Fish Assemblages in Manistee River Tributaries: Longitudinal Distribution Analysis, Seasonal Variation, and Riparian Improvement Evaluation

Sedimentation affects both stream physical and biological integrity. Improperly designed stream passage accompanied with sedimentation and altered hydrology can impede fish passage and reduce fish assemblage integrity. The purpose of this study was to: 1) quantify impacts of poorly constructed road stream crossings and eroding banks on fish assemblages, and 2) assess these sites as sediment sources and connectivity breaks on entire fish assemblages and individual fish species. Electrofishing was conducted during spring and fall 2004 and 2005. A total of 29 electrofishing reaches were sampled which included 5 road-stream and streambank restoration sites. Sickle Creek (1st order) had reduced diversity and increased dominance above a substantially perched culvert (Shannon’s diversity = 0.180 vs. 0.552; Simpson’s dominance = 0.688 and 0.412 above vs. below, respectively). Pine Creek (2nd order) had 12 reaches sampled, while Bear Creek (4th order) had 7 reaches sampled. In both river systems, fish assemblage response above and below impact sites was mixed, and largely determined by either an up vs. downstream impact. For example, undersized road-stream culverts reduced upstream habitat quality while eroding banks reduced downstream habitat quality. Improvements to road-stream crossings should be done to maximize natural river structure and function

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia

BackgroundNew treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.MethodsWe conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.ResultsThe majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.ConclusionsSelective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.)

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenstrom macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing. (C) 2017 by American Society of Clinical OncologyAbbVie; Genentech; National Institutes of Health/National Cancer Institute Cancer Center Support Grant [P30 CA008748]; Career Development Award from the American Society of Clinical Oncology6 month embargo; Published January 17, 2017.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]