objective response rate, duration of response, safety, pharmacokinetics, and correlative biomarkers. This study is open for accrual. Clinical trial information: NCT01896531.
Comparison of breast cancer recurrence and outcome patterns between patients treated in 1986-1992 and 2004-2008.
Authors: Rachel Jorge Dino Cossetti, Scott Tyldesley, Caroline Speers, Karen A. Gelmon
Journal: Journal of Clinical Oncology (2014)

521 Background: Different patterns of breast cancer (BC) recurrence overtime have been reported according to estrogen receptor (ER) status. We report a change in BC recurrence patterns. Methods: Females with biopsy proven BC, stages I-III, treated at the BCCA 1986-1992 (cohort 1 – C1) and mid 2004-2008 (cohort 2 – C2), with known ER and HER2 status were eligible. Data was prospectively collected. C2 cases were matched to C1 by random case selection for grade and stage to adjust for imbalances. Endpoints were annual hazard rates of recurrence (HRR) and annual hazard rates of death (HRD). Results: After random sampling, 10,283 pts were included: 3672 in C1 and 6611 in C2. BC subtypes in C1 and C2 were, respectively, ER+/HER2-: 71.2 vs 64.8%; ER+/HER2+: 6.7 vs 11.7%; ER-/HER2+: 6.5 vs 8.2%; ER-/HER2-: 15.5 vs 15.3%. The HRR per yearly interval (up to year 9) for all subtypes have halved in C2. For ER+/HER2- BC, HRR in C2 was half of the HRR in C1. Differences in HRR between C1 and 2 were greater in the initial 5 intervals for HER2+ and triple-negative (TN) BC. The HRD have also decreased, but to a lesser extent. Conclusions: Outcomes have improved for all BC subtypes, but particularly for HER2+ and TN BC. The early spike in disease recurrence has markedly decreased. These contemporary hazard rates are important for treatment decisions and patient discussions, but also for planning of early BC trials. HRR (%) Yearly interval 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 Cohort 1 4.7±0.4 8.8±0.5 6.8±0.5 5.0±0.4 4.2±0.4 3.7±0.4 3.0±0.4 3.1±0.4 1.8±0.3 Cohort 2 2.7±0.2 4.0±0.3 3.6±0.2 2.6±0.2 2.0±0.2 1.3±0.2 1.2±0.2 1.2±0.3 0.3±0.3 ER+/HER2- C1C2 2.7±0.3 6.2±0.5 5.0±0.5 4.3±0.5 4.1±0.5 4.1±0.5 3.3±0.4 3.4±0.5 1.9±0.4 1.5±0.2 2.5±0.2 3.0±0.3 2.2±0.2 1.9±0.2 1.4±0.2 1.7±0.3 1.3±0.4 0.4±0.4 ER+/HER2+ C1C2 6.7±1.7 13.7±2.5 12.1±2.6 21.6±2.6 6.9±2.2 3.7±1.7 3.2±1.6 4.3±1.9 2.8±1.6 2.5±0.6 3.1±0.7 3.9±0.7 3.0±0.7 2.7±0.7 1.8±0.6 0.3±0.3 0.7±0.7 0 ER-/HER2+ C1C2 13.9±2.5 23.6±3.6 17.0±3.4 7.8±2.5 6.8±2.4 2.7±1.6 1.8±1.3 1.9±1.3 2.0±1.4 4.0±0.9 8.3±1.3 5.5±1.1 3.0±0.8 1.3±0.6 0.3±0.3 0 1.7±1.2 0 TNBC C1C2 9.4±1.3 14.6±1.7 11.0±1.6 5.3±1.2 2.5±0.8 1.5±0.7 1.8±0.7 1.6±0.7 1.3±0.6 7.3±0.9 9.1±1.0 5.5±0.8 3.8±0.7 2.0±0.5 0.7±0.4 0.5±0.3 0.9±0.6 0
A phase II trial of maintenance ADAPT therapy targeting colon cancer stem cells in patients with metastatic colorectal cancer.
Authors: Edward H. Lin, Shilpen A. Patel, Jeffrey Chou, Edward Y. Kim, Veena Shankaran, Andrew L. Coveler, William Proctor Harris, James Oh Park, Alessandro Fichera, Gary N. Mann, E. Gabriela Chiorean, Colin C. Pritchard, Mika Sinanan, Melissa Upton, Barry Storer, Raymond Sze Yeung, Lingheng Li
Journal: Journal of Clinical Oncology (2014)

