tbuckley/cabot-search huggingface dataset:
Molecular profiling in gynecologic cancer and matched targeted therapy: A step toward improving personalized medicine.
Authors: Ana C. Garrido-Castro, Guillem Argilés, Debora Moreno, Victor Rodriguez-Freixinos, Marta Vilaro, Teresa Macarulla, Cristina Cruz Zambrano, Analia Azaro, Barbara Adamo, Maria Alsina, Jose Jimenez, Paolo Nuciforo, Ana Vivancos, Alba Meire, Jose Maria Del Campo, Jordi Rodon, Josep Tabernero, Ana Oaknin
Journal: Journal of Clinical Oncology (2014)

5578 Background: In the wake of personalized medicine in Oncology, genetic tumor profiling has become a cornerstone to select patients (pts) for clinical trials, exploring new molecular targeted agents. Methods: As part of the Vall d’Hebron University Hospital Molecular Prescreening/Phase 1 Trials Program, advanced gynecologic cancer (GYNT) pts were screened for molecular alterations (MA) (KRAS/PIK3CA/AKT/BRAF mutations [mut]; PD-L1 expression; PTEN loss, H score<50) and allocated to receive matched targeted therapy (MTT). We present a summary of molecular characteristics and clinical outcomes, using previous treatment as reference to evaluate potential efficacy. Results: From 01/2012 to 11/2013, 86 consecutive GYNT pts (mean age: 53.3 yrs; median no. previous treatments: 3 [0-7]) were screened for MA; 60 (69.8%) ovarian (OvC), 18 (20.9%) endometrial (EC) and 8 (9.3%) cervical carcinomas (CC). Median time from diagnosis to molecular analysis was 2.96 yrs. MA were identified in 23 pts (26.7%) as specified in Table 1: 5 type-I/8 type-II OvC; 4 type-I/4 type-II EC; 2 CC. Fifteen pts received MTT according to MA. Six harbored PIK3CA mut; 5 were treated with α-specific PI3K inh and 1 with PI3K/mTOR inh. Pts with KRAS mut (8) received MEK inh-based combinations: 6 MEK/PI3K inh, 1 MEK/AKT inh, 1 MEK/IGFR1 inh. A double-mutated pt (PIK3CA/KRAS mut) was treated with mTOR inh. Median PFS of the MTT population was 19.5 wks [CI95%: 10.7-NA], slightly superior to 17.0 wks [CI95%: 12.9-38.6] achieved with the immediately previous line of systemic therapy (p=0.121). Conclusions: Treatment based on MA may improve clinical outcome in heavily pre-treated GYNT, as results in this analysis were superior to standard therapy. Statistical significance was not reached, probably due to small sample size. Our work warrants further studies of MTT in larger less pre-treated population. GYNT (n, %) CC (8, 9.3) EC (18, 20.9) OvC (60, 69.8) ADK (2, 25) SCC (6, 75) Type I (7, 39) Type II (11, 61) Type I (13, 22) Type II (47, 78) PIK3CA (n) AKT1 E17K 1 Q546K 1 E545K 1 1 E542K 1 H1047R 2 3 R88Q 1* KRAS (n) G12D 1 1 1 1 3 G12V 1 1 G12S 1 1 A59T 1* PD-L1 (n) 1 PTEN loss (n, %) 0 (0) 9 (50) 16 (27) % MA per GYNT subtype 25 100 48.3 *Double mut: 1 pt endometrioid EC.
Abstract 16283: Nicotine-Augmented Abdominal Aortic Aneurysms are Regulated by MicroRNA-29b
Authors: Lars Maegdefessel, Junya Azuma, Denis R Merk, Ryuji M Toh, Alicia Deng, Jocelyn P Chin, Joshua M Spin, Philip S Tsao
Journal: Circulation (2011)

More than 90% of patients with an abdominal aortic aneurysm (AAA) report a history of smoking. MicroRNAs (miRs) regulate gene expression on the post-transcriptional level and play crucial roles in ...
Pilot trial of a WT-1 analog peptide vaccine in patients with high-risk myeloid neoplasms.
Authors: Jason B. Brayer, Jeffrey E. Lancet, John Joseph Powers, Alan F. List, Rami S. Komrokji, Lodovico Balducci, Javier Pinilla-Ibarz
Journal: Journal of Clinical Oncology (2014)

3089 Background: Tumor vaccines targeting known tumor-associated antigens (TAA) represent an exciting concept and, more importantly, a reasonable approach to engaging the immune system. WT-1 is once such TAA well-documented to provoke immune sensitization in myeloid tumors, and thus may serve as an ideal vaccine target. The purpose of this pilot study was to demonstrate the safety and tolerability as well as to assess for immunogenicity of a polyvalent WT-1 peptide vaccine. Methods: Patient enrollment included individuals with high-risk MDS or AML after at least 2 prior lines of therapy. The vaccine combined native and synthetic analog peptides derived from the WT-1 protein and emulsified in Montanide ISA 51 VG adjuvant, and coupled with GM-CSF injections to amplify immunogenicity. Six vaccinations were delivered over 12 weeks, then continued monthly until 12 vaccinations were delivered or until evidence of disease relapse or progression. Therapeutic efficacy was evaluated in terms of progression-free and overall survival. Interval quantitative PCR measurements of WT1 transcript levels acted as a surrogate marker of disease burden. Immune responses were evaluated by delayed-type hypersensitivity testing, T cell proliferation, and CD8+T cell IFNγ ELISPOT at specified intervals. Results: In total, 13 patients received at least 1 vaccination and 4 completed the full course of vaccinations. Vaccinations were well tolerated with no discontinuations due to adverse reaction or vaccine-induced toxicity. One of 2 patients with high-risk MDS experienced a transient decrease in transfusion dependence. Two of 11 AML patients experienced prolonged relapse-free survival greater than a year. Both patients were in CR#2 at time of vaccination and the duration of their remission exceeded the duration of their first remission, suggesting a potential benefit. Conclusions: Vaccination against WT-1 using a polyvalent peptide-based approach can be safely administered at well-tolerated doses. The subjective evidence in several patients suggests elicitation of an immune response. Although encouraging, the limited response rate and durability indicate a need for further optimization in future trials. Clinical trial information: NCT00665002.
Phase II study of eribulin mesylate in patients (pts) with advanced soft tissue sarcoma (STS).
Authors: Yoichi Naito, Akira Kawai, Nobuhito Araki, Toshifumi Ozaki, Hideshi Sugiura, Yasuo Yazawa, Hideo Morioka, Akihiko Matsumine, Masahide Hiraiwa, Shun Asami, Kazuo Isu
Journal: Journal of Clinical Oncology (2014)

10567 Background: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that has demonstrated an activity in pts with various types of tumor. The efficacy and safety of eribulin mesylate were evaluated in pretreated pts with advanced STS. Methods: This was an open-label, multi-center, single-arm, phase II study in Japanese pts with advanced STS. Pts with high or intermediate grade STS had received at least one standard chemotherapy, and also had ECOG performance status 0-1. Progressive disease had to be documented within the last 6 months. Eribulin mesylate (1.4 mg/m2) was administered as a 2-5 minute intravenous infusion on day 1 and 8 of 21-day cycle. The primary endpoint was the progression-free rate at 12 weeks (PFR12wks) in 2 independent strata of pts with STS: adipocytic (ADI) or leiomyosarcoma (LMS), and histological types other than ADI/LMS (OTH). Secondary endpoints included response, survival and safety. PFR12wks and responses were assessed by independent review using RECIST criteria. Results: A total of 52 pts were enrolled, and 51 pts received eribulin (ADI:16 pts, LMS: 19 pts and OTH:16 pts). Median age was 52 (range: 28-73) and 13 pts (25.5%) was intermediate grade and 38 pts (74.5%) high grade. Fifty-one pts (100.0%) had received anthracycline and 36 pts (70.6%) ifosfamide as prior therapeutic chemotherapy. The PFR12wks in ADI/LMS was 60.0% (21/35 pts; 95% CI 42.1-76.1%), OTH 31.3% (5/16 ; 11.0-58.7), and all subtypes (ALL) 51.0% (26/51 ; 36.6-65.2). The median progression free survival in ADI/LMS was 5.5 months (mo) (95% CI 2.8-8.2 mo), OTH 2.0 mo (1.2-4.1), and ALL 4.1 mo (2.6-5.6). There was no complete response (CR) or partial response (PR) in this study. Stable disease (SD) in ADI/LMS was 80.0%, OTH 50.0%, and ALL 70.6%. The clinical benefit rate (CR + PR + SD>11 weeks) in ADI/LMS was 74.3%, OTH 50.0%, and ALL 66.7%. 1-year overall survival rate in ADI/LMS was 60.0%, OTH 50.0% and ALL 56.9%. The most frequent treatment-related Grade 3 or above toxicities were neutropenia (86.3%), leukopenia (74.5%), lymphopenia (31.4%), anaemia (11.8%) and febrile neutropenia (7.8%). Conclusions: Eribulin has shown clinical activity in advanced pre-treated STS patients and it is well tolerated with no new safety signals. Clinical trial information: NCT01458249.
An evaluation of national treatment trends and survival in GIST.
Authors: Dana Stafkey-Mailey, Brian S. Seal, Fang Xia, Petra Rietschel, Rebecca Germino, Carl V Asche, Erin Zagadailov, Michael Eaddy
Journal: Journal of Clinical Oncology (2014)

