bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study to assess the safety, tolerability, pharmacokinetics/pharmacodynamics and preliminary efficacy of SC10914 in patients with advanced solid tumors.
Authors: Gong Jifang , Tang Jinhai , Yin Yongmei , Ye Dingwei , Zhang Jian , Zheng Hong , Gao Yunong , Jang Haoyuan , Chen Xiao , Zhang Zhe , Shen Lin 
Published: May 2020

6047 Background: SC10914 is a highly selective inhibitor of PARP enzymes, including PARP1 and PARP2. SC10914 has a similar structure with olaparib. We conducted a phase I study to assess the safety, tolerability, PK/PD and preliminary efficacy of SC10914 in patients with advanced solid tumors. Methods: This is a phase I dose-escalation study with 3+3 design, we enrolled patients at 4 sites in China. Eligible patients were diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists; had measurable disease; had adequate organ function. Patients received SC10914 daily at ten escalating doses from 30 mg QD to 500 mg TID in a 28-day cycle. We obtained blood for PK and CA125 assessments. Toxic effects were assessed by CTCAE 4.03 criteria and tumour responses ascribed by RECIST 1.1 and CA125 was assessed by GCIG criteria. Results: As of January 2020, 52 patients were enrolled, of which 14 were males and 38 were females. Ten doses were escalated to 500mg TID, and no DLT was observed, and MTD was not obtained. The incidence of grade 3/4 AEs and SAEs that were related to SC10914 were 34.6% (18/52) and 13.5% (7/52). Grade 3/4 adverse reaction happened in at least two patients were anaemia/reduced hemoglobin (10/52, 19.2%), decreased WBC count (5/52, 9.6%), neutropenia (3/52, 5.8%), thrombocytopenia (2/52, 3.8%), and decreased lymphocyte count (2/52, 3.8%). A total of 17 gBRCAm evaluable ovarian cancer patients were enrolled, 6 of them had PR, the ORR was 35.3% (6/17). 10 gBRCAm ovarian cancer patients were enrolled in TID groups (including 2 patients who received BID doses at the beginning and changed to 300 mg TID dose after several cycles of treatment), 5 of them had PR, the ORR was 50% (5/10). The ORR of 400 mg TID group was 66.7%(4/6). PK data showed that the exposure of SC10914 was increased with dose increasing at the dose of 30 mg to 250 mg. The half-life of SC10914 was about 2-5 hours. Conclusions: SC10914 was safe in patients with advanced solid tumors. The main toxicity was blood-related adverse reactions. SC10914 was effective in gBRCAm ovarian cancer patients. 400 mg TID might be RP2D. Clinical trial information: NCT02940132.
Anlotinib in patients with recurrent platinum-resistant or refractory ovarian carcinoma: A prospective, single-arm, single-center, phase II clinical study.
Authors: Shan Boer , Shen Wenbin , Wang Huaying 
Published: May 2020

6061 Background: Recurrent platinum-resistant or refractory ovarian carcinoma is difficult to treat, and how to improve the treatment effect of these patients is still an urgent problem to solve. Anlotinib is a new multi-target tyrosine kinase inhibitor and its anti-tumor vascular targets include VEGFR, PDGFR and FGFR. Previous researches have shown clinical antitumor activity of anlotinib in various cancers, including the phase I study on gynecologic tumor. This phase II study (ChiCTR2000029654) aims to further evaluate the safety and efficacy of anlotinib in patients with recurrent or refractory ovarian carcinoma. Methods: Patients who have previously received second-line or more chemotherapy, with histopathologically confirmed ovarian high-grade serous gonadal carcinoma (including salpingocarcinoma and peritoneal carcinoma), ECOG 0-2 were considered eligible for enrollment. Anlotinib was administered orally (12 mg qd, d1-14; 21 days per cycle) till disease progression, death or intolerant toxicity. Therapeutic effects are evaluated every 6 weeks. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety and quality of life (QOL). Results: Between 2019 March to 2020 January, 15 patients (female) with FIGO histopathological stage IA(6.7%), IIIA (73.3%), IIIC (6.7%) and IV (13.3%) were enrolled and 14 patients were evaluable with a median age of 59 years (range: 47-69). The mean follow-up period is 3.5 months (95% CI: 2.1-4.8). Therapeutic evaluation showed the incidence of partial response, stable disease and progression disease was 14.3%, 57.1% and 28.6% respectively, yielding the ORR of 14.3% (2/14; 95% CI: 1.8%-42.8%) and the DCR of 71.4% (10/14; 95% CI: 41.9%-91.6%). The median PFS was not reached. Most of the occurring AEs were grade 1, including hypertention (57.1%), fatigue (50.0%), hand-foot syndrome (35.7%), hoarseness (14.3%), diarrhea (7.1%), gum-pain (7.1%), decrease in leukocyte count (6.7%) and urine protein (7.1%). Only cancer pain (7.1%) was grade 2. No high grade AE was observed in these 14 patients. Neither unexpected safety signals nor treatment related death occurred. Conclusions: Anlotinib showed a promising efficacy with a favourable toxicity profile for patients with recurrent platinum-resistant or refractory ovarian carcinoma. And we will report more results ahout anlotinib in the future. Clinical trial information: ChiCTR2000029654.
Patterns of progression and subsequent management of patients with BRCA1/2 mutated platinum-sensitive recurrent epithelial ovarian cancer (EOC) progressing on olaparib versus placebo: the SOLO2/ENGOT Ov-21 trial (NCT01874353).
Authors: Frenel Jean-Sebastien , Kim Jae-Weon , Berton Dominique , Asher Rebecca , Vidal Laura , Pautier Patricia , Ledermann Jonathan A. , Penson Richard T. , Oza Amit M. , Korach Jacob , Huzarski Tomasz , Pignata Sandro , Colombo Nicoletta , Park-Simon Tjoung-Won , Tamura Kenji , Sonke Gabe S. , Lowe Elizabeth S. , Freimund Alison E. , Lee Chee Khoon , Pujade-Lauraine Eric 
Published: May 2020

6070 Background: Olaparib maintenance is a standard treatment of BRCA1/2 mutated platinum-sensitive recurrent EOC. Despite improvement in PFS, olaparib (O) resistance often occurs and the optimal management of post-olaparib progression remains undefined. Methods: Data of patients who participated in the SOLO-2 trial and progressed were analyzed. Primary objective was to depict the patterns of progression of patients treated with O compared to placebo (P). Secondary objectives include description of post-progression treatments. Results: 106/195 (54%) and 80/99 (81%) patients had a RECIST progression in the O and P arms respectively. As permitted in the protocol, 37 (35%) pts continued O despite a RECIST progression and 10 remained on treatment at the date of data base cut-off of the primary endpoint. Median duration of O post progression was 3.2 months (range: 1 to 19.4). In the placebo arm, only 20% of the patients with progressive disease continued placebo during a median of 1.6 months (range:1.1 to 16.1). Patterns of sites of progressive disease were similar in the O and P arms respectively in terms of liver (21% vs 18%), lung (4% vs 3%), lymph node (20% vs 16%) peritoneal (48% vs 32%) or brain metastases (0% vs 2%). Number of sites of relapsing disease were similar in the O and P arm respectively (1 (68% vs 64), ≥2 (32% vs 36%). A total of 54 (51%) patients in the O arm and 42 (53%) in the P arm received subsequent platinum-based therapy. In both arms, 8% received bevacizumab and 6% received no further treatment. Median PFS with first post-study platinum-based and non platinum-based therapy were 7.1 months and 5.6 months respectively. In the P arm, 18 (23) patients received PARP inhibitors following the first subsequent chemotherapy. Conclusions: Patterns of disease progression and subsequent chemotherapy were similar in patients receiving O or P in the SOLO2 trial. Instead of switching to chemotherapy, continuing O at the time of RECIST progression was an option for 35% of the patients. Clinical trial information: NCT01874353.
Methylated DNA markers for plasma detection of ovarian cancer: Discovery, validation, and clinical feasibility.
Authors: Bakkum-Gamez Jamie Nadine , Marinelli Lisa , Ahlquist David A. , Slettedahl Seth , Mahoney Douglas W. , Taylor William R. , Burger Kelli , Berger Calise K. , Doering Karen A , Lemens Maureen , Shridhar Viji , Allawi Hatim T. , Berg Hannah , Giakoumopoulos Maria , Kaiser Michael W. , Schoolmeester J. Kenneth , Kerr Sarah , Sherman Mark E. , Kisiel John B. 
Published: May 2020

6072 Background: Effective screening tests for ovarian cancer (OC) are lacking; most cases present at advanced stage and portend poor prognosis. DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. In DNA extracted from tissues, we first discovered, then validated discriminant methylated DNA marker (MDM) candidates for OC and subsequently tested independent plasma from women with and without OC. Methods: For discovery, DNA from 67 frozen tissues (18 high grade serous (HGS), 18 endometrioid, 15 clear cell (CC), 6 mucinous OCs; 10 benign fallopian tube epithelium (FT); and 19 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with OC. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent FFPE tissues from OCs (36 HGS, 22 endometrioid, 21 CC, and 14 mucinous) and 29 FT. Top performing MDMs in tissue were tested using long-probe quantitative amplified signal assays in independent pre-treatment plasma samples from women newly-diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. Results: After RRBS discovery and biological validation, 33 MDMs showed marked methylation fold changes (10 to > 1000) across all OC histologies vs FT. The top 11 MDMs ( GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, DSCR6, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (76 (84%) HGS) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95%CI 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86 - 0.96)). Among HGS, the panel correctly identified 83%, including 5/6 stage I/II, and the majority of other subtypes (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded outstanding candidate MDMs for OC that performed with promisingly high sensitivity and specificity in plasma. Larger plasma-based OC MDM testing studies, with larger numbers of non-HGS histologies are warranted. [Table: see text]
PFS by blinded independent central review (BICR) in the VELIA trial of veliparib (V) plus carboplatin/paclitaxel (CP) and as monotherapy in newly diagnosed patients (pts) with high-grade serous ovarian cancer (HGSC).
Authors: Aghajanian Carol , Bookman Michael A. , Fleming Gini F. , Brady Mark F. , Swisher Elizabeth M. , Steffensen Karina Dahl , Friedlander Michael , Okamoto Aikou , Moore Kathleen N. , Sullivan Danielle Marie , Fallstrom Mathias , Dinh Minh , Ratajczak Christine , Coleman Robert L. 
Published: May 2020

6077 Background: The phase III VELIA trial (NCT02470585) demonstrated statistically significant improvement in PFS per investigator (INV) for V added to CP and continued as maintenance (CPV-V) vs. CP alone in pts with newly diagnosed HGSC in the BRCA mutated ( BRCAm), homologous recombination deficient (HRD), and whole populations. Here we present pre-specified analyses of PFS per BICR. Methods: Pts with Stage III-IV HGSC received V or Placebo (PL) with CP (6 cycles) and as maintenance (30 additional cycles). Primary analysis of PFS by INV compared CPV-V to CP alone in the BRCAm, HRD, and whole populations. Exploratory analyses of PFS in BRCA wildtype (wt) and non-HRD HGSC were performed. Radiologic tumor assessments were also prospectively submitted to an independent central reviewer for blinded assessment per RECIST v 1.1. PFS per BICR and rates of concordance between INV and BICR for determination of disease progression were analyzed. Safety data from the primary analysis were previously reported. Results: 1140 total pts were enrolled (CPV-V 382; CP 375). In the whole population, 26% of HGSCs were BRCAm and 55% were HRD. Concordance rates between INV and BICR were 68-85% by arm for each population. Analyses of PFS per BICR and per INV were consistent (Table). PFS was prolonged in the CPV-V vs. CP arm in all primary and exploratory populations assessed. Conclusions: Analyses of PFS per BICR supported the primary analysis of PFS per INV in the BRCAm, HRD, and whole populations, as well as exploratory BRCAwt and non-HRD populations. Median PFS per BICR was longer compared to PFS per INV assessments in all populations and in both arms. These findings support the reliability of PFS by INV in ovarian cancer trials. Alternate strategies like audits may be appropriate to support PFS by INV with less time and expense than full BICR. Clinical trial information: NCT02470585. [Table: see text]
Lenvatinib (LEN) plus pembrolizumab (PEMBRO) for early-line treatment of advanced/recurrent endometrial cancer (EC).
Authors: Makker Vicky , Taylor Matthew H. , Aghajanian Carol , Oaknin Ana , Mier James , Cohn Allen Lee , Romeo Margarita , Bratos Raquel , Brose Marcia S. , DiSimone Christopher , Messing Mark , Dutta Lea , Ren Min , Schmidt Emmett V. , Orlowski Robert , McKenzie Jodi Alicia , Gillis Kathryn , Casado Herraez Antonio 
Published: May 2020

6083 Background: As part of an ongoing phase Ib/II study (NCT02501096) in patients (pts) with selected solid tumors, LEN (20 mg PO QD) + PEMBRO (200 mg IV Q3W) displayed substantial and durable antitumor activity in advanced EC. In previously treated EC that was not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR; n=94 pts), the objective response rate (ORR) by independent imaging review (IIR) per RECIST 1.1 was 38.3% (95% CI 28.5–48.9). In this post hoc analysis, we assessed 2 subgroups of pts with previously treated, advanced, non MSI-H or dMMR EC who received LEN + PEMBRO in an early-treatment setting. Methods: Pts were examined in 2 subgroups: (1) Pts with only 1 prior line of cytotoxic therapy regardless of surgical stage or setting (adjuvant treatment for local-regional disease or treatment for metastatic disease); and (2) pts from subgroup 1 with local-regional disease at diagnosis who received only adjuvant cytotoxic therapy. There were no restrictions on prior hormonal or chemoradiation therapies in either subgroup. Tumor responses were assessed by IIR per RECIST 1.1. Results: Subgroup 1 included 63 pts and subgroup 2 had 21 pts. ORR (95% CI) was 41.3% (29.0–54.4) for subgroup 1 and 57.1% (34.0–78.2) for subgroup 2. Additional efficacy outcomes are summarized in the table. In subgroup 1, treatment-related adverse events (TRAEs) occurred in 62 (98%) pts (42 [67%] ≥ grade 3). TRAEs led to study-drug interruption of one or both drugs in 43 (68%) pts and dose reductions of LEN in 42 (67%) pts; 12 (19%) pts discontinued one or both drugs due to a TRAE. Serious TRAEs occurred in 18 (29%) pts and 2 (3%) pts died from a TRAE. The safety profile for subgroup 2 was generally similar to the profile for subgroup 1. Conclusions: The efficacy of LEN + PEMBRO for early-line treatment of advanced non MSI-H or dMMR EC appears promising. No new safety signals have emerged. A phase III study of LEN + PEMBRO vs paclitaxel + carboplatin for first-line treatment in advanced or recurrent EC is underway. Clinical trial information: NCT02501096. [Table: see text]
Results of a randomized phase III study of dysphagia-optimized intensity modulated radiotherapy (Do-IMRT) versus standard IMRT (S-IMRT) in head and neck cancer.
