The CNS Relapse in T-Cell Lymphoma Index Predicts CNS Relapse in Patients with T- and NK-Cell Lymphomas.

Little is known about risk factors for central nervous system (CNS) relapse in mature T- and NK-cell neoplasms (MTNKN). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKN, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (N=182), of whom 91 had CNS relapse, we applied a LASSO Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (N=566). CNS relapse was most frequently observed in patients with PTCL, NOS (25%). Median time to CNS relapse and median overall survival after CNS relapse was 8.0 months and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (N=158) and high-risk (N=188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (HR 5.24, 95%CI 1.50-18.26, P=0.018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at highest risk of developing CNS relapse.

A US Multicenter Collaborative Study on Outcomes of Hematopoietic Cell Transplantation in Hepatosplenic T-Cell Lymphoma.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive type of peripheral T-cell lymphoma with median overall survival (OS) of approximately 1 year. Data on the effectiveness of hematopoietic cell transplantation (HCT) is limited, as is the choice between autologous HCT (auto-HCT) and allogeneic HCT (allo-HCT) in the treatment of this disease. To evaluate the outcome of patients with HSTCL who underwent either auto-HCT or allo-HCT, we performed a multi-institutional retrospective cohort study to assess outcomes of HCT in HSTCL patients. Fifty-three patients with HSTCL were included in the study. Thirty-six patients received an allo-HCT and 17 received an auto-HCT. Thirty-five (66%) were males. Median age at diagnosis was 38 (range 2 to 64) years. Median follow-up for survivors was 75 months (range 8 to 204). The median number of prior lines of therapy was 1 (range 1 to 4). Median OS and progression-free survival (PFS) for the entire cohort were 78.5 months (95% CI: 25 to 79) and 54 months (95% CI: 18 to 75), respectively. There were no significant differences in OS (HR: 0.63, 95% CI: 0.28 to 1.45, P = .245) or PFS (HR: 0.7, 95% CI: 0.32 to 1.57, P = .365) between the allo-HCT and auto-HCT groups, respectively. In the allo-HCT group, the 3-year cumulative incidence of relapse was 35% (95% CI: 21 to 57), while 3-year cumulative incidence of NRM was 16% (95% CI: 7 to 35). In the auto-HCT group, the 3-year cumulative incidence of relapse and NRM were 43% (95% CI: 23 to 78) and 14% (95% CI: 4 to 52), respectively. Both Auto-HCT and Allo-HCT are effective consolidative strategies in patients with HSTCL, and patients should be promptly referred for HCT evaluation.

A paradox of choice: Sequencing therapy in relapsed/refractory diffuse large B-cell lymphoma.

The available treatments for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have experienced a dramatic change since 2017. Incremental advances in basic and translational science over several decades have led to innovations in immune-oncology. These innovations have culminated in eight separate approvals by the US Food and Drug Administration for the treatment of patients with R/R DLBCL over the last 10 years. High-dose therapy and autologous stem cell transplant (HDT-ASCT) remains the standard of care for transplant-eligible patients who relapse after an initial remission. For transplant-ineligible patients or for those who relapse following HDT-ASCT, multiple options exist. Monoclonal antibodies targeting CD19, antibody-drug conjugates, bispecific antibodies, immune effector cell products, and other agents with novel mechanisms of action are now available for patients with R/R DLBCL. There is increasing use of chimeric antigen receptor (CAR) T-cells as second-line therapy for patients with early relapse of DLBCL or those who are refractory to initial chemoimmunotherapy. The clinical benefits of these strategies vary and are influenced by patient and disease characteristics, as well as the type of prior therapy administered. Therefore, there are multiple clinical scenarios that clinicians might encounter when treating R/R DLBCL. An optimal sequence of drugs has not been established, and there is no evidence-based consensus on how to best order these agents. This abundance of choices introduces a paradox: proliferating treatment options are initially a boon to patients and providers, but as choices grow further they no longer liberate. Rather, more choices make the management of R/R DLBCL more challenging due to lack of direct comparisons among agents and a desire to maximize patient outcomes. Here, we provide a review of recently-approved second- and subsequent-line agents, summarize real-world data detailing the use of these medicines, and provide a framework for sequencing therapy in R/R DLBCL.