e21510 Background: Systemic therapy (ST) for gastrointestinal stromal tumors (GIST) has changed considerably. Real-world data on changing patterns of therapy, including adjuvant management, are sparse. This study evaluated current treatment patterns and survival among patients receiving imatinib for GIST across 3 databases. Methods: A retrospective study was conducted from 09/2003–12/2011 utilizing pharmacy/medical data from 3 claims databases. Patients with a GIST-related ICD-9 code imatinib with minimum eligibility of 6 months prior and 12 months post (6 months post in database 3) their 1st GIST diagnosis were eligible. Patients were divided into 2 cohorts: surgical (S) and non-surgical (NS). All patients were followed to end of study period or loss of continuous eligibility. ST treatment patterns and survival were evaluated. Results: Across the 3 databases, 57, 98, and 276 patientsmet all inclusion criteria. Approximately 1/2 of all cohorts received 2L therapy, most commonly imatinib monotherapy. 3L therapy was received by <1/3 of patients in each cohort. Imatinib monotherapy was the most commonly utilized 3L treatment in each cohort with the exclusion of S patients in the 2nd database. Based upon survival data available in database 1, 29% of NS and 15% of S patients died during the study period. NS patients were more likely to die compared to S patients (HR=2.486; p=0.1286), although this was not statistically significant. Conclusions: Over half of all patients receiving imatinib undergo surgery. Among both S and NS patients, 2L therapy for GIST was dominated by imatinib, while 3L therapy was dominated by imatinib or sunitinib. S patients had improved survival although not statistically significant compared to NS patients. 1 1 2 2 3 3 NS (n=24) S (n=33) NS (n=36) S (n=62) NS (n=120) S (n=156) 2L therapy (n,%) 12 (50) 19 (58) 15 (42) 28 (45) 67 (56) 64 (41) Imatinib 8 (67) 12 (63) 6 (40) 20 (71) 37 (55) 46 (72) Sunitinib 1 (8) 2 (11) 4 (27) 4 (14) 7 (11) 5 (8) Other GIST 1 (8) 3 (16) 5 (33) 4 (14) 21 (31) 9 (14) Other non-GIST 2 (17) 2 (11) - - 2 (3) 4 (6) 3L therapy 3 (13) 10 (30) 7 (19) 12 (19) 39 (33) 32 (21) Imatinib 2 (67) 6 (60) 2 (29) 2 (17) 16 (41) 19 (59) Sunitinib 1 (33) - 2 (29) 6 (50) 6 (15) 5 (16) Other GIST - 3 (30) 2 (29) 2 (17) 12 (31) 6 (19) Other non-GIST - 1 (10) 1 (14) 2 (17) 5 (13) 2 (6)
Immune reconstitution inflammatory syndrome (IRIS)-associated Burkitt lymphoma.
Authors: Prakash Vishnu, Russell K Dorer, David Michael Aboulafia
Journal: Journal of Clinical Oncology (2014)