Authors: Nutting Christopher , Rooney Keith , Foran Bernadette , Pettit Laura , Beasley Matthew , Finneran Laura , Roe Justin , Tyler Justine , Roques Tom , Cook Audrey , Petkar Imran , Bhide Shree , Srinivasan Devraj , Boon Cheng , De Winton Emma , Frogley Robert , Mertens Kathrin , Emson Marie , Hall Emma ,   on behalf of the DARS Investigators
Published: May 2020

6508 Background: Most newly diagnosed oro- & hypopharngeal cancers (OPC, HPC) are treated with (chemo)RT with curative intent but at the consequence of adverse effects on quality of life. CRUK/14/014 investigated if using Do-IMRT to reduce RT dose to the dysphagia/aspiration related structures (DARS) improved swallowing function compared to S-IMRT. Methods: Patients with T1-4, N0-3, M0 OPC/HPC were randomised 1:1 to S-IMRT (65 Gray (Gy)/30 fractions (f) to primary & nodal tumour; 54Gy/30f to remaining pharyngeal subsite & nodal areas at risk of microscopic disease) or Do-IMRT. The volume of the superior & middle pharyngeal constrictor muscle (PCM) (OPC) or inferior PCM (HPC) lying outside the high-dose target volume was set a mandatory mean dose constraint in Do-IMRT. Treatment allocation was by minimisation balanced by centre, use of induction/concomitant chemotherapy, tumour site & AJCC stage. Primary endpoint was mean MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after RT with 102 patients needed to detect a 10 point improvement (assuming S-IMRT score of 72, standard deviation (SD) 13.8; 90% power, 2-sided 5% alpha). Patients were blind to treatment allocation. Secondary endpoints included local control. Results: 112 patients (56 S-IMRT, 56 Do-IMRT) were randomised from 22 UK centres from 06/2016 to 04/2018. Mean age was 57 years; 80% were male; 97% had OPC; 90% had AJCC stage 3&4 disease; 86% had concomitant chemotherapy only, 4% induction & concomitant and 10% no chemotherapy. 111/112 had RT doses as prescribed (1 patient died before RT). Median of the mean inferior PCM dose was S-IMRT 49.8Gy (IQR 47.1-52.4) vs. Do-IMRT 28.4Gy (21.3–37.4), p < 0.0001; superior & middle PCM dose was S-IMRT 57.2Gy (56.3–58.3) vs. Do-IMRT 49.7Gy (49.4–49.9), p < 0.0001. Do-IMRT had significantly higher MDADI scores: S-IMRT 70.3 (SD 17.3) vs. Do-IMRT 77.7 (16.1), p = 0.016. 3 local recurrences (1 S-IMRT, 2 Do-IMRT) have been reported. Conclusions: Do-IMRT reduced RT dose to the DARS and improved patient reported swallowing function compared with S-IMRT. This is the first randomised study to demonstrate functional benefit of swallow-sparing IMRT in OPC. Clinical trial information: 25458988 .
Plasma-based tumor mutational burden (bTMB) as predictor for survival in phase III EAGLE study: Durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum failure.
Authors: Li Weimin , Wildsmith Sophie , Ye Jiabu , Si Han , Morsli Nassim , He Philip , Shetty Jagdish , Yovine Alejandro Javier , Holoweckyj Nicholas , Raja Rajiv , Real Katia , Scorer Paul , Hembrough Todd , Walker Jill , Zhang Qu , Mesia Ricard , Haddad Robert I. , Licitra Lisa F. , Ferris Robert L. 
