Publications by authors named "Stephen D Smith"

120 Publications

Contrasting Mind-Wandering, (Dark) Flow, and Affect During Multiline and Single-Line Slot Machine Play.

J Gambl Stud 2021 May 6. Epub 2021 May 6.

Department of Psychology, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada.

Slot machines are a very popular form of gambling in which a small proportion of gamblers experience gambling-related problems. These players refer to a trance-like state that researchers have labelled 'dark flow'-a pleasurable, but maladaptive state where players become completely occupied by the game. We assessed 110 gamblers for mindfulness (using the Mindful Attention Awareness Scale), gambling problems (using the Problem Gambling Severity Index), depressive symptoms (using the Depression, Anxiety, and Stress Scale), and boredom proneness (using the Boredom Proneness Scale). Participants played both a multiline and single-line slot machine simulator and were occasionally interrupted with thought probes to assess whether they were thinking about the game or something else. After playing each game, we retrospectively assessed dark flow and affect during play. Our key results were that the number of "on-game" reports during the multiline game were significantly higher than the single-line game, and that we found significantly greater flow during the multiline game than the single-line game. We also found significantly lower negative affect during the multiline game than the single-line game. Using hierarchical multiple regression, we found that dark flow accounted for unique variance when predicting problem gambling severity (over and above depression, mindfulness, and boredom proneness). These assessments help bolster our previous assertions about escape gambling-if some players are prone to having their mind-wander to negative places, the frequent but unpredictable reinforcement of multiline slot machines may help rein in the wandering mind and prevent minds from unintentionally wandering to negative thoughts.
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http://dx.doi.org/10.1007/s10899-021-10027-0DOI Listing
May 2021

Umbralisib: Walking the Tightrope of PI3K Inhibition in Indolent NHL.

J Clin Oncol 2021 May 16;39(15):1671-1673. Epub 2021 Apr 16.

Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA.

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http://dx.doi.org/10.1200/JCO.21.00284DOI Listing
May 2021

Inside the lived perspective of life after spinal cord injury: a qualitative study of the desire to live and not live, including with assisted dying.

Spinal Cord 2021 May 31;59(5):485-492. Epub 2021 Mar 31.

University of Winnipeg Psychology Department, Winnipeg, Canada.

Study Design: Qualitative.

Objectives: The objective of this study was to examine whether individuals with a SCI would have considered Medical-Assistance-in-Dying (MAiD) following their SCI and whether these individuals felt they would have been able to make an informed decision about this potentially permanent option early in their experience.

Setting: Manitoba, Canada.

Methods: Participants with varying neurological levels of SCI and classification were included. The time since SCI ranged from <6 months to >50 years. A focus group of five individuals was conducted first to calibrate questions. Twenty-three participants were then individually interviewed. Participants' responses were transcribed and coded into themes.

Results: Half of the participants reported having suicidal ideation within the first 2 years of experiencing a SCI. However, no participants thought that they would have been able to make an informed decision about MAiD during this time. Most participants reported that they were able to adapt and reframe their lives to alter their views. There was higher agreement that MAiD should be available for individuals who had experienced a reframed, informed view.

Conclusion: This study indicates that people with SCI do not feel that informed decision making about ending their life can be made early after SCI despite high levels of reported suicidal ideation in that early time frame. A reframing process helps to facilitate informed decisions about living with a SCI. The reframing process is correlated with opportunities of rehabilitation, peer mentor support, and re-integration into the community.
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http://dx.doi.org/10.1038/s41393-021-00619-3DOI Listing
May 2021

Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.

Blood Adv 2021 03;5(6):1648-1659

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.
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http://dx.doi.org/10.1182/bloodadvances.2020003556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993097PMC
March 2021

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia 2021 Mar 3. Epub 2021 Mar 3.

Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
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http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
March 2021

Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multi-center cohort study.

Haematologica 2021 Feb 4. Epub 2021 Feb 4.

Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P.
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http://dx.doi.org/10.3324/haematol.2020.270876DOI Listing
February 2021

Burkitt Lymphoma International Prognostic Index.

J Clin Oncol 2021 Apr 27;39(10):1129-1138. Epub 2021 Jan 27.

Department of Haemato-oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom.

Purpose: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches.

Methods: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019.

Results: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively.