Perioperative Blood Transfusions and Anastomotic Leak After Colorectal Surgery for Cancer in an Australian Hospital.

PURPOSE: Peri-operative blood transfusion has been identified as a risk factor for anastomotic leak in recent studies, but little is known about which patients are at risk for blood transfusion. This study aims to assess the relationship between blood transfusion and anastomotic leak and factors predisposing to leak in patients undergoing colorectal cancer surgery. METHODS: This retrospective cohort study was conducted in a tertiary hospital in Brisbane, Australia, between 2010 and 2019. A total of 522 patients underwent resection of colorectal cancer with primary anastomosis with no covering stoma and the prevalence of anastomotic leak was compared between those who had had perioperative blood transfusion(s) and those who had not. RESULTS: A total of 19 of 522 patients undergoing surgery for colorectal cancer had developed an anastomotic leak (3.64%). 11.3% of patients who had had a perioperative blood transfusion developed an anastomotic leak whereas 2.2% of patients who had not had a blood transfusion developed an anastomotic leak (p = 0.0002). Patients undergoing procedure on their right colon had proportionally more blood transfusions and this approached statistical significance (p = 0.06). Patients who received a greater quantity of units of blood transfusion prior to their diagnosis of anastomotic leak were more likely to develop an anastomotic leak (p = 0.001). CONCLUSION: Perioperative blood transfusions are associated with a significantly increased risk of an anastomotic leak following bowel resection with primary anastomosis for colorectal cancer.

Premature Death in Bodybuilders: What Do We Know?

Premature deaths in bodybuilders regularly make headlines and are cited as evidence that bodybuilding is a dangerous activity. A wealth of research has revealed elite athletes typically enjoy lower mortality rates than non-athletes, but research on bodybuilder lifespan is surprisingly limited. Anabolic androgenic steroid (AAS) use is commonly cited as a key contributor to morbidity and premature mortality in bodybuilders, but this area of research is highly nuanced and influenced by numerous confounders unique to bodybuilding. It is quite possible that bodybuilders are at elevated risk and that AAS use is the primary reason for this, but there remains much unknown in this realm. As global participation in bodybuilding increases, and healthcare providers play a more active role in monitoring bodybuilder health, there is a need to identify how numerous factors associated with bodybuilding ultimately influence short- and long-term health and mortality rate. In this Current Opinion, we discuss what is currently known about the bodybuilder lifespan, identify the nuances of the literature regarding bodybuilder health and AAS use, and provide recommendations for future research on this topic.

Designing Ruby: Protocol for a 2-Arm, Brief, Digital Randomized Controlled Trial for Internalized Weight Bias.

BACKGROUND: Weight bias internalization, also known as weight self-stigma, is a serious health concern for individuals with higher body weight. Weight bias internalization is associated with the greater avoidance of health care and health-promoting activities, disordered eating, social isolation, and weight gain. Elevated weight bias internalization has been associated with low self-compassion, yet few investigations have explored self-compassion as a potential mechanism for reducing internalized weight bias. OBJECTIVE: Ruby is a 2-arm randomized controlled trial that was designed to test the efficacy of a 4-week digital self-compassion intervention to reduce internalized weight bias compared with a wait-list control. METHODS: Adults with elevated internalized weight bias and a BMI of >30 kg/m2 (N=80) were recruited. Ruby is a standalone digital trial that will be delivered entirely via a smartphone and will involve web-based data collection and text messages. The intervention content will include psychoeducation and daily mindfulness practices with a focus on self-compassion and body concerns. We will use intent-to-treat analyses to examine changes in weight bias internalization throughout time by treatment arm. The analyses will be conducted by using one-way analysis of covariance models and linear mixed models. RESULTS: The protocol was designed in May 2020 and approved in December 2020. Data collection is currently underway. CONCLUSIONS: Ruby will be the first digital standalone, self-compassion-based intervention designed to reduce internalized weight bias. Owing to its standalone digital delivery, Ruby may be a highly scalable treatment for internalized weight bias that can be delivered on its own or combined with other treatments. We expect Ruby to be accessible to many, as participants can access the digital intervention at times of the day that are the most convenient in their schedule and are not burdened by in-person time commitments, which can be a barrier for participants with competing demands on their time and resources. If efficacious, Ruby will be poised to expand a burgeoning body of literature related to psychological intervention in this area. TRIAL REGISTRATION: ClinicalTrials.gov NCT04678973; https://clinicaltrials.gov/ct2/show/NCT04678973. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31307.