Published: May 2020

6511 Background: In NSCLC, bTMB assessed from circulating tumor DNA shows promise as a predictive survival biomarker for immunotherapy, but its value in R/M HNSCC is uncertain. We evaluated bTMB as a predictor of survival in R/M HNSCC. Methods: EAGLE (NCT02369874) was a randomized, open-label, phase 3 trial evaluating D (anti-PD-L1), or D+T (anti-CTLA-4), vs CT in R/M HNSCC. Patients (pts) with disease progression after platinum-based CT were randomized (1:1:1) to D (10 mg/kg intravenous [IV] every 2 weeks [Q2W]), D (20 mg/kg IV Q4W) + T (1 mg/kg IV Q4W for up to 4 doses, followed by D at 10 mg/kg Q2W) or CT. bTMB was assessed in pretreatment plasma samples using the Guardant Health OMNI platform. Association of somatic loss of function mutations with OS was assessed. Results: 736 intent-to-treat pts were randomized; 247 were evaluable for bTMB (BEP). bTMB expression was not linked to HPV status, PD-L1 status, age, gender, tumor location, or ECOG PS. Smoking and progression within 6 months on multi-modality CT in localized disease trended with higher bTMB. OS and PFS HRs were significantly improved for D or D+T vs CT in pts with high bTMB (≥16 mut/Mb) vs low (<16 mut/Mb; Table). The benefit of D or D+T vs CT in pts with high bTMB generally improved with increasing cutoff. 74 pts (27 D, 20 D+T, 27 CT pts) were bTMB high. 18-month OS rates were higher for D+T (22%; 95% CI 7%–42%) and D (33%; 95% CI 17%–51%) vs CT (0%; 95% CI 0%–0%) in pts with high bTMB. Pts with mutations in KMT2D, a HNSCC tumor suppressor gene, showed improved OS for D+T vs CT (HR 0.39; 95% CI 0.18–0.85). A trend of improved OS for D+T vs CT (HR 0.19; 95% CI 0.03–1.03) was also seen in pts with ATM mutations. Conclusions: This is the first retrospective analysis of a phase 3 trial to show bTMB may be predictive of outcomes for checkpoint inhibitors in R/M HNSCC. In pts with high bTMB, D or D+T improved OS hazards by at least 60%, vs CT at cutoffs ≥16 mut/Mb. Validation of bTMB as a predictive biomarker is ongoing. Clinical trial information: NCT02369874 . [Table: see text]
Combination of monalizumab and cetuximab in recurrent or metastatic head and neck cancer patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors.
Authors: Cohen Roger B. , Bauman Jessica Ruth , Salas Sebastien , Colevas A. Dimitrios , Even Caroline , Cupissol Didier , Posner Marshall R. , Lefebvre Gautier , Saada-Bouzid Esma , Bernadach Maureen , Seiwert Tanguy Y. , Pearson Alexander T. , Calmels Franceline , Zerbib Robert , Andre Pascale , Rotolo Federico , Boyer-chammard Agnès , Fayette Jerome 
Published: May 2020

6516 Background: Monalizumab is a first-in-class immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), which is expressed on subsets of Natural Killer (NK), gd T and tumor-infiltrating CD8+T cells. NKG2A blockade promotes innate anti-tumor immunity mediated by NK and CD8+T cells and enhances NK cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab. In a Phase I study, the combination of monalizumab and cetuximab was well tolerated. In an initial expansion cohort 1 of 40 patients (pts) who had progressed after platinum-based therapy, we reported an overall response rate (ORR) of 27.5%, a 4.5 month median PFS and an 8.5 month median OS. In a subset of patients (n=18) previously treated with PD-(L)1 inhibitors (IO), corresponding results were 17%, 5.1, and 14.1 months, respectively (ESMO 2019). Here we present data from a second expansion cohort 2 (n=40) conducted specifically in the post-IO setting to independently confirm the cohort 1 results. Methods: Eligible patients had R/M SCCHN previously treated with platinum and a PD-(L)1 inhibitor. Pts received monalizumab 750 mg q2weeks and cetuximab according to the label until progression or toxicity. Cohort 2 was designed as a confirmatory multicenter single arm phase II study, with a pre-planned total of 40 patients. The primary endpoint was ORR assessed per RECIST 1.1. Results: As of January 31, 2020, 40 pts have been treated in cohort 2. Median follow-up is 7.3 months (range, 1.9-13.6+). Eight (8) pts have a confirmed partial response (PR); ORR is 20% [95% confidence interval: 11-35]. Median time to response is 1.6 months [1.6-5.3]. At the time of data analysis, 3 pts were still in PR and 3 pts had stable disease continue on treatment. PFS and OS are still immature. Conclusions: In pts previously treated with platinum and PD-(L)1 inhibitors, the combination of monalizumab and cetuximab demonstrated promising activity. The second extension cohort confirmed prospectively the ORR reported in cohort 1. A randomized phase III trial of monalizumab and cetuximab is planned in this platinum and IO-pretreated SCCHN population. Clinical trial information: NCT02643550 .