TPS3650 Background: Presence of cancer stem cells (CSC) appears to be the chief cause of drug resistance to cytotoxic or targeted chemotherapy. Experimental models suggest that these resistant cancer cells undergo dormancy transition that is best targeted with a stemness modulator in its activation window through a strategy that we call ADAPT: Activating (CSC) from Dormancy And Potentiate for Targeting. In vitro and in vivo data suggest that 5FU activates while celecoxib inhibits and depletes these putative colorectal CSC. We retrospectively administer three year ADAPT therapy in unresectable metastatic colorectal cancer (MCRC) patients using capecitabine and celecoxib +/- radiation following maximal responses (complete (CR) and partial response (PR) and stable disease (SD)) to first-line combination chemotherapy. ADAPT therapy led to 30% CR and additional 10% surgical CR whose median survival reached 92.7 months in patients with unresectable MCRC. (Lin et al AACR 2010 LB-254). Methods: Fred Hutch Cancer Research Center institutional review board (IRB) approved this prospective phase II ADAPT study funded by Gateway for Cancer Cure in October 2013. The primary endpoint is to determine the rate of CR at three years. The secondary objectives are to determine progression free survival, overall survival, and relapse free survival (if CR) based on intent to treat analysis. Forty-three unresectable MCRC patients except those with brain or bone metastases or severe bowel obstruction will be enrolled and patients must have achieved maximal response (CR, PR, or SD) to first-line chemotherapy before prior to three-year ADAPT protocol +/-radiation. Patient must not be allergic to NSAIDs or sulfonamide and aspirin is not allowed. Eight patients have been enrolled to date and trial will be terminated if less than one complete response (including surgical CR) in the first 20 MCRC patients. Translational
Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ,γ, in patients with relapsed/refractory CLL.
Authors: Manish R. Patel, Brad S. Kahl, Steven M. Horwitz, Anas Younes, Francine M. Foss, Yasuhiro Oki, Jennifer Sweeney, Kerstin Allen, Kerrie Faia, Patrick Francis Kelly, Ian Flinn
Journal: Journal of Clinical Oncology (2013)

7070 Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KEδ and PI3K-γ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) from an ongoing Phase I study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) &lt; MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on modified IWCLL guidelines criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with continuous 24 hr inhibition of pAKT (Ser473) in primary pt CLL cells after a single dose of 25 mg. In the 16 pts with CLL (5 pts in dose escalation &lt; 25 mg BID and 11 pts in a 25 mg BID EC), the median [range] number of cycles was 2.7 [1–14] and 81% remain on study. Treatment-related adverse events (TRAEs) occurred in 10 (63%) pts with CLL, a similar incidence as seen in the total study population (56%). The most common &gt; Grade 3 TRAE in pts with CLL was neutropenia (25%). No &gt; Grade 3 ALT elevations occurred in pts with CLL. Among evaluable pts with CLL (n=11), 82% (n=9) had a PR or nodal response after 2 cycles of IPI-145, with a best response to date of 6 PR, 4 SD (all nodal responses), and 1 PD. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity at the doses examined in pts with relapsed/refractory advanced CLL. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with CLL enrolled in dose escalation and ECs evaluating 25 mg BID and a higher dose (&lt;MTD) of IPIE145 will be presented. Clinical trial information: NCT01476657.
Freedom from progression (FFP) by adding paclitaxel (T) to doxorubicin (A) followed by CMF as adjuvant or primary systemic therapy: 10-yr results of a randomized phase III European Cooperative Trial in Operable Breast Cancer (ECTO).
Authors: Milvia Zambetti, José Baselga, Wolfgang Eiermann, Vicente Guillem, Vladimir Semiglazov, Ana Lluch, Dolores Sabadell, Alla Bozhok, Mikhail J. Byakhov, Belen Ojeda, Mauro Mansutti, Gabriella Mariani, Angela Moliterni, Hernan Cortes-Funes, Marian Colozza, Tadeusz Pienkowski, Domenico Magazzu, Pinuccia Valagussa, Gianni Bonadonna, Luca Gianni
Journal: Journal of Clinical Oncology (2013)