Conclusion: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.
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http://dx.doi.org/10.1200/JCO.20.03288DOI Listing
April 2021

Polatuzumab Vedotin for Relapsed/Refractory Aggressive B-cell Lymphoma: A Multicenter Post-marketing Analysis.

Clin Lymphoma Myeloma Leuk 2021 Mar 18;21(3):170-175. Epub 2020 Dec 18.

Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

Introduction: Polatuzumab vedotin is approved therapy in the United States for relapsed/refractory diffuse large B-cell lymphoma in combination with bendamustine and rituximab (Pola+BR). However, the safety and efficacy of Pola+BR outside of a clinical trial setting is unknown.

Patients And Methods: We analyzed use of pola-based therapy at 5 centers in the United States, including dose, response rates, progression-free survival (PFS), survival, and toxicity.

Results: Sixty-nine patients with aggressive B-cell lymphoma, including 66 with diffuse large B-cell lymphoma/high-grade B-cell lymphoma and 84% refractory to prior therapy, were treated. Responses occurred in of 50%, including 24% complete response. Median duration of response was 5.1 months, PFS was 2.0 months, and survival was 5.3 months, at 4 months median follow-up. Inferior PFS was associated with prior refractory disease (median, 57 days vs. not reached; P = .003) and lack of response to Pola+BR (PFS, 27 days vs. 152 days; P < .001). Discontinuation owing to planned cellular therapy was seen in 36% and owing to toxicity occurred in 12%; unplanned hospitalizations occurred in 36%.

Conclusions: We conclude that commercial Pola is applied to highly refractory lymphomas at our centers, often with intent to bridge to subsequent therapy. Although some clinical benefit was observed, efficacy was inferior to clinical trial data, especially among those with refractory disease.
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http://dx.doi.org/10.1016/j.clml.2020.12.013DOI Listing
March 2021

Ibrutinib Monotherapy in Relapsed or Refractory, Transformed Diffuse Large B-cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2021 Mar 3;21(3):176-181. Epub 2020 Dec 3.

Division of Medical Oncology, University of Washington Medicine, Seattle, WA; Clinical Research Division, Fred Hutch Cancer Research Center, Seattle, WA. Electronic address:

Background: Histologic transformation to diffuse large B-cell lymphoma (tDLBCL) occurs in a significant proportion of indolent lymphomas. However, few studies of novel agents inform its management, particularly when relapsed after or refractory (R/R) to prior treatment.

Patients And Methods: We prospectively evaluated ibrutinib monotherapy in pathologically documented patients with R/R tDLBCL in a single-arm study. The primary endpoint was overall response rate.

Results: Twenty patients who had received a median of 4 (range, 2-9) prior lines of therapy overall (median, 2.5; range, 1-9 for tDLBCL) were treated. The overall response rate was 35%, including complete responses in 15%. The median progression-free survival and overall survival were 4.1 months (95% confidence interval, 2.4-6.2 months) and 22.4 months (95% confidence interval, 7.5 months to not reached), respectively. Disease control > 2 months was seen in 75% and > 1 year in 15%. Response was associated with either low tumor bulk or low metabolic tumor volume (P = .05) but not with antecedent lymphoma histology (P = 1.0). Treatment-related adverse events were consistent with prior studies of ibrutinib.

Conclusions: Ibrutinib showed low toxicity and meaningful efficacy in R/R tDLBCL, including short-term disease control in most cases. Results demonstrate the potential utility of ibrutinib in this challenging clinical setting, including as a potential bridge to more definitive treatments.
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http://dx.doi.org/10.1016/j.clml.2020.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904587PMC
March 2021

An electroencephalographic examination of the autonomous sensory meridian response (ASMR).

Conscious Cogn 2021 01 21;87:103053. Epub 2020 Nov 21.

Department of Psychology, University of Winnipeg, Winnipeg, Manitoba, Canada. Electronic address:

Autonomous sensory meridian response (ASMR) is a perceptual phenomenon characterized by pleasurable tingling sensations in the head and neck, as well as pleasurable feelings of relaxation, that reliably arise while attending to a specific triggering stimulus (e.g., whispering or tapping sounds). Currently, little is known about the neutral substrates underlying these experiences. In this study, 14 participants who experience ASMR, along with 14 control participants, were presented with four video stimuli and four auditory stimuli. Half of these stimuli were designed to elicit ASMR and half were non-ASMR control stimuli. Brain activity was measured using a 32-channel EEG system. The results indicated that ASMR stimuli-particularly auditory stimuli-elicited increased alpha wave activity in participants with self-reported ASMR, but not in matched control participants. Similar increases were also observed in frequency bands associated with movement (gamma waves and sensorimotor rhythm). These results are consistent with the reported phenomenology of ASMR, which involves both attentional and sensorimotor characteristics.
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http://dx.doi.org/10.1016/j.concog.2020.103053DOI Listing
January 2021

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis.

