tbuckley/cabot-search huggingface dataset:
The messenger matters: Relative influence of oncologists versus other care team members on advanced cancer patients' illness understanding.
Authors: Simon Mentis Cohen, Renee Maciejewski, Judith Eve Nelson, Manish A. Shah, Kelly Marie Trevino, Megan Johnson Shen, David Kwak, Ronald D Adelman, Deborah Schrag, Paul K Maciejewski, Holly Gwen Prigerson
Journal: Journal of Clinical Oncology (2016)

6545 Background: In 2016 Medicare began reimbursing clinicians for engaging in all end-of-life discussions. Communicating with patients about the status and progression of their disease is a vital component of end-of-life discussions, but research has yet to determine the importance of whom on the care team conveys this information to advanced cancer patients. This study examines whether advanced cancer patients' illness understanding varies as a function of whether they discussed their re-staging scan results with an oncologist versus another care team member. Methods: Data were derived from a multi-institutional, longitudinal cohort study of patients recruited between 2010 and 2015. Patients (n = 126) with metastatic solid tumor cancers that had progressed on prior chemotherapy regimens were interviewed before and after the first clinic meeting in which their re-staging scan results were discussed. Patients reported whether they discussed their re-staging scan results with an oncologist or another care team member (i.e., an oncology fellow or nurse practitioner). Patients who discussed their results with multiple providers were excluded. Patients also reported whether or not they thought that their cancer was late- or end-stage before and after the re-staging scan meeting. Multiple logistic regression analysis was used to estimate the effect of discussing re-staging scan results with an oncologist versus another care team member on patients' post-scan illness understanding, adjusting for scan results communicated, pre-scan illness understanding, and clinic site. Results: In adjusted analyses, patients who discussed their re-staging scan results with an oncologist versus another care team member were approximately four times more likely (AOR = 4.25; 95% CI = 1.13, 14.12; P = 0.02) to recognize that their disease was at a late- or end-stage. Conclusions: Advanced cancer patients who discuss their re-staging scan results with an oncologist are more likely to acknowledge that they are at a late- or end-stage of their disease than those who discuss their re-staging scan results with another care team member.
Abstract A023: Regulation of ERG function in prostate cells by phosphorylation and interaction with Ewing’s sarcoma breakpoint protein EWS
Authors: Vivekananda Kedage, Taylor R. Nicholas, Brady G. Strittmatter, Nagarathinam Selvaraj, Justin A. Budka, Travis J. Jerde, Peter C. Hollenhorst
Journal: Cancer Research (2018)

Abstract More than one-half of prostate tumors have a chromosomal rearrangement that results in the overexpression of an oncogenic ETS family transcription factor. The most common fusion, TMPRSS2/ERG, results in expression of ERG, a protein that is not normally expressed in prostate epithelia. When ERG is expressed in prostate cells it is thought to bind to enhancer elements and regulate gene expression by recruiting transcriptional coactivators and/or corepressors. We have recently shown that the EWS protein acts as a coactivator for ERG in prostate cells and this interaction is required for ERG-mediated xenograft tumor growth. Interestingly, the EWS interaction may be the key requirement that separates oncogenic from nononcogenic ETS factors, as EWS only interacts with four ETS family members involved in prostate cancer gene rearrangements (ERG, ETV1, ETV4, and ETV5), but not with other ETS family members. This ETS/EWS interaction also indicates a common molecular mechanism involved in prostate cancer and Ewing’s sarcoma, a cancer caused by gene fusions that express chimeric EWS/ETS proteins. ERG also interacts with corepressors such as EZH2, a subunit of PRC2. We have recently found that the interaction between ERG and EZH2/PRC2 is regulated by a series of phosphorylation events on ERG. The MAP kinase ERK can bind a high-affinity docking sequence in ERG, resulting in phosphorylation of a nearby serine, S215. This phosphorylation event leads to a conformational change in ERG that allows ERK to phosphorylate a second serine, S96. S96 phosphorylation then disrupts the interaction between ERG and EZH2/PRC2, allowing ERG to activate gene expression. Together, the interaction of ERG with EWS and the regulation of ERG function by ERK-mediated phosphorylation, represent molecular mechanisms that could serve as targets for therapeutic intervention in ERG-positive prostate cancer. Citation Format: Vivekananda Kedage, Taylor R. Nicholas, Brady G. Strittmatter, Nagarathinam Selvaraj, Justin A. Budka, Travis J. Jerde, Peter C. Hollenhorst. Regulation of ERG function in prostate cells by phosphorylation and interaction with Ewing’s sarcoma breakpoint protein EWS [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A023.