537 Background: At the time the ECTO was designed in 1996, taxanes were only indicated for patients with metastatic breast cancer. However, paclitaxel and docetaxel were still to be tested in the adjuvant setting. In addition there was relatively scarce information on the comparative efficacy of neoadjuvant and adjuvant regimens. The ECTO trial was designed to evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy. Methods: A total of 1,355 women with operable breast cancer were randomized to one of three treatments: 1) surgery followed by adjuvant single agent doxorubicin (A) followed by CMF (arm A); 2) surgery followed by adjuvant paclitaxel plus doxorubicin (AT) followed by CMF (arm B); 3) AT followed by CMF followed by surgery (arm C). The two co-primary objectives were to assess the effects on freedom from progression (FFP) of: 1) the addition of paclitaxel to post-operative chemotherapy (arm B versus arm A); and 2) primary versus adjuvant chemotherapy (arm B versus arm C). Results: At 10 years, in the adjuvant setting FFP remained statistically significant in favor of AT followed by CMF (arm B, HR 0.77, P=0.045). Distant FFP was similarly improved but overall survival was not (HR 0.82, P=0.24). There was no significant difference in FFP when chemotherapy was given after surgery compared with the same regimen given before surgery (arm B vs arm C, HR 0.79, P=0.07). In the primary chemotherapy arm, patients who achieved a pathological complete remission (pCR) had improved distant FFP (P &lt; 0.001) compared to patients who did not achieve pCR. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients, which did not translate in an increased risk of ipsilateral breast recurrence compared to the risk observed in patients in the adjuvant arms. Conclusions: Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significantly improved FFP and DFFP.
The efficacy of irinotecan, paclitaxel, and oxaliplatin (IPO) in relapsed germ cell tumours: A non-cisplatin-based regimen.
Authors: Waleed Badreldin, Simon Chowdhury, Stephen John Harland, Danish Mazhar, Thomas Powles, Peter Wilson, Jonathan Shamash
Journal: Journal of Clinical Oncology (2012)

4529 Background: Cisplatin-based chemotherapy with or without high dose chemotherapy remains the standard approach in managing relapsed germ cell tumors (GCT). The feasibility of IPO was first described in 2006.Non cisplatin-based therapies offer the advantage of differing side effect profiles which may be useful to certain patients.Here we describe the outcome of an expanded cohort of these patients. Methods: The results of 72 consecutive patients were reviewed (18% had metastatic mediastinal GCTs). IPO was used either as 2 nd line treatment (n=29) of which 20 had HDCT or 3 rd line (n=43) of which 32 had HDCT. IPO consisted of oxaliplatin 100mg/m 2 , irinotecan 200mg/m 2 and weekly pac litaxel 80mg/m 2 ( IPO) every 3 weeks for 3-4 cycles with the intention of high dose carboplatin , thiotepa and topotecan as consolidation (HDCT). Results: The 2 year PFS and 3 year OS for the whole cohort was 28.4% (95%CI 17.3-40.5%) and 31.6% (95%CI: 20.1-43.8 %) respectively. The overall response was as follows; CR – 3%, m-ve PR 41%, m+ve PR 18%, SD 17%, PD 20%. In the second line setting, the 2 year PFS was 41.8% (95%CI: 21.7-60.8%) and 3y OS 45.8% (95%CI: 24.2-65.1%). The 2 year PFS according to the IGCCCG2 prognostic score was Intermediate = 34%, High risk =50% and very high risk = 30%. In the 3 rd line setting the 2 year PFS was 20.9% (95%CI 9.5-35.4%) and 3 year OS was 23.8% (95%CI 11.7-38.2). For HDCT the 2 y PFS was good risk= 52%, Intermediate =29% and poor risk= 0%. There were 2 treatment related deaths from IPO, and 4 from HDCT. Grade 3 or 4 toxicities were as follows (&gt;5%): neutropenia 35%, thrombocytopenia 18%, infection 15%, diarrhea 11%, lethargy 8%. Conclusions: IPO is a safe, non-nephrotoxic day care regimen which produces encouraging responses particularly in high risk cases. Where cisplatin is contra-indicated this is may be a useful alternative.
Exposure to any antenatal corticosteroids and outcomes in preterm infants by gestational age: prospective cohort study
Authors: Colm P Travers, Reese H Clark, Alan R Spitzer, Abhik Das, Thomas J Garite, Waldemar A Carlo
Journal: BMJ (2017)

