tbuckley/cabot-search huggingface dataset:
Daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (CASTOR).
Authors: Suzanne Lentzsch, Katja C. Weisel, Maria-Victoria Mateos, Vania Hungria, Markus Munder, Ajay K. Nooka, Tomer Mark, Hang Quach, Emma Catherine Scott, Je-Jung Lee, Pieter Sonneveld, Tineke Casneuf, Christopher Chiu, Xiang Qin, Himal Amin, Piruntha Thiyagarajah, Jordan Mark Schecter, Ming Qi, Andrew Spencer
Journal: Journal of Clinical Oncology (2017)

8036 Background: Daratumumab (D), a human, CD38-targeting mAb, is well tolerated and induces deep and durable responses in patients (pts) with RRMM. We provide an update of CASTOR (NCT02136134), a multicenter, phase 3, randomized study of DVd vs Vd in RRMM. Methods: All pts received ≥1 prior line of therapy (LOT) and were administered 8 cycles (Q3W) of Vd (1.3 mg/m 2 SC bortezomib on days 1, 4, 8, and 11; 20 mg PO/IV dexamethasone on days 1-2, 4-5, 8-9, and 11-12) ± D (16 mg/kg IV once weekly in Cycles 1-3, every 3 weeks for Cycles 4-8, then every 4 weeks until progression). Bortezomib-refractory pts were ineligible. Minimal residual disease (MRD) was assessed upon suspected CR and at 6 and 12 months following the first dose at sensitivities of 10 –4 , 10 –5 , and 10 –6 using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 2 (1-10) prior LOTs. 66% were previously treated with bortezomib and 21% were refractory to lenalidomide in their last prior LOT. After a median follow-up of 13.0 months, PFS was significantly prolonged with DVd vs Vd (median: not reached vs 7.1 months; HR, 0.33; 95% CI, 0.26-0.43; P&lt; 0.0001). This PFS benefit was seen regardless of number of prior LOTs received, with greatest benefit observed in 1 prior line pts (median: not reached vs 7.9 months; HR, 0.22; 95% CI, 0.14-0.34; P&lt; 0.0001). ORR was also significantly higher for DVd vs Vd (84% vs 63%), along with ≥VGPR (62% vs 29%) and ≥CR (26% vs 10%; P&lt; 0.0001 for all). MRD-negative rates were ≥4-fold higher at all three sensitivity thresholds with DVd vs Vd (10% vs 2% at 10 –5 threshold). Pts who achieved MRD negativity demonstrated prolonged PFS compared with MRD-positive pts. 37 (15%) and 58 (24%) deaths were observed in DVd vs Vd, respectively, and follow up is ongoing. The most common grade 3/4 TEAE was thrombocytopenia (45% vs 33%). Updated efficacy and safety data will be presented. Conclusions: DVd provided significant benefits with respect to PFS, ORR, depth of response, and MRD-negative rate vs Vd. No new safety signals were reported. These data continue to support the use of DVd in RRMM pts and indicate that pts with 1 prior LOT will derive the most benefit. Clinical trial information: NCT02136134.
Surgeon influence on receipt of contralateral prophylactic mastectomy for breast cancer.
Authors: Steven J. Katz, Monica Morrow, Sarah T. Hawley, Reshma Jagsi
Journal: Journal of Clinical Oncology (2017)

e18145 Background: Rates of contralateral prophylactic mastectomy (CPM) have markedly increased but virtually nothing is known about the influence of surgeons on variability of the procedure in the community. We quantified the influence of attending surgeon on rates of CPM and clinician attitudes that explained it. Methods: Population-based sample of 7810 patients newly diagnosed with curable breast cancer (BC) in Georgia and Los Angeles County treated in 2013-15 were surveyed (response rate 70%, n = 5018) and responses were linked to 488 attending surgeons through patient report. Surveys were sent to surgeons towards the end of the patient data collection period and 377 completed them (response 77%). We linked 3718 respondent patients with unilateral disease to 365 respondent surgeons. Two surgeon attitudes scales were developed based on a scenario of a patient with early stage BC at average risk of a 2 nd primary cancer: 1) favors initial breast conservation and, 2) reluctance to perform CPM if patient asks. We did multilevel analyses using information from patient and surgeon reports merged to SEER data. Results: A model including patient clinical factors and surgeon id predicted CPM extremely well as it explained 37% of the variability in the likelihood of CPM. Patient factors explained 16% of the variability but the surgeon identifier alone explained even more (21%). The odds of a patient receiving CPM increased 3-fold (95% CI 1.9, 4.7) if she saw a surgeon with a practice approach one standard deviation above a surgeon with the average CPM rate (15%). One quarter (24%) of the surgeon influence was explained by attending attitudes about initial recommendations for surgery and responses to patient requests for CPM. The rate of CPM was 34% for surgeons who least favored initial breast conservation and were least reluctant to perform CPM. By contrast, the estimated rate was 5% for surgeons who most favored initial breast conservation and were most reluctant to perform CPM if asked. Conclusions: Attending surgeons exert strong influence on the likelihood of receipt of CPM for breast cancer. Variations in surgeon attitudes about recommendation for surgery and response to patients request for CPM explain a substantial amount of this influence.
Cancer stem cells related marker CD44 and Notch activation in metastatic colon cancer patients.
Authors: Francesca Negri, Cecilia Bozzetti, Cinzia Azzoni, Lorena Bottarelli, Costanza Lagrasta, Giuseppe Pedrazzi, Ione Tamagnini, Alessandra Bisagni, Anna Squadrilli, Gianluca Tomasello, Rosa Porzio, Francesco Leonardi, Roberto Sala, Andrea Ardizzoni, Federico Quaini
Journal: Journal of Clinical Oncology (2016)

e23007 Background: Notch pathway has been suggested to play an important role in regulating cancer stem cells (CSCs) in colon cancer. CSCs are responsible for colon cancer initiation, progression and may be involved in resistance to conventional therapies. Moreover, CSCs promote angiogenesis throughout several factors such as MDK, EGF, IL-8. CD44 is a transmembrane glycoprotein reported as a putative marker for isolating CSCs. Preclinical studies and a clinical study from our group (Negri et al, 2015) showed that strong Notch intracellular cleaved domain (NICD) is associated with resistance to anti-vascular endothelial growth factor (VEGF) therapy. Based on these reports, we assessed NICD and CD44 expression in a series of metastatic colon cancer patients treated with anti-VEGF monoclonal antibody bevacizumab within first-line clinical trials. Methods: NICD and CD44 expression were assessed by immunohistochemistry (IHC) on paraffin-embedded samples from 42 pretreatment primary tumors. Samples were stained by antibody against NICD (1:50, Cell Signaling Technology, MA, USA) and CD44 (1:50, Novocastra Laboratories, Newcastle upon Tyne, UK), processed using the streptavidin-biotin-peroxidase complex (Dako Corp.,CA, USA) and counterstained with hematoxylin eosin solution. Level of positivity on scale from 0 (negative) to 3 (strong positivity) was assessed for NICD and CD44 staining. Results: Table 1 shows a positive association between NICD and CD44 expression in colon cancer patients. Cases with strong NICD reactivity and high CD44 staining experienced a shorter progression-free (PFS) and overall survival (OS) as compared with cases with strong NICD and low CD44 expression (PFS: 4.7 vs 14.7 months, p = 0.029; OS: 14.5 vs 33.4 months, p = 0.073). Conclusions: Our hypothesis is that Notch activation could maintain tissue stem cells and that in this scenario the anti-VEGF therapy could be of reduced relevance. Correlation between CD44 and NICD expression in colon cancer patients. Low NICD (0/1+) (n=9) High NICD (2/3+) (n=33) Low CD44 (0/1+) (n=13) 7 6 High CD44 (2/3+) (n=29) 2 27 Fisher exact test p = 0.002
Feasibility study of trastuzumab (T) and pertuzumab (P) added to neoadjuvant chemoradiotherapy (nCRT) in resectable HER2+ esophageal adenocarcinoma (EAC) patients (pts): The TRAP study.
Authors: Sandor Schokker, Remco Jurriaan Molenaar, Sybren L. Meijer, Ron A.A. Mathot, Stephanie Van Der Woude, Sheila K. Krishnadath, Geert-Jan Creemers, Grard A. P. Nieuwenhuijzen, Maurice Van Der Sangen, Laurens Victor Beerepoot, Joos Heisterkamp, Maartje Los, Marije Slingerland, Annemieke Cats, Geke Hospers, Maarten F Bijlsma, Cornelis J. A. Punt, Mark I. van Berge Henegouwen, Maarten C.C.M. Hulshof, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2018)

4057 Background: Around 15% of EACs are HER2+ and treatment with T is effective in metastatic EAC. Given the success of dual neoadjuvant HER2 targeted therapy with P and T in breast cancer, we performed a phase 1B feasibility study of nCRT combined with P and T. Methods: HER2-positive pts (IHC 3+, or 2+ with ISH+) with resectable EAC received nCRT with carboplatin and paclitaxel (CROSS regimen), combined with 840 mg P q3w, and T in a loading dose of 4 mg/kg, followed by 2 mg/kg qw for 5 weeks (wks) and 6 mg/kg in wks 7, 10 and 13. Peak and trough serum samples were collected throughout treatment for pharmacokinetics (PK) and shed HER2 (sHER2). Cardiac safety was assessed with pre- and posttreatment MUGA scans. Primary endpoint was feasibility, defined as ≥80% completion of treatment with P and T, for which 40 pts had to be included. Results: We enrolled 40 pts (78% males, median age 63) of which 83% completed treatment with P and T. Reasons for non-completion were logistics (n = 3), pt request (n = 3) and death of pulmonary fibrosis during treatment (n = 1). Toxicity was similar to conventional nCRT except for rash (28%) and diarrhea grade 3 (20% of pts). Transient LVEF < 50% or decreases of ≥10% occurred in n = 4 (3 asymptomatic) without delay of surgery or cardiopulmonary complications. One pt had interval metastases preoperatively; 38 pts were operated. No unforeseen complications were reported. Thirteen pts (33%) had a pathological complete response (pCR, Mandard 1). Mandard 2, 3, 4 and 5 was seen in 8, 11, 3 and 3 pts, respectively. One year progression free survival (PFS) and overall survival (OS) were 85% and 90% (median follow up 19.4 months). PK of P was similar to prior reports in metastatic gastric cancer (all trough levels > 20 µg/ml). Median baseline sHER2 was 11.9 µg/ml; levels decreased in wk 4 (median 6.7 µg/ml) to return to baseline in wk 13 (median 10.9 µg/ml). Conclusions: Addition of P and T to nCRT in EAC pts is feasible and has limited additional toxicity. It shows a high pCR of 33% compared to 23% after conventional nCRT and a promising 1 year PFS and OS of 85% and 90% compared to 72% and 80% after conventional nCRT, respectively. Further biomarker research is ongoing. Clinical trial information: NCT02120911.
P01.131 Non-invasive detection ofIDH-wildtype genotype in gliomas using dynamic18F-FET-PET
Authors: B Suchorska, F Vettermann, M Unterrainer, D Nelwan, R Forbrig, M Dorostkar, F W Kreth, P Bartenstein, J C Tonn, N Albert
Journal: Neuro-Oncology (2018)

Gliomas with an isocitarate dehydrogenase (IDH) wildtype (wt) status have a dismal prognosis comparable to glioblastoma as reflected by the 2016 revision of the WHO classification of gliomas. In order to ensure timely adjustment of surgical and adjuvant treatment strategy, demand for non-invasive imaging methods is high. 18F-FET-PET has been shown to be an important diagnostic tool for glioma management, delivering information on prognosis and therapy response. Aim of this study was to evaluate dynamic 18F-FET-PET for non-invasive evaluation of IDH wt status prior to therapy. 341 patients with WHO II-IV glioma were included, in whom IDH mutation status, MRI and dynamic 18F-FET-PET scans were available at initial diagnosis prior to any further therapy. We assessed sensitivity, specificity, accuracy and positive as well as negative predictive values for maximal tumour-to-background ratio (TBRmax) and minimal time-to-peak (TTPmin) for prediction of IDH wt status in the entire group as well as in the subgroup of non-contrast enhancing (non-CE) tumors. Molecular analyses revealed 178 IDH mutant and 163 IDH wt tumors; 270 patients were classified as FET-positive, in these cases, TTP analysis was performed. Median TBRmax in IDH wt gliomas was 3.1 compared to 2.8 in IDH mutant tumors (p=<0.01). ROC-analyses revealed no reliable cut-off using TBRmax, due to high overlap of the two groups. In contrast, searching for a threshold in dynamic analysis, TTPmin ≤ 12.5 minutes identified IDH wt gliomas with a high positive predictive value (accuracy: 79%, PPV: 87%; NPV: 72%). In the subgroup of non-CE glioma in MRI (n=161), IDH wt genotype was identified with an accuracy of 84% (PPV 83%, NPV: 84 %). Dynamic 18F-FET PET using TTPmin analysis provides a reliable non-invasive method for detection of IDH wt genotype especially in tumors without CE on MRI and can help to identify high-risk patients prior to treatment initiation.
Comparison of adverse event costs of nivolumab combined with ipilimumab versus sunitinib for previously untreated metastatic renal cell carcinoma.
Authors: Keith Betts, Shuo Yang, Ella X. Du, Jennifer Johansen, Sumati Rao
Journal: Journal of Clinical Oncology (2018)

e16561 Background: In the phase 3, open-label, randomized CheckMate 214 trial, nivolumab (N) combined with ipilimumab (I) (N 3 mg/kg + I 1 mg/kg every 3 weeks for 4 doses followed by N 3 mg/kg every 2 weeks) significantly improved overall survival and objective response compared with sunitinib (50 mg once daily for 4 weeks followed by 2 weeks off) for untreated advanced or metastatic renal cell carcinoma (aRCC) patients with intermediate/poor-risk per International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) definition. This analysis estimated the adverse event (AE) costs among intermediate/poor-risk aRCC patients in CheckMate 214. Methods: Frequencies of treatment-related grade 3-4 AEs were based on patient-level data from CheckMate 214, including 839 treated intermediate/poor-risk patients (N+I: 423; S: 416). Unit AE costs were obtained from the US 2014 Healthcare Cost and Utilization Project database. Per-patient treatment-related grade 3-4 AE costs during the first year and at the time of the last database lock (median follow-up time = 25.2 months) were calculated and inflated to 2017 US dollars. The all-cause grade 3-4 AE costs were estimated in a sensitivity analysis. Results: The 3 most frequent treatment-related grade 3-4 non-lab AEs were fatigue (3.8%), diarrhea (3.5%), and hyponatremia (3.5%) in the N+I arm; and hypertension (14.4%), fatigue (8.2%), and palmar-plantar erythrodysesthesia syndrome (7.7%) in the S arm. Patients in the N+I arm had lower treatment-related grade 3-4 AE frequency (1-year: 400 vs. 602 AEs; trial period: 447 vs. 695 AEs) and per-patient costs (1-year: $7,654 vs. $13,389; trial period: $8,520 vs. $15,484) compared to S. In the sensitivity analysis, the N+I arm was also associated with lower per-patient costs for all-cause grade 3-4 AEs (1-year: $14,923 vs. $20,422; trial period: $17,528 vs. $23,650), compared to the S arm. Conclusions: In CheckMate 214, aRCC patients with IMDC intermediate/poor risk in the N+I arm had lower average grade 3-4 AE costs compared to those treated with S within the first year and during the evaluated trial period.
The potential of gemcitabine, cisplatin, and bevacizumab combination therapy for patients with ovarian clear cell carcinoma.