Blood Adv 2020 11;4(22):5773-5784

City of Hope National Medical Center, Duarte, CA.

Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.
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http://dx.doi.org/10.1182/bloodadvances.2020003121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686907PMC
November 2020

Using deliberate mind-wandering to escape negative mood states: Implications for gambling to escape.

J Behav Addict 2020 Oct 2;9(3):723-733. Epub 2020 Oct 2.

1Department of Psychology, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada.

Background And Aims: Slot machines are a pervasive form of gambling in North America. Some gamblers describe entering "the slot machine zone"-a complete immersion into slots play to the exclusion of all else.

Methods: We assessed 111 gamblers for mindfulness (using the Mindful Attention Awareness Scale (MAAS)), gambling problems (using the Problem Gambling Severity Index (PGSI)), depressive symptoms (using the Depression, Anxiety, and Stress Scale), and boredom proneness (using the Boredom Proneness Scale). In a counterbalanced order, participants played a slot machine simulator and completed an auditory vigilance task. During each task, participants were interrupted with thought probes to assess whether they were: on-task, spontaneously mind-wandering, or deliberately mind-wandering. After completing each task, we retrospectively assessed flow and affect. Compared to the more exciting slots play, we propose that gamblers may use deliberate mind-wandering as a maladaptive means to regulate affect during a repetitive vigilance task.

Results: Our key results were that gamblers reported greater negative affect following the vigilance task (when compared to slots) and greater positive affect following slots play (when compared to the vigilance task). We also found that those who scored higher in problem gambling were more likely to use deliberate mind-wandering as a means to cope with negative affect during the vigilance task. Using hierarchical multiple regression, we found that the number of "deliberately mind-wandering" responses accounted for unique variance when predicting problem gambling severity (over and above depression, mindfulness, and boredom proneness).

Conclusions: These assessments highlight a potential coping mechanism used by problem gamblers in order to deal with negative affect.
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http://dx.doi.org/10.1556/2006.2020.00067DOI Listing
October 2020

Functional connectivity associated with five different categories of Autonomous Sensory Meridian Response (ASMR) triggers.

Conscious Cogn 2020 10 25;85:103021. Epub 2020 Sep 25.

Department of Psychology, University of Winnipeg, Winnipeg, Manitoba, Canada; Department of Radiology, University of Manitoba, Winnipeg, Manitoba, Canada.

Autonomous sensory meridian response (ASMR) is a sensory-emotional phenomenon in which specific sensory stimuli ("ASMR triggers") reliably elicit feelings of relaxation and tingling sensations on the head, neck, and shoulders. However, there are individual differences in which stimuli elicit ASMR and in the intensity of these responses. In the current research, we used resting-state fMRI to examine the functional connectivity associated with these differences. Fifteen individuals with self-reported ASMR completed the ASMR Checklist, which measures sensitivity to different ASMR triggers, and a resting-state fMRI scan. Checklist scores were entered as covariates to determine whether the functional connectivity of eight resting-state networks differed as a function of participants' sensitivity to five categories of triggers. The results indicated unique patterns of functional connectivity associated with sensitivity to each ASMR trigger category. Sensitivity to two trigger categories was positively correlated with the dorsal attention network, suggesting that ASMR may involve atypical attentional processing.
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http://dx.doi.org/10.1016/j.concog.2020.103021DOI Listing
October 2020

A Phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma.

Future Oncol 2021 Jan 28;17(3):255-262. Epub 2020 Sep 28.

Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France.