<b>Objective</b>&nbsp;To determine whether exposure to any antenatal corticosteroids is associated with a lower rate of death at each gestational age at which administration is currently recommended. <b>Design</b>&nbsp;Prospective cohort study. <b>Settings</b>&nbsp;300 participating neonatal intensive care units of the Pediatrix Medical Group in the United States. <b>Participants</b>&nbsp;117 941 infants 23 0/7 to 34 6/7 weeks’ gestational age born between 1 January 2009 and 31 December 2013. <b>Exposure</b>&nbsp;Any antenatal corticosteroids. <b>Main outcomes measures</b>&nbsp;Death or major hospital morbidities analyzed by gestational age and exposure to antenatal corticosteroids with models adjusted for birth weight, sex, mode of delivery, and multiple births. <b>Results</b>&nbsp;Infants exposed to antenatal corticosteroids (n=81 832) had a significantly lower rate of death before discharge at each gestation 29 weeks or less, 31 weeks, and 33-34 weeks compared with infants without exposure (range of adjusted odds ratios 0.32 to 0.55). The number needed to treat with antenatal corticosteroids to prevent one death before discharge increased from six at 23 and 24 weeks’ gestation to 798 at 34 weeks’ gestation. The rate of survival without major hospital morbidity was higher among infants exposed to antenatal corticosteroids at the lowest gestations. Infants exposed to antenatal corticosteroids had lower rates of severe intracranial hemorrhage or death, necrotizing enterocolitis stage 2 or above or death, and severe retinopathy of prematurity or death compared with infants without exposure at all gestations less than 30 weeks and most gestations for infants born at 30 weeks’ gestation or later. <b>Conclusion</b>&nbsp;Among infants born from 23 to 34 weeks’ gestation, antenatal exposure to corticosteroids compared with no exposure was associated with lower mortality and morbidity at most gestations. The effect size of exposure to antenatal corticosteroids on mortality seems to be larger in infants born at the lowest gestations.
Expression of exportin 1 (XPO1/CRM1) in pancreatic adenocarcinoma.
Authors: David M Saulino, Pamela S Younes, Jennifer M Biley, Mamoun Younes
Journal: Journal of Clinical Oncology (2017)

327 Background: Exportin 1 (XPO1/CRM1) is a nuclear export chaperone that mediates the nuclear export of several proteins that are essential to growth regulation and tumor suppression. It was found to be overexpressed in several types of human malignancies and overexpression was found to be associated with poor prognosis. Pancreatic adenocarcinoma (PAC) is associated with very poor survival and currently has no effective treatment. Selective inhibitors of nuclear export are currently undergoing phase I and II clinical trials in hematologic malignancies and solid tumors. The aim of this study was to determine the expression of XPO1/CRM1 in pancreatic adenocarcinoma (PAC) and its relation to survivin expression and proliferative activity as determined by the S-phase fraction (SPF). Methods: Sections of tissue microarray containing 77 formalin fixed and paraffin embedded human PAC were stained by immunohistochemistry (IHC) using monoclonal antibodies to XPO1/CRM1, survivin, and for Cyclin A. The levels of XPO1/CRM1 and survivin expression in tumor cells and the S-phase fraction (SPF) were determined using a quantitative digital image analysis solution (OTMIAS). Results: Sixty-six of the 77 (86%) cases were positive for XPO1/CRM1, with the mean expression value ranging from 0.3 to 53 units and the median ranging from 0.3 to 45 units. There was significant correlation between the mean and median expression values of XPO1/CRM1 in tumor cells with the mean and median values of expression of survivin (p &lt; 0.001). Moreover, the mean and median XPO1/CRM1 expression levels in tumor cells correlated significantly with SPF (p = 0.005). Conclusions: XPO1/CRM1 is expressed in a significant proportion of PAC, and increased expression correlates with both survivin expression and increased proliferative activity, suggesting that selective inhibitors of nuclear export may be effective against PAC.
The genomic relationship among matched prostate cancer foci.
Authors: David James VanderWeele, Christopher D. Brown, Robert L. Grossman, Jerome B. Taxy, Walter Michael Stadler, Kevin P. White
Journal: Journal of Clinical Oncology (2013)

5028 Background: Cancer management is influenced by how one views progression and how one calculates the risk of metastases and death. For prostate cancer, this is based largely on histologic appearance, or Gleason score. Cancers with a Gleason score of 6 exhibit indolent behavior and are often considered low risk. Despite recommendations supporting active surveillance for Gleason 6 prostate cancer, the vast majority of American patients receive aggressive local therapy, in part based on a presumption that low grade cancer progresses to high grade, lethal disease. Methods: To assess the genomic relationship between low and high grade disease, laser capture microdissection was used to isolate concurrent cancer foci from prostates with multifocal disease, and somatic mutations were identified using exome sequencing. The relationship between a Gleason 6 focus and a concurrent Gleason 8 or higher focus was determined for four subjects, and a lymph node metastasis was examined for two of those subjects. Results: We obtained an average of 41-fold median coverage of the exome, with an average high confidence mutation rate of 0.8/Mb. Seventy of 79 (0.886) high confidence somatic mutations in low grade disease were private to the low grade foci. For the cases for which a metastatic focus was available, 15 of 80 (0.188) high confidence somatic mutations in the high grade focus were private. Seven of the 80 (0.088) were shared with low grade foci, and 65 (0.813) were shared with metastatic foci. Conclusions: The pattern of shared versus private mutations is consistent with early divergence between Gleason 6 and Gleason 8 or 9 disease, and late divergence between Gleason 8 disease and lymph node metastases. These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores.