tbuckley/cabot-search huggingface dataset:
Total therapy 5 (TT5) for newly diagnosed high-risk multiple myeloma (HRMM): Comparison with predecessor trials total therapy 3a and 3b (TT3 a/b).
Authors: Saad Zafar Usmani, Sarah Waheed, Frits Van Rhee, Alan Mitchell, Alejandro Restrepo, Monica Grazziutti, John Crowley, Bart Barlogie
Journal: Journal of Clinical Oncology (2013)

8539 Background: HRMM has not benefited from advances achieved in the remainder 85% with low-risk MM. In order to guard against relapses during previous drug-free intervals in TT3, TT5 was designed as a dose-dense and less dose-intense program. Here we are reporting for the first time on the TT5 outcomes in comparison with TT3a/b results in HRMM. Methods: TT5 called for M-VTD-PACE induction with HPC collection. This was followed by tandem autologous stem cell transplants (ASCT) with hybrid regimens Mel80 plus VRD-PACE, sandwiched in between were 2 inter-transplant cycles of MEL20-VTD-PACE. Maintenance consisted of 3 years of alternating VRD and VMD (M, melphalan). As relapses were observed during maintenance, bortezomib was increased from 1.3mg/m2 to 1.5mg/m2 weekly. Results were compared with HRMM treated with TT3a/b (n=40/37). Data were compared with TT3 HRMM, involving 77 patients. Overall survival and progression free survival was analyzed employing Kaplan-Meier curves. Cox regression modeling was done for univariate and multivariate analyses. Results: Of 59 patients enrolled in TT5, CR was 66% including 10% with s-CR. The 18-mo OS was 92% v 74% with TT3 (p=0.009), whereas PFS was similar at 67% and 69%, respectively. A newly developed GEP-5 model distinguished 8 patients with a 36-mo OS estimate of 20% versus almost 90% for the remainder (p=0.04). On multivariate analysis that included TT5 and TT3, our GEP80 low-risk score, TT5 (vs TT3) and age &lt;65yr were independent features linked to superior OS. Conclusions: This isthe first report of a dose-dense chemotherapeutic approach for newly diagnosed HRMM, which also introduced a hybrid Mel80-VRDPACE hybrid preparative regimen for ASCT. TT5 represents an advance in the management of GEP70-defined HRMM compared to predecessor trials TT3a/b for similar patients, with significant improvement in overall survival and tolerability compared with TT3 a/b. Clinical trial information: NCT00081939, NCT00572169, NCT00869232.
A randomized, double-blind, multicenter phase III study evaluating paclitaxel with and without RAD001 in patients with gastric cancer who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC).
Authors: Salah-Eddin Al-Batran, Jorge Riera-Knorrenschild, Claudia Pauligk, Thorsten Oliver Goetze, Susanna Hegewisch-Becker, Jörg Seraphin, Peter C. Thuss-Patience, Hans-Georg Kopp, Tobias Nicolaas Dechow, Arndt Vogel, Kim Barbara Luley, Daniel Pink, Michael Stahl, Frank Kullmann, Holger Frithjof Hebart, Jens T. Siveke, Matthias Egger, Nils Homann, Stephan Probst, Sylvie Lorenzen
Journal: Journal of Clinical Oncology (2017)

4 Background: There is a need for effective treatments in the second- or further line setting in advanced gastric cancer, especially for new agents. In the current trial we evaluated paclitaxel with RAD001 (everolimus) in patients with gastric carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen. Methods: This is a randomized, double-blind, multi-center phase III study. Patients with gastric carcinoma or adenocarcinoma of the esophagogastric junction which has progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomly assigned to receive Paclitaxel (80 mg/m2) on day 1, 8 and 15 plus placebo (arm A) or RAD001 (10mg daily, arm B) d1-d28, repeated every 28 days as 2 nd , 3 rd or 4 th line therapy. Primary end point was overall survival (OS), secondary endpoints were best overall response, disease control rate, progression free survival (PFS) and toxicity. Results: 300 patients (median age: 62 years; median lines prior therapy: 2) were randomly assigned (Arm A, 150, Arm B, 150). Response rate (complete and partial response) was 8.0% (95%CI: 4.2%-13.6%) in the paclitaxel/RAD001 arm and 7.3% (95% CI: 3.7%-12.7%) in the paclitaxel/placebo arm (p = 0.4).There was no significant difference in median PFS (placebo, 2.07 vs. RAD001, 2.2 months, HR 0.88, p = 0.3) and median OS (placebo, 5.1 vs. RAD001, 6.1 months, HR 0.92, p = 0.48). Combination of paclitaxel and RAD001 was tolerable, but the placebo arm was associated with significantly less (any grade) mucositis (15.8% vs. 37.2%), fever (10.3% vs 20.7%), leukopenia (11.6% vs. 21.4%), neutropenia (13.0% vs. 27.6%) and thrombocytopenia (2.1% vs 14.5%). Conclusions: The addition of RAD001 to paclitaxel/RAD001 did not significantly improve outcomes in pretreated metastatic gastric or esophagogastric junction adenocarcinoma. Additional biomarker studies are planned to look for subgroups that may have a benefit. Clinical trial information: NCT01248403.
Comparison of the pathological features among HBV, HCV, and nonviral etiology-related hepatocellular carcinoma using explanted whole liver examinations.
Authors: Hayato Akashi, Masaaki Hidaka
Journal: Journal of Clinical Oncology (2017)

245 Background: The aim of this study is to compare the pathological features among HBV, HCV and non-viral etiology related hepatocellular carcinoma (HCC) in the explanted cirrhotic liver using whole liver examinations. Methods: Ninety patients (HBV 23, HCV 53, HBV+HCV 3, nonBnonC 16) out of 246 recipients of liver transplantation were analyzed. All specimens were sectioned serially at 5-7 mm intervals and then were examined by an experienced pathologist. The pathological characteristics of HCC among each group were retrospectively analyzed using whole liver thin sliced histological examinations. Results: The median number and maximum size of HCC were one nodule (range 0-3 nodules), 22 mm (range 7-50 mm) by pre-operative imaging, and two nodules (range 0-37 nodules), 20 mm (range 4-50 mm) based on histological examinations. Twenty-six patients (27.4%) had more than 3 nodules measuring less than 1 cm diameter based on histological examinations. Fifteen patients (15.8%) had HCC with micro vascular invasion. Twenty-seven patients (28.4%) demonstrated findings beyond the Milan Criteria based on pathological examinations. NonBnonC related HCC tended to be within the Milan Criteria based on pathological examinations in contrast to viral related HCC (nonBnonC 12.5%, HBV 34.8% and HCV 39.6%). There were significantly more undetectable HCCs in HCV related HCC than in detectable HCCs by imaging. Conclusions: The undetectable HCCs in HCV tended to be found in the explanted liver. HCCs exceeding the rate of the Milan Criteria were less frequently found in non-viral related HCC than in viral related HCC.
Smoking status and prognosis in patients with stage III colon cancer: A correlative analysis of NCCTG phase III trial N0147.