Authors: Kimihiko Ito, Mio Nakagawa, Lena Tashima, Taro Yagi, Chihiro Odani, Hitomi Ono, Rieko Okubo, Kanoko Shimoji, Mayako Goto, Tomohiko Tsuruta, Kensuke Hori
Journal: Journal of Clinical Oncology (2017)

e17065 Background: Patients with advanced ovarian clear cell carcinoma (OCC) have poor prognosis, and response rate of chemotherapy for relapsed OCC is less than 10%. The effective standard treatment has not been established yet. The synergic effect between gemcitabine and cisplatin in ovarian cancer patients has been reported. And bevacizumab added on chemotherapy has some evidences of progression-free survival improvement at primary, platinum sensitive relapse and platinum resistant relapse situation than chemotherapy only. Therefore, we conducted a retrospective charts review to examine the safety and efficacy of gemcitabine, cisplatin, and bevacizumab combination (GPB) therapy in OCC patients treated in our hospital. Methods: Intravenous gemcitabine (1,000 mg/m 2 , day 1, 15), cisplatin (40 mg/m 2 , day 1, 15), and bevacizumab (15 mg/kg, day 1) were administrated every 28 days. This combination therapy was continued until disease progression or appearance of intolerable toxicity. This retrospective study was approved by our institutional ethics board. Results: Eight patients were treated with this GPB therapy in our institution between April 2013 and August 2015. Six patients received this therapy due to presence of relapse, and 2 patients were administered GPB as post-operative adjuvant therapy. Four patients were not treated with bevacizumab due to their medical conditions. The median treatment cycle was 5.5 (range: 1-15). Six patients were evaluable and their responses were partial response (PR) 1, stable disease (SD) 2, and progressive disease (PD) 3. The overall response rate was 13% and the disease control rate was 50%. Four patients needed dose reduction or treatment delay. Grade 3 adverse events observed were anemia (25%), nausea (13%), and elevation of G-GTP (13%). Conclusions: GPB therapy is feasible and moderately effective for patients with OCC. We are currently conducting the prospective multi-institutional phase II trial (UMIN 000023097) and expect that GPB therapy will be used as the standard treatment regimen for OCC, in future.
Conversion of nontumorigenic dormant MOLT3 by lactate into a glycolytic cancer via epigenetic changes and lymphangiognesis.
Authors: John Haaga, Hilary Coller, Hung-Ying Kao, Richard T. Lee
Journal: Journal of Clinical Oncology (2017)

e23176 Background: Lactate considered a "waste product" lactate is a multifunctional modulator. Processes modulated by lactate are: 1. initiation of the transformation of the microenvironment 2.production of hyaluronan which interacts with RHAMM to cause cell motility, stabilize mitotic spindle, and supports stem cells. With these many processes, we hypothesized that lactate might interrupt the dormant state of the MOLT3 dormant cell line. Previous authors Indraccola et al, PNAS, 2006 reported that the dormant MOLT3 cell line implanted in SCID mice could be interrupted to become tumorigenic by co-implantation with VEGF,FGF, or irradiated (dead) Kaposi Sarcoma. We used this model to determine if lactate could stimulate tumorigenesis in a similar manner. Methods: In multiple cohorts of SCID mice, lactate was coimplanted with MOLT3 cells. In approximately 40 days, tumors grew rapidly in an exponential manner. Arterial perfusion was measured by contrast enhanced dual energy CT and MRI perfusion. Immunohistochemistry was performed for vascular stains CD21,VEGFR3, Notch 1, Ephrin B, VEGFA,VEGFD, Macrophages, VEGFD. Rna sequencing was performed on six samples, 3 Molt3 cell plugs, 3 MOLT3/lactate tumors (sequencing done at UCLA, data processed at Broad Street Institute MIT). Results: The data confirmed lactates's modulator role. Perfusion studies showed no arterial flow. The IHC showed many cancer cell with many mitotic figures and apoptosis.IHC confirmed presence of numerous macrophages, increased VEGFD, lymphatics and no arteries. Indraccola's reported their tumors showed no mitotic figures. 1114 genes were up/down regulated. In general rna showed: 1.mitochondrial dysfunction 2.Down regulated tumor suppressors 3) Up regulated oncogenes 4)Increased Stem cell markers 5) increased NFK-b and other pathways. Conclusions: Lactate induced an avascular "cancer" with features similar to natural pancreatic ductal and triple negative breast cancer. Results question the universality of the angiogenic switch. We hypothesize Lactate from marophages may be the cause of inflammation induced cancer.