TCT-103 Ultraseal Left Atrial Appendage Occluder: Initial Multicenter Experience
Authors: Lluis Asmarats, Jean-Bernard Masson, Paolo Pagnotta, None stephane cook, Mike Foresti, Reda Ibrahim, Adam Sukiennik, Robert Sabiniewicz, Ignacio Cruz-Gonzalez, Carmelo Grasso, Gaetano Senatore, Giuseppe Tarantini, Adolphe Kasongo Mukombola, Mauro Chiarito, Nathan Messas, Jose Carlos Moreno Samos, Gilles O'Hara, Josep Rodés-Cabau
Journal: Journal of the American College of Cardiology (2018)
A phase I study of AL101, a pan-NOTCH inhibitor, in patients (pts) with locally advanced or metastatic solid tumors.
Authors: Anthony B. El-Khoueiry, Jayesh Desai, Swaminathan Padmanabhan Iyer, Shirish M. Gadgeel, Suresh S. Ramalingam, Leora Horn, Patricia LoRusso, Gaurav Bajaj, Georgia Kollia, Zhenhao Qi, Shashwati Basak, Bruce S. Fischer, Matti Davis, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2018)

2515 Background: Notch signaling can be deregulated in human cancer. AL101 (formerly BMS-906024), a gamma secretase inhibitor that potently inhibits all Notch receptors, was evaluated. The primary objective was safety and tolerability of multiple IV doses of AL101 and to establish a RP2D. Methods: Pts with advanced tumors refractory to standard therapies were included. Primary and secondary endpoints included safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Cohorts were administered escalating doses of AL101 IV weekly (QW) or q 2 weeks (Q2W) using a 3+3 design, with expansion at the MTD in TNBC, NSCLC, and selected other tumors with reported Notch activation. The DLT period was 4 weeks (4 doses QW or 2 doses Q2W). PD markers of Notch activity, including HES1 mRNA, were evaluated in serial whole blood. Results: As of 1Feb2018, preliminary data are available on 94 pts dosed at 0.3 mg to 8.4 mg QW, and 4 mg to 6 mg Q2W. The MTD for QW was 4 mg with 0 DLTs in 7 evaluable pts; DLTs occurred at 8.4 mg QW (Gr 3 infusion reaction, Gr 3 vomiting, Gr 5 liver failure) and 6 mg in de-escalation (Gr 3 vomiting/lipase elevation, Gr 3 diarrhea [n = 3]). The MTD for Q2W was 6 mg, with 1 DLT in 6 evaluable pts (Gr 3 diarrhea). In escalation/expansion at the QW MTD (n = 43), Gr 3 or higher related AEs were: hypophosphatemia (42%), diarrhea (16%), hypokalemia (7%), and anaphylaxis, anemia, AST increase, nausea, pruritus, and vomiting (2% each). There were dose related increases in exposures over 0.3 to 8.4 mg, and the mean plasma half-life following 4 doses QW was 67 - 148 hours, supporting QW dosing. Dose related reduction of HES1 mRNA was seen with > 80% peak inhibition and > 50% inhibition sustained over several days at QW doses of 4 mg and higher. Objective responses were seen in 4 pts (RECIST v1.1): gastroesophageal junction adenocarcinoma (n = 1, 1 cCR ongoing > 1 y), desmoid tumor (n = 3, 2 cPR, ongoing > 1 y, > 3 y), adenoid cystic carcinoma (n = 2, 1 cPR with PD at 8 m). SD was best response in 9 pts (9.6%). Conclusions: AL101 at the RP2D was generally well-tolerated and demonstrated sustained Notch inhibition as well as clinical activity across different tumor types. Future trials will evaluate AL101 in tumors with Notch activating mutations. Clinical trial information: NCT01292655.