Integrating Datasets on Public Health and Clinical Aspects of Sickle Cell Disease for Effective Community-Based Research and Practice.

Sickle cell disease (SCD) is a genetic disease that has multiple aspects including public health and clinical aspects. The goals of the research study were to (1) understand the public health aspects of sickle cell disease, and (2) understand the overlap between public health aspects and clinical aspects that can inform research and practice beneficial to stakeholders in sickle cell disease management. The approach involved the construction of datasets from textual data sources produced by experts on sickle cell disease including from landmark publications published in 2020 on sickle cell disease in the United States. The interactive analytics of the integrated datasets that we produced identified that community-based approaches are common to both public health and clinical aspects of sickle cell disease. An interactive visualization that we produced can aid the understanding of the alignment of governmental organizations to recommendations for addressing sickle cell disease in the United States. From a global perspective, the interactive analytics of the integrated datasets can support the knowledge transfer stage of the SICKLE recommendations (Skills transfer, Increasing self-efficacy, Coordination, Knowledge transfer, Linking to adult services, and Evaluating readiness) for effective pediatric to adult transition care for patients with sickle cell disease. Considering the increased digital transformations resulting from the COVID-19 pandemic, the constructed datasets from expert recommendations can be integrated within remote digital platforms that expand access to care for individuals living with sickle cell disease. Finally, the interactive analytics of integrated expert recommendations on sickle cell disease management can support individual and team expertise for effective community-based research and practice.

Phenotypic plasticity and local adaptation in freeze tolerance: Implications for parasite dynamics in a changing world.

Marshallagia marshalli is a multi-host gastrointestinal nematode that infects a variety of artiodactyl species from temperate to Arctic latitudes. Eggs of Marshallagia are passed in host faeces and develop through three larval stages (L1, L2, and L3) in the environment. Although eggs normally hatch as L1s, they can also hatch as L3s. We hypothesised that this phenotypic plasticity in hatching behaviour may improve fitness in subzero and highly variable environments, and this may constitute an evolutionary advantage under current climate change scenarios. To test this, we first determined if the freeze tolerance of different free-living stages varied at different temperatures (-9 °C, -20 °C and -35 °C). We then investigated if there were differences in freeze tolerance of M. marshalli eggs sourced from three discrete, semi-isolated, populations of wild bighorn and thinhorn sheep living in western North America (latitudes: 40°N, 50°N, 64°N). The survival rates of eggs and L3s were significantly higher than L1s at -9 °C and -20 °C, and survival of all three stages decreased significantly with increasing freeze duration and decreasing temperature. The survival of unhatched L1s was significantly higher than the survival of hatched L1s. There was no evidence of local thermal adaptation in freeze tolerance among eggs from different locations. We conclude that developing to the L3 in the egg may result in a fitness advantage for M. marshalli, with the egg protecting the more vulnerable L1 under freezing conditions. This phenotypic plasticity in life-history traits of M. marshalli might be an important capacity, a potential exaptation capable of enhancing parasite fitness under temperature extremes.