Authors: Amanda I. Phipps, Qian Shi, Paul J. Limburg, Garth D. Nelson, Daniel J. Sargent, Polly A. Newcomb, Steven R. Alberts
Journal: Journal of Clinical Oncology (2012)

3526 Background: Prior observational studies have suggested that smoking is associated with poorer overall survival after colon cancer (CC) diagnosis. Using data from N0147, a phase III randomized adjuvant trial of patients with stage III CC, we assessed the relationship between smoking status and cancer outcomes (disease-free survival (DFS) and time to recurrence (TTR)), accounting for possible heterogeneity by patient and tumor characteristics. Methods: Patients completed a risk factor questionnaire at baseline prior to randomization to FOLFOX or FOLFOX+cetuximab (N=1968). Information was collected on smoking and other lifestyle factors, including alcohol consumption, body mass index (BMI), and physical activity. Multivariate Cox models assessed the association between smoking history and the primary trial outcome of DFS, as well TTR, adjusting for other lifestyle and clinical factors. The median follow-up was 3.5 years. Results: Overall, 52% of patients were former or current smokers. Compared to never smokers, ever smokers experienced significantly shorter DFS [3-year DFS: 70% vs 74%, hazard ratio (HR)=1.21, 95% confidence interval (CI): 1.02-1.42]. This association persisted after adjusting for age, sex, tumor subsite, number of nodes involved, T-stage, mismatch repair deficiency, BRAF mutation status, performance score, physical activity, BMI, and alcohol consumption (HR=1.23, 95% CI: 1.02-1.49). There was significant interaction in this association by BRAF mutation status (p=0.02): smoking was associated with shorter DFS in BRAF wildtype CC patients (HR=1.25, 95% CI: 1.04-1.51) but not in BRAF mutant CC patients (HR=0.72, 95% CI: 0.47-1.10). Patterns of association with smoking, overall and by BRAF status, were identical in analyses of TTR. Conclusions: Overall, smoking was significantly associated with shorter DFS and TTR in CC patients. These adverse relationships were most evident in patients with BRAF wildtype CC.
Role of axillary ultrasound after neoadjuvant chemotherapy in women with node-positive breast cancer (T1-4, N1-2, M0) at initial diagnosis (ACOSOG Z1071).
Authors: Huong T. Le-Petross, Linda Mackie McCall, Kelly Hunt, Elizabeth Ann Mittendorf, Gretchen M. Ahrendt, Lee G Wilke, A. Marilyn Leitch, Bret Taback, Judy Caroline Boughey
Journal: Journal of Clinical Oncology (2012)

1107 Background: The role of axillary ultrasound (AUS) after neoadjuvant chemotherapy (NAC) to assess for residual nodal disease in patients presenting with node positive breast cancer remains unclear. ACOSOG Z1071 is a prospective multi-institutional trial evaluating sentinel node biopsy in patients with biopsy proven node positive breast cancer (T0-4, N1-2, M0) receiving NAC. Herein we report on the secondary objective evaluating the correlation of lymph node (LN) features on AUS with residual nodal disease. Methods: AUS images from diagnosis and after NAC were centrally reviewed for cortex size, LN size and LN morphology. Morphologic features were defined as: type I, no visible cortex, type II, &lt; 3 mm hypoechoic cortex, type III, &gt; 3mm hypoechoic cortex, type IV, generalized lobulated hypoechoic cortex, type V, focal hypoechoic cortical lobulation, and type VI, totally hypoechoic node with no hilum. Type I and II are considered normal. Results: Surgical and imaging data are available on 294 patients. Median age was 50 years (range 23-93 years), mean initial tumor size 3cm (0 to 15cm) and clinical stage II in 64.5% and III in 35.5%. The maximum LN diameter decreased after NAC (mean 22mm pre-NAC to 14mm post-NAC)(p&lt;0.0001); however, there was no significant difference after NAC between the pathologically N+ (13mm, range 5-46mm) and N0 cases (12mm, range 3-32mm)(p=0.13). LN cortical thickness correlated with residual nodal disease after NAC (p-value = 0.04). Using a cutoff point of cortical thickness of 3 mm, the sensitivity was 33% (48/145) and specificity 80% (66/82). AUS morphological features after NAC was associated with false negative rate 62%, false positive rate 28%, sensitivity 38%, and specificity 72%. Conclusions: AUS after NAC is useful to assess nodal response. Cortical thickness was the best predictor of residual nodal metastasis. LN size and morphological features do not reliably exclude residual nodal metastasis in patients after NAC. [Table: see text]
Tumor, skin, and plasma concentrations of protein kinase inhibitors (PKIs) in patients with advanced cancer.