The GATTO study: A phase I of the anti-MUC1 Gatipotuzumab (GAT) in combination with the anti-EGFR Tomuzotuximab (TO) in patients with EGFR positive solid tumors.
Authors: Sebastian Ochsenreither, Ulrich Keilholz, Konrad Friedrich Klinghammer, Christina Dicke, Maxim Kebenko, Elena Garralda, Josep Tabernero, Ignacio Matos, Domenica Lorusso, Francesco Raspagliesi, Luca Gianni, Gianluca Del Conte, Beate Habel, Hans Baumeister, Riccardo Belli, Alfredo Zurlo, Walter M. Fiedler
Journal: Journal of Clinical Oncology (2018)

TPS2596 Background: TO (CetuGEX) is a second-generation anti-EGFR antibody that specifically binds to EGFR and acts as a competitive antagonist at the ligand binding site. GAT (PankoMab-GEX) is a novel humanized monoclonal antibody, which recognizes the tumor-specific epitope of mucin-1 (TA-MUC1) expressed on tumor cells. Both antibodies are glyco-engineered to potentiate antibody-dependent cellular cytotoxicity (ADCC). Compelling preclinical evidence suggests a complex interaction between EGFR and cell surface expressed TA-MUC1 in driving cancerogenesis processes as well as shows a synergistic ADCC activity with the dual targeting of these molecules. Based on this evidence, this study aims to assess the tolerability, safety and preliminary activity of a combination with anti-EGFR and anti-TA-MUC1 glyco-engineered antibodies. Methods: The GATTO is an open label phase Ib dose evaluation study in patients with EGFR positive metastatic solid tumors, for whom no standard treatment is available. The proposed doses and schedule are 1400 mg Q2W for GAT and 1200 mg Q2W for TO. A staggered approach will be utilized in order to minimize the number of patients exposed and to evaluate the safety of the combination treatment. The first 6 patients will be enrolled into a safety run-in phase where the number of dose-limiting toxicities (DLTs) will be evaluated. Assuming that the safety criteria are met (ie. observation of 0 or 1 DLT), the dose will remain unchanged and further patients will be recruited at this dose level. If this is not the case, a step-wise dose reduction approach will be applied. The antitumor activity of the combined treatment will be evaluated as secondary endpoints including best overall response rate (ORR), duration of objective response, progression-free (PFS) and overall (OS) survival. Extensive pharmacokinetics (PK) and pharmacodynamics (PD) (cellular immune status, serum and tissue biomarkers) will be also analyzed. As of January 2018, the study is ongoing and 2 patients have been treated. (ClinicalTrials.gov Identifier: NCT03360734). Clinical trial information: NCT03360734.
Efficacy of hyperthermic intraperitoneal chemotherapy and cytoreductive surgery in treatment of recurrent uterine sarcoma.
Authors: Sarah Lynam, Teresa Diaz-Montes, Amy Harper, Michelle Sittig, Ryan MacDonald, Vadim Gushchin, Armando Sardi
Journal: Journal of Clinical Oncology (2016)

e17122 Background: Uterine sarcomas including leiomyosarcoma are among the most aggressive forms of gynecologic malignancy with characteristically poor response to systemic chemotherapy. This study evaluates whether the use of hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) confers survival benefit in comparison to CRS in patients with recurrent disease. Methods: A retrospective analysis of patients with recurrent uterine sarcoma at a single institution over a fifteen-year study period was performed. All women with a pathologic diagnosis of high-grade uterine sarcoma or leiomyosarcoma were identified. Follow-up evaluation for disease recurrence or progression was performed via physical examination and computed tomography or magnetic resonance imaging of the chest, abdomen and pelvis. Only patients with recurrent disease were included. Results: A total of 29 patients were identified. Eight patients received CRS/HIPEC for recurrent disease while 21 received secondary CRS and/or systemic chemotherapy. There was no treatment-related mortality in the CRS/HIPEC group, and five patients (63%) had National Cancer Institute grade III-IV complications. Actuarial overall survival at one year was 100% for CRS/HIPEC group vs. 79% for conventional treatment group, and 88% vs. 57% at 5 years, respectively (p = 0.244). Median disease-free survival was 19.9 months for patients treated with HIPEC vs. 12.4 months for standard treatment group (p = 0.48). Overall survival after diagnosis was 61.7 months for patients treated with CRS/HIPEC vs. 29.1 months, suggesting survival benefit with this intervention (p = 0.41). Conclusions: Our study is the first to compare survival outcomes in CRS/HIPEC vs. conventional therapies for recurrent uterine sarcoma and is suggestive of treatment benefit. Further studies with more patients and longer follow-up to evaluate the role of HIPEC in management of this disease are warranted.
NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development
Authors: Vedrana Jelenčić, Marko Šestan, Inga Kavazović, Maja Lenartić, Sonja Marinović, Tim D. Holmes, Michaela Prchal-Murphy, Berislav Lisnić, Veronika Sexl, Yenan T. Bryceson, Felix M. Wensveen, Bojan Polić
Journal: Nature Immunology (2018)
Single institution experience of allogeneic stem cell transplantation for Hodgkin lymphoma.
Authors: Mauricio Pineda-Roman, Solmaz F. Afshar, Zachary Galitzeck, Amir Steinberg
Journal: Journal of Clinical Oncology (2017)

7529 Background: Hodgkin lymphoma (HL) is curable in the majority of cases without stem cell transplantation (SCT). However, patients(pts) who relapse after chemotherapy require autologousSCT, and about half of those pts relapse. For over 3 decades, allogeneic SCT has been implemented in more refractory HL pts. We present the long term follow up of a group of pts from a our institution who underwent alloSCT for HL. Methods: 21 pts with HL transplanted from 2008 to 2015 and disease characteristics (HL type, status at SCT, chemosensitivity), treatment( graft source, donor type, auto and allo SCTdates, GVHD prophylaxis ) and outcomes (maximum grade of acute and chronic GVHD, survival (OS) and causes of death) were analyzed. Results: 13 males and 8 females received an alloSCT from 2008 to 2015, 11 pts had Nodular sclerosis HL, 6 NOS, 2 mixed cellularity, 1 lymphocyte predominant and 1 lymphocyte depleted. Performance status was 60 to 100, median of 90. 16 grafts were unrelated and 5 HLA identical. 18 pts received PBSC, 2 bone marrow and one double cord transplant. Most pts, 19, had a prior autoSCT, one had 2 prior autoSCT and for one , the allo was the first SCT. One patient was transplanted in unconfirmed first CR, 2 in confirmed CR, 4 in PR without prior CR, 3 in 1 st relapse, 5 in 2 nd relapse, 5 in 3 rd relapse, and one in primary induction failure. All patients had a reduce intensity conditioning: 14 Flu/Mel, 4 Flu/Mel ATG, and one each Flu/TBI/ATG, Flu/TBI, Flu/Cy. Acute GVHD happened in 11 pts: max grade I in 1 , II in 7, III in 1 and IV in 2. 6 pts had extensive chronic GVHD. 12 pts (57.1%) have died (survival range 0.65-43.45 months, mean 13.1, median 6.12). Causes of death were primary disease in 4, infection in 3 pts, GVHD and infection in 2, ARDS, organ failure, pulmonary toxicity in 1 each. 9 pts (42.8%) are alive (survival range 1.63-8.44 years, mean 4.97, median 4.47) Conclusions: AlloSCT for pts with relapsed HL is a feasible treatment modality that can lead to long term OS in a significant proportion of pts. Our data is comparable with other published studies for HL alloSCT. The utility of alloSCT should not be dismissed even in the age of Brentuximab and checkpoint inhibitors.
A double-blind, randomized pilot study of NS-21 in the prevention of radiation dermatitis for patients with head and neck cancer.