e19529 Background: IRIS as described in people living with HIV-AIDS (PLWHA) is associated with a paradoxical worsening or unmasking of infections and autoimmune diseases, following initiation of combination anti-retroviral therapy (cART). Epidemiologic studies suggest an increased incidence of Kaposi’s sarcoma, and some forms of lymphoma within a few months of initiation of cART in the backdrop of improving CD4+ T-cell counts and well controlled HIV viremia. Most cases of IRIS-associated lymphoma are diffuse-large B-cell phenotype. Herein, we describe cases of IRIS-associated Burkitt lymphoma (BL) and examine the immunologic and virologic factors associated with potential IRIS-mediated BL. Methods: PLWHA who received lymphoma treatment at our center between Jan 2009 and Dec 2013 were included. IRIS-associated BL was defined as BL occurring within 6 months after initiation of cART and a ≥ 0.7 log10copies/mL reduction in HIV RNA between values taken prior to cART and at lymphoma diagnosis. Results: Three PLWHA were diagnosed with IRIS-associated BL; their ages were 32, 43 and 45 years, respectively. All 3 patients, at the time of beginning cART had high HIV viral loads (mean: 163,800 copies/mL). There was a temporal relationship between HIV viral suppression and appearance of BL. Significant inhibition of HIV viral replication was documented within a mean of 15 weeks after beginning cART. All had bulky lymphadenopathy with high serum LDH and β-2 μglobulin levels. In each instance BL was heralded by fevers, night sweats and weight loss. All 3 patients received R-CODOX/M-IVAC chemotherapy. Two patients achieved complete remission; third patient achieved rapid cytoreduction after 1 cycle of chemotherapy, but just prior to starting cycle 2B, died suddenly from a cardiac arrest. Conclusions: Pathogenesis of IRIS-associated lymphoma may be related to immune deterioration, chronic antigenic stimulation, aberrant cytokine expression and rapid restoration of immune response through control of HIV replication. In BL, presence of c-Myc gene mutation further adds to unregulated oncogene expression and B-cell proliferation. IRIS-associated NHL should be suspected in PLWHA who present with rapidly progressive lymphadenopathy within a few months of beginning cART.
Circulating tumor cells in peripheral and pulmonary venous blood and long-term survival in surgically resected non-small cell lung cancer patients.
Authors: Yungsong Li, Zhidong Liu, Shaofa Xu, Chongyu Su, Yi Han
Journal: Journal of Clinical Oncology (2014)

e22039 Background: We tested the hypothesis that the circulating tumor cells (CTCs) in preoperative peripheral blood (PPB) and intraoperative pulmonary venous blood (IPVB) could predict poor long term survival in surgically resected NSCLC patients. Methods: CTCs were separated from the blood using magnetic beads coated by antibody against epithelial-cell adhesion molecule (EpCAM) through magnetic activated cell sorting (MACS). The CTCs were quantified with fluorescence labeled antibodies against pan-cytokeratin through flow cytometry. CTCs were prospectively quantified in PPB and IPVB in 23 consecutive stage I-IIIA patients with surgically resected NSCLC. Association between CTCs and prognosis of these patients was evaluated after 5-year follow-up. Results: In the NSCLC patients, outcomes were assessed according to levels of CTCs at surgery, and compared with CTCs detected in benign pulmonary diseases, and healthy volunteers, where the mean and 95%CI of CTCs counts were all <1.0 CTCs/15 mL. In cancer patients, the median of PPB-CTCs was 5/15mL, and the median of IPVB-CTCs was 28/15mL. NSCLC patients were identified as high-risk groups, as >5 CTCs/15mL in PPB and >50 CTCs/15mL in IPVB. Univariate Cox proportional-hazards regression analysis showed that CTCs count in PPB or IPVB was an independent risk factor for tumor-free and overall survivals. The high risk group of patients had a shorter median tumor-free survival (22 months vs. >60.0 months, P<0.0012) and shorter overall survival (27 months vs. >60 months, P<0.0015). Conclusions: CTCs count in PPB and IPVB was an independent risk factor for tumor-free and overall survival in surgically resected NSCLC patients.
RNA G-quadruplexes at upstream open reading frames cause DHX36- and DHX9-dependent translation of human mRNAs
Authors: Pierre Murat, Giovanni Marsico, Barbara Herdy, Avazeh Ghanbarian, Guillem Portella, Shankar Balasubramanian
Journal: Genome biology (2018)

RNA secondary structures in the 5'-untranslated regions (5'-UTR) of mRNAs are key to the post-transcriptional regulation of gene expression. While it is evident that non-canonical Hoogsteen-paired G-quadruplex (rG4) structures somehow contribute to the regulation of translation initiation, the nature and extent of human mRNAs that are regulated by rG4s is not known. Here, we provide new insights into a mechanism by which rG4 formation modulates translation.
Phase 1/2 study of investigational hypoxia-targeted drug, TH-302, and bevacizumab (bev) in recurrent glioblastoma (GBM) following bev failure.
Authors: Andrew Jacob Brenner, Jessica D Sun, John Floyd, Charles P Hart, Clarence Eng, Stew Kroll, Lisa Fichtel, Aleksandra Gruslova, Alessia Lodi, Stefano Tiziani
Journal: Journal of Clinical Oncology (2014)