Authors: Mariette Labots, Maarten Neerincx, Johannes C. Van der Mijn, Henk Dekker, Richard Honeywell, Maria Rovithi, Kristy Gotink, Margreet Voebel-De Jong, Donald L. Van der Peet, Martijn R. Meijerink, Gerrit A. Meijer, Connie R. Jiménez, Godefridus J Peters, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2013)

11087 Background: PKIs are selective for target receptors at low concentrations, but they act promiscuously at higher concentrations (PMID 18183025). This lack of selectivity may be relevant for their antitumor activity and for the development of PKI treatment selection tools. To obtain more insight in their clinical mechanism of action, we designed a pilot study to determine PKI tumor, skin and plasma concentrations in patients (pts) after 2 weeks of treatment. Results are related to cell line sensitivity data. Methods: Prior to standard palliative systemic treatment, pts were allocated to standard-dose PKI treatment (N=5 per PKI) for 10-14 days. Plasma, tumor and skin biopsies were collected within 24 hours of last dose. Sample PKI concentrations were determined by liquid chromatography – tandem mass spectrometry (LC-MS/MS); tissue concentrations in pg/mg were converted to molarity for comparison with preclinical sensitivity data (PMID 21980135). Concentrations of sunitinib (SUN), sorafenib (SOR), erlotinib (ERL), dasatinib (DAS) and everolimus (EVE) that inhibit 50% of cell proliferation (IC50) were determined by MTT assay in 1 RCC (786-O) and 8 CRC cell lines (HCT 116, HT-29, RKO, SW480, SW1398, DLD-1, COLO 205, CaCo-2). Results: Since August 2011 samples were obtained from 27 pts; 5 received SUN, 4 SOR, 4 ERL, 5 DAS and 5 EVE. After 12 ± 1 days of treatment, median tumor concentration (TC) was 9.0 µM (2.3-50.0) (range) for SUN, 8.5 µM (3.7-22.0) for SOR, 5.3 µM (0.9-10.8) for ERL and 2.1 µM (0.2-64.0) for DAS. EVE was measurable in 2 of 5 tumors: 3.5 µM (3.4-3.6). On average, PKI skin concentrations were 2.4-fold lower than TCs. SOR and ERL plasma concentrations (PCs) were in the range of TCs while SUN and DAS PCs were at least 14-fold lower than in tumors. Mean IC50 of the cell line panel was 1.3 µM (0.8-1.4) for SUN, 2.2 µM (1.4-3) for SOR, 8.2 µM (4-11.5) for ERL, 0.06 µM (0.02-1.8) for DAS and 1.2 µM (0.05-11) for EVE. Conclusions: PKI tumor concentrations may vary considerably from plasma concentrations, but are in the IC50 range of cancer cells in vitro. These results are indicative for the inhibitory concentrations of PKIs in patient tumors and should be considered for the development of individualized treatment strategies. Clinical trial information: NCT01636908.
A phase 1b/2 study of the combination of the IDO pathway inhibitor indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors: Safety analysis and preliminary efficacy of the phase 1b component.