Authors: Chen-Hsi Hsieh, Hsiu-Ling Chou, Pei-Wei Shueng, Chen-Xiong Hsu, Deng-Yu Kuo, Li-Jen Liao, Wu-Chia Lo, Li-Ying Wang, Chi-Huang Hsiao
Journal: Journal of Clinical Oncology (2018)

6065 Background: The purpose of this single-institution pilot study was to evaluate the feasibility and safety of NS-21, a natural cortisone-free ingredient, on skin-related toxicity in patients with head and neck cancer (HNC) undergoing concurrent chemoradiation (CCRT) or radiotherapy (RT). Methods: Between July 2015 and November 2017, 29 HNC patients underwent RT or CCRT were double-blind, randomly allocated to application of either NS-21 (14 patients) or placebo (aloe vera gel, 15 patients) to the irradiated fields in neck three times per day from the first day of RT to the 2 weeks after RT is completed or to the development of severe skin toxicity. The skin moisture and dermatitis in the left and right irradiated-area of neck were recorded separately. The area in the level I-II-III-Va was named as upper neck and the area in the level IV was named as lower neck. The RT dose to the low- and intermediate-risk area was 46 Gy and 60 Gy, respectively. The maximum grade of radiation used the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The relative humidity of skin was monitored by digital hygrometer. Results: The number of neck fields received radiation dose larger than 46 Gy (Neck> 46Gy) was 80 and 82 in the study and placebo group, respectively. The occurrence of acute grade 3 or higher dermatitis in Neck> 46Gy was significantly lower in the NS-21 group than in the placebo group (5.0% vs. 20.3%; p = 0.024). The median time of grade 3 or higher dermatitis occurred was 6 and 7 weeks for the control and NS-21 group, respectively (p < 0.001). From beginning of RT to 2 weeks after the completion of RT, Neck> 46Gy (p < 0.001) and applying NS-21 (p = 0.014) were independent factors for the incidence of grade 3 dermatitis. There was a trend of skin moisture protection by using NS-21 in HNC patients under RT or CCRT (p = 0.052). Moreover, Neck> 46Gy (p < 0.001) and dermatitis grading (p = 0.006) were independent factors associated with the skin moisture. Conclusions: For HNC patients, applying NS-21 from the first day of RT or CCRT and through the treatment course that can decrease the incidence of acute grade 3 or higher dermatitis in the neck effectively and protect the skin moisture in the neck potentially. Clinical trial information: FEMH 104048F.
High RDW as a predictive and prognostic factor in patients with diffuse large B-cell lymphoma treated with chemoimmunotherapy.
Authors: Sally Paredes, Brady Ernesto Beltran, Eduardo M. Sotomayor, Jorge J. Castillo, Renzo Salas
Journal: Journal of Clinical Oncology (2018)

e19547 Background: Red blood cell distribution width (RDW) has emerged as a potential prognostic factor in diffuse large B-cell lymphoma (DLBCL) and a reliable and easy-to-use predictive tool. Methods: We performed a retrospective study on consecutive patients with a de novo diagnosis of DLBCL treated at our institution between 2010 and 2012. All patients included were treated with chemotherapy or chemoinmunotherapy with a curative intent. RDW > 14.6% was our cut-off. We fitted logistic regression models and Cox proportional-hazard regression models. Results: 121 patients with de novo DLBCL were included. Eighty patients (66%) had age ≥60 years, 54 patients (45%) were men, 41 patients (34%) had ECOG ≥2, 70 patients (58%) had increased LDH levels, 69 patients (57%) had > 1 extranodal site, 49 patients (41%) had stage III/IV disease, and 72 patients (60%) had B symptoms. Patients with high RDW (45 patients, 39%) were more likely to have ECOG ≥2 (53% vs. 21%; p < 0.001), elevated LDH levels (77% vs. 46%, p = 0.001), stage III/IV (53% vs. 34%; p = 0.04) and presence of B symptoms (54% vs. 18%; p < 0.001). Patients with high RDW also had higher IPI score (59% vs. 24%; p < 0.001) and also higher NCCN-IPI scores (53% vs. 21%, p < 0.001). They were less likely to achieve CR to therapy (48% vs. 83%; p < 0.001). In the multivariate logistic regression analyses, high RDW was a strong predictor of not achieving CR (OR 0.25, 95% CI 0.10-0.66; p = 0.005). With a median follow-up time of 5.6 years, the 5-year OS rate for patients with high RDW was 51% (95% CI 36-65%) versus 79% (95% CI 68-87%) in patients with normal RDW (p = 0.001). In the univariate Cox regression analysis, high RDW was associated with HR 2.63 (95% CI 1.41-4.89; p = 0.002). In the multivariate Cox regression analyses, high RDW was a stronger predictor of poor survival (HR 1.92, 95% CI 0.99-3.73; p = 0.05) than the IPI score (HR 1.34, 95% CI 0.58-3.11; p = 0.49) and the NCCN-IPI score (HR 2.21, 95% CI 0.87-5.59; p = 0.09). Conclusions: High RDW appears to be an adverse predictor of response and survival in patients with de novo DLBCL treated with R-CHOP, independent of the IPI and NCCN-IPI scores.