The Emotional and Behavioral Impact of Delivering Bad News to Virtual versus Real Standardized Patients: A Pilot Study.

Phenomenon: Virtual standardized patients (vSPs) are becoming increasingly common in medical education, though one limitation of vSPs is the artificiality of computer-based simulators. Past research on the use of vSPs has not clearly established whether learners have different emotional responses to real SPs (rSPs) compared with vSPs; however, understanding learners' emotional responses to vSPs is important in providing realistic learning experiences and establishing the validity of this teaching and assessment tool. This study compared the emotional experiences of individuals who interacted with rSPs and vSPs. Approach: Sixty medical students at a medical school in the southeastern United States participated in the study. Participants were randomly assigned to deliver bad news to an rSP or vSP. The vSP for this study used a hybrid intelligence model that allowed a person to "inhabit" the vSP. Salivary cortisol and a self-report measure of mood-the Profile of Mood States, Second Edition (POMS 2)-were gathered before and after delivering the bad news. The SP and 2 independent evaluators rated the behavioral performance of each participant in real and virtual conditions. Participants also rated the performance of the SP. Findings: Participants in both conditions reported increased negative emotionality on the POMS 2 following the SP interaction. There were no significant between-group differences on the POMS 2 or salivary cortisol concentration following the SP interaction. Ratings by the SP and independent evaluators indicated that participants performed similarly on most interpersonal dimensions, except tone of voice. Participants perceived the vSP as less realistic than the rSP. Insights: These results suggest that medical students may have similar emotional and behavioral responses when delivering bad news to a vSP when compared to an rSP. These findings provide support for the continued use of vSPs in training learners to deliver bad news and other communication-based skills and to assess their performance on these tasks.

Consistent self-monitoring in a commercial app-based intervention for weight loss: results from a randomized trial.

Self-monitoring is the strongest predictor of success in lifestyle interventions for obesity. In this secondary analysis of the GoalTracker trial, we describe outcomes of consistently self-monitoring in a standalone weight loss intervention. The 12-week intervention focused on daily self-monitoring of diet and/or body weight in a commercial app (MyFitnessPal). Participants (N = 100; 21-65 years; BMI 25-45 kg/m2) were categorized as Consistent Trackers if they tracked ≥ 6 out of 7 days for at least 75% of the targeted weeks. One-fourth of participants were Consistent Trackers. This subset was more likely to be married or living with a partner, be non-Hispanic White, and have higher health literacy than Inconsistent Trackers (ps < .05). Consistent tracking was associated with greater weight change than inconsistent tracking at 1 month (mean difference [95% CI] - 1.11 kg [- 2.12, - 0.10]), 3 months (- 2.42 kg [- 3.80, - 1.04]), and 6 months (- 2.13 kg [- 3.99, - 0.27]). Over 3 times as many Consistent Trackers as Inconsistent Trackers achieved ≥ 5% weight loss at 3 months (48 vs. 13%) and at 6 months (54 vs. 15%; ps < .001). Though causality cannot be determined by the present study, tracking weight and/or diet nearly every day per week for 12 weeks in a commercial app may serve as an effective strategy for weight loss. Strategies are needed to promote greater consistency in tracking.

Comparing Self-Monitoring Strategies for Weight Loss in a Smartphone App: Randomized Controlled Trial.