2029 Background: Despite vascular dependence, GBM is resistant to antiangiogenic therapy. Co-targeting tumor angiogenesis and tumor hypoxia, a key driver of treatment resistance, is one approach to potentially prevent or reverse this mechanism of resistance. An ongoing Phase 1/2 study investigates TH-302 with bev in patients (pts) with recurrent GBM following bev failure. Median PFS and 3-mo PFS (PFS-3) in this pt population has been reported as 37.5 days and ~16% (Quant, Neuro-Onc 2009). Methods: Single center, dose-escalation, prospective study (NCT01403610) with 2:1 randomization to TH-302 single dose of 575 mg/m2 or placebo administered pre-surgery (cohorts 1-3 only), followed by post-surgery combination therapy of bev at 10 mg/kg and TH-302 dose escalated 240-670 mg/m2every 2 weeks (4 week cycle) until disease progression. Following the first 5 pts in cohort 3, pts were allowed to proceed directly to TH-302/bev combination therapy without surgery. Resected tumor tissue was evaluated for hypoxia induced pimonidazole (PIMO) adducts, endogenous CA-IX staining, ɣH2AX and TUNEL DNA damage biomarkers, and by metabolomic profiling. Results: 21 pts have been enrolled: 14 randomized in presurgery cohorts 1-3 with 9 proceeding to TH-302/bev after surgery and 7 pts proceeding directly to TH-302/bev. No Gr 4 AEs were observed. Two Gr 3 AEs were observed at 340 mg/m2 (skin ulceration) and 670 mg/m2 (thrombocytopenia). Primary TH-302 related toxicities were mucosal but not dose limiting: rectal mucositis in 2/4 pts at 480 mg/m2 and 4/4 pts at 670 mg/m2. Oral mucositis was limited. Co-localized PIMO and CA-IX staining showed extensive tumor hypoxia. MR-spectra showed significant differences in metabolites before treatment compared to at progression. Best tumor responses in 16 evaluable pts: 1 CR, 2 PRs, 9 SDs. Median PFS is 3.1 mos (95% CI: 2.1 to 4.0 mos) and PFS-3 is 52% (95% CI: 27% to 78%). Conclusions: Extensive tumor hypoxia was observed in GBM pts previously treated with bev. The recommended Phase 2 dose of TH-302 is 670 mg/m2 when combined with bev. These preliminary data suggest potential activity of TH-302/bev in GBM pts with poor prognosis. Dose expansion at 670 mg/m2 is ongoing. Clinical trial information: NCT01403610.
Utility of restaging bone marrow biopsy (BMB) in PET-negative patients with diffuse large B-cell lymphoma (DLBCL) with bone marrow involvement.
Authors: Amie Elissa Jackson, Jacob Paul Smeltzer, Thomas Matthew Habermann, Jason Michael Jones, Brian Leslie Burnette, Kay Ristow, Gregory A. Wiseman, William R Macon, Grzegorz S. Nowakowski, Thomas E. Witzig
Journal: Journal of Clinical Oncology (2014)