Low vs high dose carfilzomib (Cfz) with dexamethasone (Dex) for relapsed/refractory multiple myeloma (RRMM): Results of SWOG S1304.
Authors: Sikander Ailawadhi, Rachael Sexton, Suzanne Lentzsch, Muneer Hyder Abidi, Peter Michael Voorhees, Adam D. Cohen, Eric Rohren, Stephen Heitner, Kevin Kelly, Niklas J. Mackler, David M. Baer, Antje Hoering, Brian G. Durie, Robert Z. Orlowski
Journal: Journal of Clinical Oncology (2018)

8015 Background: Cfz has > 1 FDA approved doses in RRMM. Dose-response correlation is assumed without prospective data to compare efficacy of low-dose (27 mg/m2; LDC) vs high-dose Cfz (56 mg/m2; HDC). Methods: S1304 (NCT01903811), a randomized phase 2 trial compared LDC + dex vs HDC + dex, in Cfz nave RRMM pts with ²6 prior lines of treatment (Tt). Cycle 1 was 20 mg/m2 with total planned Tt 1 year on each arm. Those progressing on LDC could cross to HDC. Results: 143 pts were enrolled, with 121 eligible + evaluable (LDC: 64, HDC: 57). Median follow up was 32 months (mo). There were no significant differences in pt characteristics or ORR between study arms (Table). Median PFS on HDC was 8 mo vs 6 mo on LDC (intent to treat); not statistically significant (HR 0.996 95% CI 0.785, 1.265). OS on 2 arms was also not significantly different (HR 1.069 95% CI 0.797, 1.434). PFS or OS were not significantly different between 2 arms in 1-3 vs 4-6 prior lines of Tt, bortezomib (btz) refractoriness or among pts who received ³2 or 12 cycles (2- and 12-month landmarks). There was a trend that HDC benefitted pts with any number of prior lines and not btz refractory, while LDC benefitted more 1-3 prior lines. Significantly different grade 3-5 AEs on the 2 arms are shown (Table). Cardiac AEs were not significantly different. Conclusions: In this only randomized comparison of different Cfz doses we did not find a PFS or OS benefit with HDC despite improved VGPR rates. Certain AEs were significantly higher with HDC. Ongoing weekly Cfz trials will further help define its utilization in RRMM.Clinical trial information: NCT01903811.Selected patient characteristics, responses and grade 3-5 AEs at least possibly attributable to study treatment. Characteristic HDC (n = 57) LDC (n = 64) P-value Age ³65 56% 48% 0.467 B2M ³3.5 mg/L 54% 56% 0.857 Cr ³2 mg/dL 0% 2% 1.000 Hb < 10 g/dL 11% 23% 0.091 4-6 Prior lines 26% 22% 0.671 Bortezomib refractory 49% 50% 1.000 Response Category (n = 53) (n = 59) VGPR 26% 8% 0.113 PR 21% 31% SD 40% 41% Increasing Disease 13% 20% AE Category (n = 57) (n = 64) General (most common: fatigue) 19% 3% 0.006 Nervous system (most common: peripheral neuropathy) 7% 0% 0.047 Investigations (most common: thrombocytopenia) 35% 16% 0.020 Cardiac 5% 8% 0.721 Maximum grade any AE 65% 39% 0.006
Prevalence of Self-Reported Head Injury in the United States
Authors: Andrea L C Schneider, Dan Wang, Geoffrey Ling, Rebecca F Gottesman, Elizabeth Selvin
Journal: New England Journal of Medicine (2018)

Prevalence of Head Injury in the U.S. In a survey of adults 40 years of age or older from the 2011–2014 National Health and Nutrition Examination Survey (NHANES) cohort, the prevalence of recalled ...