BACKGROUND: Self-monitoring of dietary intake is a valuable component of behavioral weight loss treatment; however, it declines quickly, thereby resulting in suboptimal treatment outcomes. OBJECTIVE: This study aimed to examine a novel behavioral weight loss intervention that aims to attenuate the decline in dietary self-monitoring engagement. METHODS: GoalTracker was an automated randomized controlled trial. Participants were adults with overweight or obesity (n=105; aged 21-65 years; body mass index, BMI, 25-45 kg/m2) and were randomized to a 12-week stand-alone weight loss intervention using the MyFitnessPal smartphone app for daily self-monitoring of either (1) both weight and diet, with weekly lessons, action plans, and feedback (Simultaneous); (2) weight through week 4, then added diet, with the same behavioral components (Sequential); or (3) only diet (App-Only). All groups received a goal to lose 5% of initial weight by 12 weeks, a tailored calorie goal, and automated in-app reminders. Participants were recruited via online and offline methods. Weight was collected in-person at baseline, 1 month, and 3 months using calibrated scales and via self-report at 6 months. We retrieved objective self-monitoring engagement data from MyFitnessPal using an application programming interface. Engagement was defined as the number of days per week in which tracking occurred, with diet entries counted if ≥800 kcal per day. Other assessment data were collected in-person via online self-report questionnaires. RESULTS: At baseline, participants (84/100 female) had a mean age (SD) of 42.7 (11.7) years and a BMI of 31.9 (SD 4.5) kg/m2. One-third (33/100) were from racial or ethnic minority groups. During the trial, 5 participants became ineligible. Of the remaining 100 participants, 84% (84/100) and 76% (76/100) completed the 1-month and 3-month visits, respectively. In intent-to-treat analyses, there was no difference in weight change at 3 months between the Sequential arm (mean -2.7 kg, 95% CI -3.9 to -1.5) and either the App-Only arm (-2.4 kg, -3.7 to -1.2; P=.78) or the Simultaneous arm (-2.8 kg, -4.0 to -1.5; P=.72). The median number of days of self-monitoring diet per week was 1.9 (interquartile range [IQR] 0.3-5.5) in Sequential (once began), 5.3 (IQR 1.8-6.7) in Simultaneous, and 2.9 (IQR 1.2-5.2) in App-Only. Weight was tracked 4.8 (IQR 1.9-6.3) days per week in Sequential and 5.1 (IQR 1.8-6.3) days per week in Simultaneous. Engagement in neither diet nor weight tracking differed between arms. CONCLUSIONS: Regardless of the order in which diet is tracked, using tailored goals and a commercial mobile app can produce clinically significant weight loss. Stand-alone digital health treatments may be a viable option for those looking for a lower intensity approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT03254953; https://clinicaltrials.gov/ct2/show/NCT03254953 (Archived by WebCite at http://www.webcitation.org/72PyQrFjn).

Author Correction: Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration.

Myeloid derived suppressor cells (MDSC) produce nitric oxide (NO) and inhibit dendritic cell (DC) immune responses in cancer. DCs present cancer cell antigens to CD4+ T cells through Jak-STAT signal transduction. In this study, NO donors (SNAP and DETA-NONOate) inhibited DC antigen presentation. As expected, MDSC isolated from peripheral blood mononuclear cells (PBMC) from cancer patients produced high NO levels. We hypothesized that NO producing MDSC in tumor-bearing hosts would inhibit DC antigen presentation. Antigen presentation from DCs to CD4+ T cells (T cell receptor transgenic OT-II) was measured via a [3H]-thymidine incorporation proliferation assay. MDSC from melanoma tumor models decreased the levels of proliferation more than pancreatic cancer derived MDSC. T cell proliferation was restored when MDSC were treated with inhibitors of inducible nitric oxide synthase (L-NAME and NCX-4016). A NO donor inhibited OT II T cell receptor recognition of OT II specific tetramers, thus serving as a direct measure of NO inhibition of antigen presentation. Our group has previously demonstrated that STAT1 nitration also mediates MDSC inhibitory effects on immune cells. Therefore, a novel liquid chromatography-tandem mass spectrometry assay demonstrated that nitration of the STAT1-Tyr701 occurs in PBMC derived from both pancreatic cancer and melanoma patients.

MicroRNA profiling of patient plasma for clinical trials using bioinformatics and biostatistical approaches.

BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs that function to repress translation of mRNA transcripts and contribute to the development of cancer. We hypothesized that miRNA array-based technologies work best for miRNA profiling of patient-derived plasma samples when the techniques and patient populations are precisely defined. METHODS: Plasma samples were obtained from five sources: melanoma clinical trial of interferon and bortezomib (12), purchased normal donor plasma samples (four), gastrointestinal tumor bank (nine), melanoma tumor bank (ten), or aged-matched normal donors (eight) for the tumor bank samples. Plasma samples were purified for miRNAs and quantified using NanoString® arrays or by the company Exiqon. Standard biostatistical array approaches were utilized for data analysis and compared to a rank-based analytical approach. RESULTS: With the prospectively collected samples, fewer plasma samples demonstrated visible hemolysis due to increased attention to eliminating factors, such as increased pressure during phlebotomy, small gauge needles, and multiple punctures. Cancer patients enrolled in a melanoma clinical study exhibited the clearest pattern of miRNA expression as compared to normal donors in both the rank-based analytical method and standard biostatistical array approaches. For the patients from the tumor banks, fewer miRNAs (<5) were found to be differentially expressed and the false positive rate was relatively high. CONCLUSION: In order to obtain consistent results for NanoString miRNA arrays, it is imperative that patient cohorts have similar clinical characteristics with a uniform sample preparation procedure. A clinical workflow has been optimized to collect patient samples to study plasma miRNAs.

A phase I study of recombinant (r) vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-α-2b in patients with CEA-expressing carcinomas.

Prime-boost vaccination with recombinant (r) vaccinia(V)-CEA(6D)-TRICOM (triad of co-stimulatory molecules B7.1, ICAM-1 and LFA-3) and rFowlpox(F)-CEA(6D)-TRICOM infect antigen-presenting cells and direct expression of co-stimulatory molecules. We hypothesized that co-administration of vaccine with GM-CSF and interferon alpha (IFN-α) would have efficacy in CEA-expressing cancers. Patients with CEA-expressing cancers received the rV-CEA(6D)-TRICOM vaccine subcutaneously (s.c.) on day 1 followed by GM-CSF s.c. to the injection site on days 1-4. In Cycle 1, patients received thrice weekly s.c. injections of IFN-α-2b the week after rV-CEA(6D)-TRICOM. In Cycles 2-4, patients received thrice weekly s.c. injections of IFN-α-2b the same week that rF-CEA(6D)-TRICOM was given. The first cohort received no IFN followed by dose escalation of IFN-α in subsequent cohorts. Thirty-three patients were accrued (mean 59.8 years). Grade 3 toxicities included fatigue and hyperglycemia. Grade 4-5 adverse events (unrelated to treatment) were confusion (1), elevated aspartate transaminase (AST)/alanine transaminase (ALT) (1), and sudden death (1). No patients had a partial response, and eight patients exhibited stable disease of ≥3 months. Median progression-free survival and overall survival (OS) were 1.8 and 6.3 months, respectively. Significantly higher serum CD27 levels were observed after vaccine therapy (p = 0.006 post 1-2 cycles, p = 0.003 post 3 cycles, p = 0.03 post 4-7 cycles) and 42 % of patients assayed developed CEA-specific T cell responses. Pre-treatment levels of myeloid-derived suppressor cells correlated with overall survival (p = 0.04). Administration of IFN-α led to significantly increased OS (p = 0.02) compared to vaccine alone. While the vaccine regimen produced no clinical responses, IFN-α administration was associated with improved survival.

Roles of natural killer cells in antiviral immunity.

Natural killer (NK) cells are important in immune defense against virus infections. This is predominantly considered a function of rapid, innate NK-cell killing of virus-infected cells. However, NK cells also prime other immune cells through the release of interferon gamma (IFN-γ) and other cytokines. Additionally, NK cells share features with long-lived adaptive immune cells and can impact disease pathogenesis through the inhibition of adaptive immune responses by virus-specific T and B cells. The relative contributions of these diverse and conflicting functions of NK cells in humans are poorly defined and likely context-dependent, thereby complicating the development of therapeutic interventions. Here we focus on the contributions of NK cells to disease in diverse virus infections germane to human health.