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Hematopoietic cell transplant (HCT) is an increasingly common and curative treatment strategy to improve survival among individuals with malignant and nonmalignant diseases, with over one million HCTs having been performed worldwide. Neurocognitive dysfunction is a common and untoward consequence of HCT for many recipients, although few studies have examined the profile of neurocognitive impairments in HCT or their association with clinical features, such as frailty, or the incidence of pre-HCT neurocognitive impairments across all ages, which may influence post-HCT neurocognitive impairments. We examined the pattern and correlates of pre-transplant neurocognitive dysfunction in a prospective sample of adults undergoing HCT. Neurocognition was assessed using the Montreal Cognitive Assessment Battery. Frailty was assessed using the Short Physical Performance Battery. Linear regression analysis was used to examine the associations between neurocognitive performance and frailty. Neurocognitive screening profiles were also examined by partitioning MoCA into domain scores, including Executive Function and Memory. We also examined the associations between neurocognition, frailty, and clinical outcomes, including length of transplant hospitalization and survival. One hundred and ten adults were evaluated across a wide age range (range: 19-75; mean age = 54.7 [SD = 14.1]). Neurocognitive performance tended to fall below published normative levels (mean MoCA = 25.5 [SD = 4.1]), with 17% of participants demonstrating impaired performance compared with medical normative data (MoCA ≤ 22) and 34% exhibiting impaired performance relative to healthy samples (MoCA ≤ 25). Mild impairments (MoCA ≤ 25) were common across age ranges, including middle-aged patients (23% for age < 50; 35% for age 50-60, 41% for age ≥ 60), particularly for items assessing Executive Function. Greater levels of frailty associated with lower neurocognitive screening scores (r = -0.29, P < 0.01) and Executive Functioning (r = -0.24, P < 0.01), whereas greater age was associated with poorer Memory performance only (r = -0.33, P < 0.01). Greater levels of frailty prior to transplant associated with longer length of stay (β = 0.10, P = 0.046), but were not associated with survival. Neurocognitive impairments are common among adults undergoing HCT and the pattern of performance varies by age. Pre-transplant frailty is associated with neurocognitive functioning and may portend worse post-transplant early clinical outcomes.

Background Non-small cell lung cancer (NSCLC) is responsible for the most cancer-related deaths in the United States. A better understanding of treatment-related disparities and ways to address them are important to improving survival for patients with metastatic NSCLC. Materials and Methods We performed a retrospective analysis using the National Cancer Database. Included in this analysis were 107,116 patients with metastatic NSCLC who were treated at academic centers (AC), community-based centers (CC), and integrated centers (IC) between 2004 and 2015. The primary end point was overall survival, with comparisons of AC, CC, and IC. Results The survival disparity between AC and CC continued to grow over the study period, from a 5.7% difference in 2-year survival to a 7.5% difference. Treatment at IC was initially associated with survival similar to CC (hazard ratio [HR], 0.93), however, later in the study period treatment at IC improved (HR, 0.74) outpacing the improvement in survival in CC (HR, 0.82) but not to the same degree as the improvement in AC (HR, 0.64). The improvement in survival at IC was noted predominantly in patients with adenocarcinoma (HR, 0.72; P Conclusion Treatment of metastatic NSCLC at IC was associated with improved survival during our study period compared with treatment at CC. This appeared to be histology-dependent, suggesting a treatment-related improvement in survival because over this period newer therapies were preferentially available for adenocarcinoma. Integrating care across treatment facilities might be one way to bridge the growing gap in survival between AC and CC.

We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken.

Recent developments in precision oncology have increased the complexity of diagnostic and therapeutic decisions. Here, we broadly review the field of precision oncology and discuss common mutational drivers in non-small cell lung cancer (NSCLC) that directly relate to the diagnosis, evaluation, and treatment of patients with metastatic disease.

Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for both malignant and nonmalignant hematologic diseases; however, reported rates of treatment-related mortality approach 30%. Outcomes are worse in patients who begin HCT with functional impairments. To detect such impairments, a geriatric assessment (GA) is recommended in adults age ≥65 years. Younger HCT candidates also may be impaired because of chemotherapy regimens pre-HCT. Therefore, we hypothesized that GA can be beneficial for adult patients of all ages and subsequently created a clinical pretransplantation optimization program to assess all HCT candidates using a modified GA. One-hundred fifty-seven patients were evaluated in 4 functional domains- physical, cognitive, nutritional, and psychological-at 2 time points prior to HCT-new patient evaluation (NPE) and sign-off (SO)-between October 2017 and January 2020. At NPE, 80.9% of the patients had at least 1 domain with a functional impairment, and physical (P = .006), cognitive (P = .04), and psychological (P = .04) impairments were associated with an increased likelihood of not proceeding to HCT. In addition, patients age 18 to 39 years were more likely than older patients to have a physical function impairment (P = .001). Between NPE and SO, 51.9% of the patients had resolution of 1 or more impairments, and nutritional impairment at SO was predictive of worse overall survival (P = .01). Our study shows that GA can identify functional impairments in patients of all ages. Early identification of impairments could facilitate referrals to supportive care and resolution of impairments prior to HCT, suggesting that GA could be recommended for HCT candidates of all ages.

Evidence for hematopoietic stem cell transplantation (HCT) in autoimmune disease has been building since the 1990s; however, many clinicians may not yet be aware of its applications to autoimmune disease. We review the basic tenets of HCT and evidence for autologous HCT in multiple sclerosis (MS), systemic sclerosis (SSc), and lupus with an emphasis on recent advanced phase trials. In MS, the phase 3 randomized MIST trial and the phase 2 randomized ASTIMS trial demonstrated the efficacy of autologous HCT in refractory MS over disease-modifying therapies and mitoxantrone, respectively. In SSc, the phase 3 randomized ASTIS trial and the phase 2 randomized SCOT trial demonstrated the efficacy of autologous HCT in advanced SSc compared to cyclophosphamide. The evidence for HCT in autoimmune diseases continues to grow, particularly in MS and SSc. In lupus, large, comparative trials are still needed. Across autoimmune diseases, questions that still remain to be answered include optimizing patient selection to limit TRM, the appropriate use of MAC, and the necessity for graft manipulation. Furthermore, collaboration between disease-specific and transplant physicians is imperative to expand the appropriate use of HCT in routine clinical practice.

Hematopoietic cell transplant (HCT) is an increasingly common and curative treatment strategy to improve survival among individuals with malignant and nonmalignant diseases, with over one million HCTs having been performed worldwide. Neurocognitive dysfunction is a common and untoward consequence of HCT for many recipients, although few studies have examined the profile of neurocognitive impairments in HCT or their association with clinical features, such as frailty, or the incidence of pre-HCT neurocognitive impairments across all ages, which may influence post-HCT neurocognitive impairments. We examined the pattern and correlates of pre-transplant neurocognitive dysfunction in a prospective sample of adults undergoing HCT. Neurocognition was assessed using the Montreal Cognitive Assessment Battery. Frailty was assessed using the Short Physical Performance Battery. Linear regression analysis was used to examine the associations between neurocognitive performance and frailty. Neurocognitive screening profiles were also examined by partitioning MoCA into domain scores, including Executive Function and Memory. We also examined the associations between neurocognition, frailty, and clinical outcomes, including length of transplant hospitalization and survival. One hundred and ten adults were evaluated across a wide age range (range: 19-75; mean age = 54.7 [SD = 14.1]). Neurocognitive performance tended to fall below published normative levels (mean MoCA = 25.5 [SD = 4.1]), with 17% of participants demonstrating impaired performance compared with medical normative data (MoCA ≤ 22) and 34% exhibiting impaired performance relative to healthy samples (MoCA ≤ 25). Mild impairments (MoCA ≤ 25) were common across age ranges, including middle-aged patients (23% for age50; 35% for age 50-60, 41% for age ≥ 60), particularly for items assessing Executive Function. Greater levels of frailty associated with lower neurocognitive screening scores (r = -0.29, P 0.01) and Executive Functioning (r = -0.24, P 0.01), whereas greater age was associated with poorer Memory performance only (r = -0.33, P 0.01). Greater levels of frailty prior to transplant associated with longer length of stay (β = 0.10, P = 0.046), but were not associated with survival. Neurocognitive impairments are common among adults undergoing HCT and the pattern of performance varies by age. Pre-transplant frailty is associated with neurocognitive functioning and may portend worse post-transplant early clinical outcomes.