Mantle cell lymphoma is an aggressive B-cell malignancy. Current frontline chemoimmunotherapies produce high response rates but relapse is inevitable. Furthermore, the elderly and those with comorbidities are precluded from standard regimens and stem cell transplant, leaving them with limited options. Targeted therapies, including Bruton tyrosine kinase inhibitors, are an effective treatment strategy in mantle cell lymphoma. Zanubrutinib is a potent next-generation Bruton tyrosine kinase inhibitor that has demonstrated complete and sustained Bruton tyrosine kinase occupancy, minimal off-target effects and favorable pharmacokinetic/pharmacodynamic properties. Described herein is an ongoing Phase III study comparing the efficacy and safety of zanubrutinib plus rituximab followed by zanubrutinib monotherapy versus bendamustine plus rituximab followed by observation in transplant-ineligible patients with previously untreated mantle cell lymphoma. Clinical Trial Registration: NCT04002297 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0794DOI Listing
January 2021

Yttrium-90 Anti-CD45 Immunotherapy Followed by Autologous Hematopoietic Cell Transplantation for Relapsed or Refractory Lymphoma.

Transplant Cell Ther 2021 Jan 25;27(1):57.e1-57.e8. Epub 2020 Sep 25.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, Washington. Electronic address:

Autologous hematopoietic cell transplantation (AHCT) is a standard of care for several subtypes of high-risk lymphoma, but durable remissions are not achieved in the majority of patients. Intensified conditioning using CD45-targeted antibody-radionuclide conjugate (ARC) preceding AHCT may improve outcomes in lymphoma by permitting the delivery of curative doses of radiation to disease sites while minimizing toxicity. We performed sequential phase I trials of escalating doses of yttrium-90 (Y)-labeled anti-CD45 antibody with or without BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy followed by AHCT in adults with relapsed/refractory or high-risk B cell non-Hodgkin lymphoma (NHL), T cell NHL (T-NHL), or Hodgkin lymphoma (HL). Twenty-one patients were enrolled (16 NHL, 4 HL, 1 T-NHL). Nineteen patients received BEAM concurrently. No dose-limiting toxicities were observed; therefore, the maximum tolerated dose is estimated to be ≥34 Gy to the liver. Nonhematologic toxicities and engraftment kinetics were similar to standard myeloablative AHCT. Late myeloid malignancies and 100-day nonrelapse deaths were not observed. At a median follow-up of 5 years, the estimates of progression-free and overall survival of 19 patients were 37% and 68%, respectively. Two patients did not receive BEAM; one had stable disease and the other progressive disease post-transplant. The combination of Y-anti-CD45 with BEAM and AHCT was feasible and tolerable in patients with relapsed and refractory lymphoma. The use of anti-CD45 ARC as an adjunct to hematopoietic cell transplantation regimens or in combination with novel therapies/immunotherapies should be further explored based on these and other data.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990745PMC
January 2021

Selinexor for relapsed or refractory diffuse large B-cell lymphoma: examining the artifact.

Lancet Haematol 2020 10;7(10):e707

Division of Medical Oncology and Fred Hutchinson Cancer Research Center, Clinical Research Division, University of Washington, Seattle, WA 98109, USA.

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http://dx.doi.org/10.1016/S2352-3026(20)30290-8DOI Listing
October 2020

Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity.

J Clin Oncol 2020 09 15;38(27):3095-3106. Epub 2020 Jul 15.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Axicabtagene ciloleucel (axi-cel) was approved by the Food and Drug Administration for relapsed aggressive B-cell non-Hodgkin lymphoma in part on the basis of durable remission rates of approximately 40% in a clinical trial population. Whether this efficacy, and the rates of toxicity, would be consistent in a postcommercial setting, with relaxed eligibility criteria and bridging therapy, is unknown. This study describes the efficacy and safety correlates and outcomes in this setting.

Patients And Methods: One hundred twenty-two patients from 7 medical centers in the United States were treated with axi-cel and were included in a modified intent-to-treat (mITT) analysis. Seventy-six patients (62%) were ineligible for the ZUMA-1 trial. Response and toxicity rates, duration of response (DOR), survival, and covariates are described on the basis of the mITT population. Correlative studies on blood and tumor samples were performed to investigate potential biomarkers of response and resistance.

Results: Median follow-up was 10.4 months. In the mITT population, the best overall and complete response (CR) rates were 70% and 50%, respectively. Median DOR and progression-free survival (PFS) were 11.0 and 4.5 months in all patients and were not reached (NR) in CR patients. Median overall survival (OS) was NR; 1-year OS was 67% (95% CI, 59% to 77%). Although response rates were similar in the ZUMA-1-eligible and ZUMA-1-ineligible groups (70% 68%), there was a statistically significant improvement in CR rate (63% 42%, = .016), DOR (median, NR 5.0 months; = .014), PFS (median, NR 3.3 months; = .020), and OS (1-year OS, 89% 54%; < .001) in patients who were ZUMA-1 eligible. Rates of grade ≥ 3 cytokine release syndrome and neurotoxicty were 16% and 35%, respectively.