Some local immunity factors in basal cell skin cancer.
Authors: Victoria V. Pozdnyakova, Oleg Ivanovich Kit, Yury Valentinovich Przhedetskiy, Elena Yurievna Zlatnik, Inna Arnoldovna Novikova, Ekaterina Komarova, Ekaterina Sharay, Galina I. Zakora, Olesya N. Selyutina, Elena Bondarenko, Ekaterina I. Matveeva, Oksana G. Shulgina
Journal: Journal of Clinical Oncology (2016)

e21078 Background: The purpose of the study was to analyze some factors of local cellular immunity in microenvironment of basal cell carcinoma (BCC) with different T stages and patients characteristics. Methods: 43 patients (24 women and 19 men aged 21-86 years) with primary (29) and recurrent (14) BCC T2N0M0-T4N0M0 received tumor resection. Tumor fragments were homogenized; levels of cytokines IL-1ß, IL-6, IL-8 and TNF-α, as well as populations and subpopulations of lymphocytes were determined by ELISA using flow cytometer FACSCantoII (BD) with a panel of antibodies T-, B-, NK (CD45+, CD3, CD4, CD8, CD19, CD16/56). Intact tissue obtained during plastic surgery was used as the control. Results: Contents of proinflammatory cytokines in BCC tissue exceeded their levels in intact tissue statistically significantly for IL-1ß (50.0±6.5 vs. 17.2±7.5 pg/g of protein) and IL-8 (48.8±8.5 vs. 15.7±6.3 pg/g of protein). Levels of NK-cells in tumors were lower (2.1±0.6 vs. 8.85±2.7%) and levels of B-lymphocytes – higher (5.1±1.5 vs. 0.8±0.4% respectively); p < 0.05 in all cases. Levels of IL-1ß, IL-8 and NK-cells in tumors of patients under 50 years of age exceeded the values in older patients. Solid tumors showed a higher content of CD3+CD4+ lymphocytes and IL-1ß compared to infiltrative and superficial tumors; TNF-α level in recurrent tumors was lower than in infiltrative ones (1.44±0.3 vs. 2.9±0.7 pg/g of protein respectively, p < 0.05) but higher than in intact tissue. Т4N0М0 tumors had minimal tissue level of TNF-α in comparison with T1-T3 tumors. Conclusions: BCC microenvironment showed a number of immunological characteristics different in various stages and types of tumor and age of patients; a common characteristic for all tumors was their high content of IL-1ß and IL-8 cytokines potentially contributing to their growth.
Association of loss of nuclear BAP1 expression with prognosis in oral mucosal melanoma.
Authors: Wei Guo
Journal: Journal of Clinical Oncology (2017)

e21021 Background: The prognostic factors of oral mucosal melanoma (OMM),a rare and aggressive neoplasm, remain to be determined. BAP1 is a tumor suppressor that has been associated with the outcome of melanomas and other malignancies. In this study, we investigated the genetic alterations in BAP1 and the prognostic potential of BAP1 protein expression in oral mucosal melanoma. Methods: DNA sequence analysis of BAP1 from 12 OMM patient samples revealed missense mutations in the tissues from four patients. Results: Based on immunohistochemical staining, loss of nuclear BAP1 expression was associated with poor overall survival (P &lt; 0.001, Log-rank = 21.308) and distant metastasis (P = 0.034, OR = 0.320). Multivariate analysis showed BAP1 to be an independent prognostic factor (P = 0.027, HR = 0.479). Conclusions: It thus appears that loss of nuclear BAP1 expression is an independent prognostic factor of poor overall survival and associated with distant metastasis in OMM.