Authors: Howard Colman, Frank Mott, Alexander I. Spira, Theodore S. Johnson, Yousef Zakharia, Nicholas N. Vahanian, Charles J. Link, Eugene Paul Kennedy, Ramses F. Sadek, David Munn, Olivier Rixe
Journal: Journal of Clinical Oncology (2015)

2070 Background: Indoleamine 2, 3-dioxygenase (IDO) is a key immune-modulatory enzyme within the IDO pathway that inhibits CD8+ T cells and enhances the suppressor activity of Tregs. IDO is expressed in a large proportion of solid tumors including 50 to 90% of glioblastomas (GBM). High IDO expression is correlated with poor prognosis in GBM. IDO pathway inhibitors such as indoximod (1-methyl-D-tryptophan / D-1MT) can improve anti-tumor T cell response slowing the tumor growth in vivo. We have demonstrated a synergistic effect of indoximod when combined with temozolomide (TMZ) and radiation in a syngeneic orthotopic brain tumor model. This phase 1b/2study is designed determine the safety profile and maximal tolerated dose (MTD) of indoximod in combination with TMZ in recurrent refractory malignant brain tumors with subsequent expansion into a phase 2 portion evaluating efficacy of the combination. Methods: After progression to standard front line-therapy with TMZ, patients were enrolled in a 3+3 dose escalation study of indoximod (600, 1000 or 1200 mg twice daily orally) with a standard dose of TMZ (150mg/m2 x 5 days). Indoximod was administered for all 28 days of each treatment cycle. Results: 12 patients were required to fully enroll all three dose cohorts with no DLTs requiring cohort expansion at lower doses. Median age was 48.5 years (27-62) with 5 female and 7 male. 83% had a diagnosis of GBM. 6 patients remain on study, the longest on cycle 12. Best responses in these previously TMZ-refractory patients to date include SD in 3 patients lasting between 5 and 10 months duration (ongoing) with one patient demonstrating a progressive, ongoing substantial reduction in tumor size, approaching RANO criteria for PR. No patients to date have experienced a reduction or delay in temozolomide dosing due to the addition of indoximod nor an indoximod related serious adverse event. Conclusions: The MTD for indoximod in this combination and setting was 1200mg twice daily. Expansion into the phase 2 portion is proceeding to evaluate the exciting preliminary observations made in this trial. Clinical trial information: NCT02052648.
Phase III design for a trial of single-dose fosaprepitant (FA) in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC).
Authors: Stephen Joseph Noga, Cindy Weinstein, Elber S Camacho, Saleem A Khanani, Elizabeth Beckford-Brathwaite, Waldimir Vallejos, Kelly McGowan, Grace Tamburri, Joanne Force, Arlene Taylor
Journal: Journal of Clinical Oncology (2014)

TPS9664 Background: CINV is a common side effect that may occur in acute (0-24 hours [h]) and delayed (25-120 h) post-chemotherapy phases. Aprepitant is a potent and selective oral NK1 receptor antagonist (RA) indicated for prevention of acute and delayed CINV associated with highly emetogenic chemotherapy (HEC) and MEC using a 3-day regimen combined with a 5HT3 RA and corticosteroid. FA, a water-soluble prodrug rapidly converted to aprepitant after intravenous (IV) administration, is approved as a single dose for HEC-related CINV. To further study FA with MEC, this study will evaluate the efficacy and safety of a single IV dose of 150mg FA given with a 5-HT3 RA and corticosteroid vs a 5-HT3 RA and corticosteroid alone in preventing MEC-associated CINV (NCT01594749). Methods: This is a global, phase III, randomized, double-blind, parallel-group study in 990 subjects ≥18 years of age naïve to HEC and MEC scheduled to receive an IV dose of MEC on treatment Day 1. Other moderate and low emetogenic chemotherapy agents may be added to the MEC through Day 3; there are no restrictions on the use of minimally emetogenic agents. Subjects are randomly assigned 1:1 to a control or treatment group. Control group consists of 8mg ondansetron and 20mg dexamethasone on Day 1, followed by 8mg ondansetron PO (by mouth) every 12 h on Days 2 and 3. The treatment group adds 150mg IV FA to the same dose of ondansetron PO and dose-adjusted dexamethasone (12mg PO) before the first dose of MEC on Day 1, followed by 8mg ondansetron PO 8 h after the first dose and no additional antiemetic beyond Day 1. Primary objectives will evaluate the proportion of subjects with a complete response (CR: no vomiting and no rescue medication use) during the delayed phase and FA safety/tolerability. Secondary objectives include CR in acute and overall (0-120 h post MEC) phases. Exploratory objectives further evaluate vomiting, nausea, rescue use, and impact on daily life. Treatment comparisons, stratified by gender, will include a formal test for superiority for the primary efficacy analysis. Primary and secondary efficacy analyses will be tested at a 2-sided significance level of 0.05. Clinical trial information: NCT01594749.