Conclusion: Axi-cel yields similar rates of overall response and toxicity in commercial and trial settings, although CR rates and DOR were more favorable in patients eligible for ZUMA-1.
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http://dx.doi.org/10.1200/JCO.19.02103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499617PMC
September 2020

Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers.

Blood 2021 01;137(3):374-386

Division of Hematology/Oncology, NYU Cancer Institute, New York University School of Medicine, New York, NY.

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.
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http://dx.doi.org/10.1182/blood.2020006926DOI Listing
January 2021

Addressing the conundrum of male predominance in mantle cell lymphoma using androgen receptor blockade.

Br J Haematol 2020 09 22;190(6):e332-e335. Epub 2020 Jun 22.

Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA, USA.

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http://dx.doi.org/10.1111/bjh.16902DOI Listing
September 2020

Early network properties of the COVID-19 pandemic - The Chinese scenario.

Int J Infect Dis 2020 Jul 26;96:519-523. Epub 2020 May 26.

Department of Psychology, College of Charleston, Charleston, USA.

Objectives: To control epidemics, sites more affected by mortality should be identified.

Methods: Defining epidemic nodes as areas that included both most fatalities per time unit and connections, such as highways, geo-temporal Chinese data on the COVID-19 epidemic were investigated with linear, logarithmic, power, growth, exponential, and logistic regression models. A z-test compared the slopes observed.

Results: Twenty provinces suspected to act as epidemic nodes were empirically investigated. Five provinces displayed synchronicity, long-distance connections, directionality and assortativity - network properties that helped discriminate epidemic nodes. The rank I node included most fatalities and was activated first. Fewer deaths were reported, later, by rank II and III nodes, while the data from rank I-III nodes exhibited slopes, the data from the remaining provinces did not. The power curve was the best fitting model for all slopes. Because all pairs (rank I vs. rank II, rank I vs. rank III, and rank II vs. rank III) of epidemic nodes differed statistically, rank I-III epidemic nodes were geo-temporally and statistically distinguishable.

Conclusions: The geo-temporal progression of epidemics seems to be highly structured. Epidemic network properties can distinguish regions that differ in mortality. This real-time geo-referenced analysis can inform both decision-makers and clinicians.
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http://dx.doi.org/10.1016/j.ijid.2020.05.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250076PMC
July 2020

Considerations for Managing Patients With Hematologic Malignancy During the COVID-19 Pandemic: The Seattle Strategy.

JCO Oncol Pract 2020 09 5;16(9):571-578. Epub 2020 May 5.

Seattle Cancer Care Alliance, Seattle, WA.

In January 2020, the first documented patient in the United States infected with severe acute respiratory syndrome coronavirus 2 was diagnosed in Washington State. Since that time, community spread of coronavirus disease 2019 (COVID-19) in the state has changed the practice of oncologic care at our comprehensive cancer center in Seattle. At the Seattle Cancer Care Alliance, the primary oncology clinic for the University of Washington/Fred Hutchinson Cancer Consortium, our specialists who manage adult patients with hematologic malignancies have rapidly adjusted clinical practices to mitigate the potential risks of COVID-19 to our patients. We suggest that our general management decisions and modifications in Seattle are broadly applicable to patients with hematologic malignancies. Despite a rapidly changing environment that necessitates opinion-based care, we provide recommendations that are based on best available data from clinical trials and collective knowledge of disease states.
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http://dx.doi.org/10.1200/OP.20.00241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489485PMC
September 2020

ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1.

Future Oncol 2020 May 6;16(15):991-999. Epub 2020 Apr 6.

University of Washington/Fred Hutchinson Cancer Center, Seattle, WA, USA.

While combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) cures most patients with diffuse large B-cell lymphoma (DLBCL), those with high-risk international prognostic index disease have inferior survival. Enzastaurin as a potent inhibitor of PKC-β and PI3K/AKT pathway suppressor has been tested in many clinical trials including two key studies in DLBCL: Phase III maintenance study (Preventing Relapse in Lymphoma Using Daily Enzastaurin [PRELUDE]) and a first-line Phase II study (S028). DNA extracted from PRELUDE patients' blood samples was retrospectively genotyped identifying a novel genetic biomarker, DGM1 that showed high correlation with response to enzastaurin. A similar finding observed in the S028 study suggested that addition of enzastaurin to R-CHOP may significantly improve outcomes as frontline therapy for high-risk DGM1 positive DLBCL patients. ENGINE is a global, multicenter, placebo-controlled and randomized study to compare the effect of R-CHOP/enzastaurin as frontline treatment in high-risk DLBCL patients. The primary end point for this study is overall survival in patients who are DGM1 positive. Clinical Trial Registration Identifier: NCT03263026.
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http://dx.doi.org/10.2217/fon-2020-0176DOI Listing
May 2020

Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy.

Br J Haematol 2020 06 6;189(6):1119-1126. Epub 2020 Feb 6.

Division of Medical Oncology, Department of Internal Medicine, University of Washington, Seattle, WA, USA.

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.
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http://dx.doi.org/10.1111/bjh.16494DOI Listing
June 2020

Impact of Double- or Triple-Hit Pathology on Rates and Durability of Radiation Therapy Response Among Patients With Relapsed or Refractory Large B-Cell Lymphoma.

Pract Radiat Oncol 2020 Jan - Feb;10(1):44-52. Epub 2019 Oct 1.

Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington. Electronic address:

Purpose: Double-hit lymphomas and triple-hit lymphomas (DHL/THL), also known as high-grade B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, are associated with chemoresistance and inferior survival. However, whether radiation therapy (RT) efficacy is altered in DHL/THL is less well characterized. Among patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), we compared rates and durability of response between patients with and without DHL/THL.

Methods And Materials: We retrospectively reviewed consecutive R/R LBCL patients who were irradiated at a single institution from January 2008 to June 2017. Patients in whom c-MYC rearranged status was known were evaluated for response to RT, in-field control, progression-free, and overall survival.

Results: Among 245 irradiated patients with LBCL, 41 patients with confirmed c-MYC status were treated for R/R disease (14 DHL/THL, 27 non-DHL/THL) and formed our cohort. Compared with non-DHL/THL, more DHL/THL patients had progressive disease at RT (71% vs 48%), had larger gross tumor volumes (GTV; median 696 mL vs 117 mL), and were treated with palliative intent (71% vs 41%). Despite similar RT doses (median 35 Gy), radiographic complete response rate was lower among DHL/THL patients: 14.3% versus 64.7% (P = .01). With a median 2 years of follow-up, one in-field failure was observed in each group. DHL/THL patients had inferior progression-free survival (7% vs 46%; P = .02) and overall survival (14% vs 68%; P = .03) at 6 months.

Conclusions: R/R LBCL is responsive to RT, although rates of response are lower among DHL/THL patients. Given poor survival after RT, in-field control was hard to evaluate in this cohort. Larger cohorts are required to better elucidate whether differences in response rates are driven by larger disease burden at RT versus tumor biology. These findings are of increasing pertinence in light of use of RT as bridging therapy to cellular immunotherapies.
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http://dx.doi.org/10.1016/j.prro.2019.09.013DOI Listing
June 2020

Refugia under threat: Mass bleaching of coral assemblages in high-latitude eastern Australia.

Glob Chang Biol 2019 11 31;25(11):3918-3931. Epub 2019 Aug 31.

Australian Research Council Centre of Excellence for Coral Reef Studies, School of Biological Sciences, The University of Queensland, St. Lucia, QLD, Australia.

Environmental anomalies that trigger adverse physiological responses and mortality are occurring with increasing frequency due to climate change. At species' range peripheries, environmental anomalies are particularly concerning because species often exist at their environmental tolerance limits and may not be able to migrate to escape unfavourable conditions. Here, we investigated the bleaching response and mortality of 14 coral genera across high-latitude eastern Australia during a global heat stress event in 2016. We evaluated whether the severity of assemblage-scale and genus-level bleaching responses was associated with cumulative heat stress and/or local environmental history, including long-term mean temperatures during the hottest month of each year (SST ), and annual fluctuations in water temperature (SST ) and solar irradiance (PARZ ). The most severely-bleached genera included species that were either endemic to the region (Pocillopora aliciae) or rare in the tropics (e.g. Porites heronensis). Pocillopora spp., in particular, showed high rates of immediate mortality. Bleaching severity of Pocillopora was high where SST was low or PARZ was high, whereas bleaching severity of Porites was directly associated with cumulative heat stress. While many tropical Acropora species are extremely vulnerable to bleaching, the Acropora species common at high latitudes, such as A. glauca and A. solitaryensis, showed little incidence of bleaching and immediate mortality. Two other regionally-abundant genera, Goniastrea and Turbinaria, were also largely unaffected by the thermal anomaly. The severity of assemblage-scale bleaching responses was poorly explained by the environmental parameters we examined. Instead, the severity of assemblage-scale bleaching was associated with local differences in species abundance and taxon-specific bleaching responses. The marked taxonomic disparity in bleaching severity, coupled with high mortality of high-latitude endemics, point to climate-driven simplification of assemblage structures and progressive homogenisation of reef functions at these high-latitude locations.
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http://dx.doi.org/10.1111/gcb.14772DOI Listing
November 2019