8541 Background: Less than 10% of DLBCL patients have stage IV disease with BM involvement at diagnosis. For these patients, restaging BMB is required to document complete remission (CR). In addition to cost, BMB is a potential source of anxiety and pain for patients. PET-CT is the standard for response assessment in DLBCL and may accurately detect BM involvement at diagnosis (Khan 2013). This raises the question of whether BM assessment on restaging PET-CT could obviate the need for repeat BMB. Methods: This was a single institution, retrospective cohort study. After IRB approval, patients with DLBCL and a positive BMB at diagnosis were identified from the Mayo Clinic Lymphoma Data Base. The concordance of BM status on restaging histopathology and PET-CT reports and the positive (PPV) and negative predictive value (NPV) of PET-CT were determined. Findings were validated in a prospective cohort of 68 DLBCL patients treated on an ongoing phase II clinical trial of frontline lenalidomide and RCHOP (R2CHOP). Results: Between 2004 and 2013, 1080 patients with DLBCL were evaluated. Of those, 69 (6%) had DLBCL involving the BM at diagnosis. Forty-six patients completed frontline chemoimmunotherapy; 8 were lost to follow-up; and 15 did not complete therapy because of death or progression. Of 46 patients completing therapy, 31 had restaging PET-CT and BMB and were included in the analysis. The concordance between BMB and PET-CT was 100%. Thirty patients had a negative BM by PET-CT and BMB (29 CR; 3PR; 1PD). One patient had persistent BM involvement by biopsy and PET-CT. Thus, restaging PET-CT had 100% PPV and 100% NPV for assessing residual BM disease. In the validation cohort, four patients (6%) had DLBCL involving the BM at diagnosis. All had a negative BM by both restaging BMB and PET-CT. Conclusions: Compared with the gold standard of BMB, PET-CT had a 100% NPV to exclude residual BM disease in DLBCL patients after frontline therapy. These findings are being further studied in ECOG1412 testing RCHOP vs R2CHOP in untreated DLBCL. If further validated, DLBCL practice guidelines and response criteria could be modified so BMB is no longer required to document CR if the restaging PET-CT is negative.
Landmark analysis of overall survival (OS) in patients with chronic (CP) or accelerated (AP) phase chronic myeloid leukemia (CML) treated with omacetaxine mepesuccinate.
Authors: Meir Wetzler, Hagop M. Kantarjian, Franck E. Nicolini, Jeffrey Howard Lipton, Luke Paul Akard, Michele Baccarani, Hanna Jean Khoury, Elizabeth Li, Mihaela C. Munteanu, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2014)

7066 Background: Response milestones are used as prognostic indicators in CML. This analysis compared OS in patients with/without response to omacetaxine. Methods: This was a post hoc landmark analysis in a subset of CP and AP patients in 2 phase II trials of single-agent omacetaxine; all had received ≥2 tyrosine kinase inhibitors. Kaplan-Meier analysis was used to estimate OS from time of omacetaxine initiation in patients with/without hematologic response (HR; complete [CHR] in CP and major [MHR] in AP) or cytogenetic response (CyR) at 3, 6, and 12 months (mo); patients unevaluable for response at a timepoint were excluded. Results: At 3 months, 53 (70%) CP and 15 (43%) AP patients continued treatment; median OS in these patients was 49.3 mo (95% CI, 27.8-NR) and 21.7 mo (6.8-37.2), respectively (vs 27.2 mo [6.8-37.2] and 8.2 mo [1.9-16.0] in those who discontinued prior to 3 mo). In CP and AP patients evaluable for response at 3 mo, median OS was longer in those with HR vs those without (Table). Median OS was similar in CP patients with/without CyR at 3 and 6 mo. Median OS was not reached in CP patients with CyR at 12 mo (n=12; 11 patients were alive with a median follow-up of 48.7 mo [range, 29.5-57.2]), compared with a median OS of 49.5 mo in those without CyR (n=13). Conclusions: HR by 3 mo may be a positive predictor of OS in CML patients treated with omacetaxine. In this heavily pretreated population, presence/absence of CyR by 6 months may not be predictive of OS. These findings are limited by the relatively small number of patients and the noncomparative study design. Clinical trial information: NCT00375219 and NCT00462943. Time pt, mo Response N Deaths, n (%) Median OS, mo (95% CI) CP 3 CHR 47 21(45) 49.5 (31.6-NR) No CHR 6 4 (67) 15.0 (7.8-NR) Any CyR 11 4 (36) 49.3 (9.6-NR) No CyR 42 21 (50) 49.5 (22.9-NR) MCyR 8 4 (50) 49.3 (9.6-49.3) No MCyR 45 21 (47) 49.5 (22.9-NR) 6 Any CyR 14 4 (29) 49.3 (40.3-NR) No CyR 29 15 (52) 49.5 (20.3–NR) MCyR 8 4 (50) 49.3 (14.2-49.3) No MCyR 35 15 (43) 59.4 (27.8-NR) 12 Any CyR 12 1 (8) NR(49.3-NR) No CyR 13 8 (62) 49.5 (17.8-59.4) MCyR 6 1 (17) NR (49.3-NR) No MCyR 19 8 (42) 59.4 (27.8-59.4) AP 3 MHR 3 3 (100) 33.0 (24.6-37.2) No MHR 12 9 (75) 17.3 (6.7-40.3) Abbreviations: NR, not reached.