Parallel sequencing of a 50 genes panel in metastatic colorectal cancer (MCRC) patients (pts) treated with intensive first-line FIr-B/FOx triplet chemotherapy plus bevacizumab (BEV): Preliminary data and clinical outcome.
Authors: Gemma Bruera, Umberto Malapelle, Francesco Pepe, Pasquale Pisapia, Antonella Dal Mas, Giuseppe Calvisi, Giancarlo Troncone, Enrico Ricevuto
Journal: Journal of Clinical Oncology (2017)

644 Background: RAS/BRAF genotype guide MCRC treatment. First line triplet chemotherapy/BEV significantly improved PFS and OS. OS was significantly worse in KRAS c.35G &gt; A and BRAF mutant (mt). Most CRC (86%) harbored mt genes, prevalently TP53, RAS, BRAF, PIK3CA. Methods: MCRC samples of 67 pts treated with FIr-B/FOx (77% overall) were analyzed through a 50 genes panel (PGM/Colon Lung Cancer) by ION Torrent: 57 (85%) primary, 10 (15%) metastatic samples; 59 (88%) pre-, 8 (12%) post-treatment. Molecular diagnostic criteria: &gt; 50% coverage; &gt; 1% mutant allelic fraction. Clinical outcomes were evaluated and compared by log-rank. Results: All wild-type (wt) and mt MCRC were 6 (8.9%) and 61 (91.1%), respectively; median mt genes 3 (1-12). Mt genes, 35 (%): KRAS 44 (65.6%), TP53 38 (56.7%), APC 26 (38.8%), KIT 23 (34.3%), PDGFRA 19 (28.3%), PIK3CA 18 (26.8%), EGFR and NRAS 15 (22.3%), SMAD4 10 (14.9%), FBXW7 and MET 7 (10.4%), GNAS and PTEN 6 (8.9%), BRAF and NOTCH1 5 (7.4%), ATM, PTPN11 and SMARCB1 4 (5.9%), HRAS, KDR, JAK3 and VHL 3 (4.4%), ERBB2, FGFR2, FGFR3, IDH1 and STK11 2 (2.9%), ABL1, AKT1, CDKN2A, FGFR1, FLT3, HNF1A, RB1, RET 1 (1.4%). BRAF mutations: c.1756G &gt; A, 1796C &gt; T, 1405G &gt; A, 1406G &gt; C. Median follow-up 21 months (m), overall PFS 13, OS 27m: KRAS exon 2 ( KRAS 2 ) wt/mt, PFS 14/12m, OS 28/21m, respectively, not significantly different; c.35G &gt; A KRAS mt showed trendly worse OS 14m; BRAF mt significantly worse PFS (8 vs 14m, p .026) and OS (11 vs 28m, p .002); RAS 2-4 / BRAF 15 wt/mt, PFS 18/13m (p .954), OS 28/22m (p .956). TP53 wt/mt, PFS 14/12m, OS 28/23m. All wt, PFS 24, OS 44m, not significantly different vs ≥ 1 mt gene. Conclusions: Multigenic analysis of MCRC patients treated with FIr-B/FOx shows worse clinical outcome conferred by uncommon BRAF mutations.
PIGMENTED CONTACT DERMATITIS
Authors: P. E. OSMUNDSEN
Journal: British Journal of Dermatology (1970)

An intense and bizarre hyperpigmentation developed in 7 patients with contact allergy to the optical whitener Tinopal CH 3566. In 4 of the patients the pigmentation followed a contact dermatitis, but the other 3 patients had not observed any skin changes or itching prior to or during the development of the pigmentation. Biopsies showed damage to the cells of the basal layer (hydropic degeneration, localized or complete destruction) and incontinence of pigment.