Reward reactivity and dark flow in slot-machine gambling: "Light" and "dark" routes to enjoyment.

J Behav Addict 2019 Sep 28;8(3):489-498. Epub 2019 Aug 28.

Department of Psychology,University of Winnipeg, Winnipeg, MB,Canada.

Background And Aims: Slot machines are a very popular form of gambling. In this study, we look at two different routes to enjoying slots play. One route involves the degree to which players react to rewards. The other route involves what we call dark flow - a pleasurable, but maladaptive state where players become completely engrossed in slots play, providing an escape from the depressing thoughts that characterize their everyday lives.

Methods: One hundred and twenty-nine high-frequency slots players were tested on slot-machine simulators set up in the lobby of a casino. We measured reward reactivity using post-reinforcement pauses (PRPs) and the force with which players pressed the spin button following different slot-machine outcomes. For each player, we calculated the slopes of PRPs and force as a function of credit gains. We also assessed players' slots game enjoyment and their experience of dark flow, depression, and problem gambling.

Results: Both the PRP and the force measures of reward reactivity were significantly correlated with players' enjoyment of the slots session, but neither measure was correlated with either problem gambling or depression. Ratings of dark flow were strongly correlated with slots enjoyment (which accounted for far more positive affect variance than the reward reactivity measures) and were correlated with both problem gambling scores and depression.

Discussion And Conclusions: Our results suggest that of these two routes to enjoying slot-machine play, the dark flow route is especially problematic. We contend that the dark flow state may be enjoyable because it provides escape from the negative thoughts linked to depression.
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http://dx.doi.org/10.1556/2006.8.2019.38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044632PMC
September 2019

A functional magnetic resonance imaging investigation of the autonomous sensory meridian response.

PeerJ 2019 21;7:e7122. Epub 2019 Jun 21.

Department of Radiology, University of Manitoba, Winnipeg, MB, Canada.

Background: Autonomous Sensory Meridian Response (ASMR) is a sensory-emotional experience in which specific stimuli (ASMR "triggers") elicit tingling sensations on the scalp, neck, and shoulders; these sensations are accompanied by a positive affective state. In the current research, functional magnetic resonance imaging (fMRI) was used in order to delineate the neural substrates of these responses.

Methods: A total of 17 individuals with ASMR and 17 age- and sex-matched control participants underwent fMRI scanning while watching six 4-minute videos. Three of the videos were designed to elicit ASMR tingling and three videos were not.

Results: The results demonstrated that ASMR videos have a distinct effect on the neural activity of individuals with ASMR. The contrast of ASMR participants' responses to ASMR videos showed greater activity in the cingulate gyrus as well as in cortical regions related to audition, movement, and vision. This activity was not observed in control participants. The contrast of ASMR and control participants' responses to ASMR-eliciting videos detected greater activity in right cingulate gyrus, right paracentral lobule, and bilateral thalamus in ASMR participants; control participants showed greater activity in the lingula and culmen of the cerebellum.

Conclusions: Together, these results highlight the fact that ASMR videos elicit activity in brain areas related to sensation, emotion, and attention in individuals with ASMR, but not in matched control participants.
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http://dx.doi.org/10.7717/peerj.7122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590446PMC
June 2019

NCCN Guidelines Insights: B-Cell Lymphomas, Version 3.2019.

J Natl Compr Canc Netw 2019 06;17(6):650-661

National Comprehensive Cancer Network.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.
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http://dx.doi.org/10.6004/jnccn.2019.0029DOI Listing
June 2019