Background Allogeneic hematopoietic stem cell transplantation (HCT) is an often curative intent treatment, however it is associated with significant gastrointestinal (GI) toxicity and treatment related mortality. Graft-versus-host disease is a significant contributor to transplant-related mortality. We performed a phase 2 trial of the somatostatin analog pasireotide to prevent gastrointestinal toxicity and GVHD after myeloablative allogeneic HCT. Methods Patients received 0.9mg pasireotide every 12 hours from the day prior to conditioning through day +4 after HCT (or a maximum of 14 days). The primary outcomes were grade 3–4 gastrointestinal toxicity through day 30 and acute GVHD. Secondary outcomes were chronic GVHD, overall survival and relapse free survival at one year. Stool and blood samples were collected from before and after HCT for analyses of stool microbiome, local inflammatory markers, and systemic inflammatory and metabolic markers. Results were compared with matched controls. Results Twenty-six patients received pasireotide and were compared to 52 matched contemporaneous controls using a 1–2 match. Grade 3–4 GI toxicity occurred in 21 (81%) patients who received pasireotide and 35 (67%) controls (p = 0.33). Acute GVHD occurred in 15 (58%) patients in the pasireotide group and 28 (54%) controls (p = 0.94). Chronic GVHD occurred in 16 patients in the pasireotide group (64%) versus 22 patients in the control group (42%) (p = 0.12). Overall survival at 1 year in the pasireotide group was 63% (95% CI: 47%,86%) versus 82% (95% CI: 72%, 93%) in controls (log-rank p = 0.006). Relapse-free survival rate at one year was 40% (95% CI: 25%, 65%) in the pasireotide group versus 78% (95% CI: 68%, 91%) in controls (log-rank p = 0.002). After controlling for the effect of relevant covariates, patients in the pasireotide group had attenuated post-HCT loss of microbial diversity. Analysis of systemic inflammatory markers and metabolomics demonstrated feasibility of such analyses in patients undergoing allogeneic HCT. Baseline level and pre-to-post transplant changes in several inflammatory markers (including MIP1a, MIP1b, TNFa, IL8Pro, and IL6) correlated with likelihood of survival. Conclusions Pasireotide did not prevent gastrointestinal toxicity or acute GVHD compared to contemporaneous controls. Pasireotide was associated with numerically higher chronic GVHD and significantly decreased OS and RFS compared to contemporaneous controls. Pasireotide may provide a locally protective effect in the stool microbiome and in local inflammation as measured by stool calprotectin, stool beta-defensin, and stool diversity index.

Hematopoietic stem cell transplantation (HCT) is a curative treatment option for patients with hematologic conditions but presents many complications that must be managed as a complex, chronic condition. Mobile health applications (mHealth apps) may permit tracking of symptoms in HCT. In seeking strategies to manage the complexities of HCT, our team collaborated with Sicklesoft, Inc., to develop an mHealth app specifically for HCT patients to allow for daily evaluation of patient health, Technology Recordings to better Understand Bone Marrow Transplantation (TRU-BMT). The primary value of this application is that of potentially enhancing the monitoring of symptoms and general health of patients undergoing HCT, with the ultimate goal of allowing earlier detection of adverse events, earlier intervention, and improving outcomes. To first evaluate patient interest in mHealth apps, we designed and administered an interest survey to patients at the 2017 BMT-InfoNet reunion. As a follow-up to the positive feedback received, we began testing the TRU-BMT app in a Phase 1 pilot study. Thirty patients were enrolled in this single-arm study and were given the TRU-BMT mHealth app on a smartphone device in addition to a wearable activity tracker. Patients were followed for up to 180 days, all the while receiving daily app monitoring. Adherence to TRU-BMT was approximately 30% daily and 44% weekly, and greater adherence was associated with increased meal completion, decreased heart rate, and shorter hospital stay. TRU-BMT assessments of symptom severity were significantly associated with duration of hospital stay and development of chronic graft-versus-host disease. Our findings suggest that using TRU-BMT throughout HCT is feasible for patients and established a proof-of-concept for a future randomized control trial of the TRU-BMT application in HCT. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Allogeneic-HCT (allo-HCT), while potentially curative, can result in significant complications including graft versus host disease (GVHD). Prior studies suggest that metabolic syndrome may be one risk factor for GVHD. We hypothesized that hepatic steatosis on pre-HCT computed tomography (CT) scans may be a marker for development of GVHD and poor outcomes in allo-HCT. In this retrospective study, we reviewed the pre-HCT CT scans and transplant outcome data of patients who underwent allo-HCT at Duke University Medical Center from 2009 to 2017. The presence of steatosis was confirmed using CT attenuation measurements. We then assessed the association between pre-HCT hepatic steatosis and HCT-related outcomes including GVHD. 80 patients who had pre-HCT CT scans were included in the study. Pre-transplant hepatic steatosis was associated with the development of chronic GVHD (OR 4.2, p = 0.02), but was not associated with acute GVHD (OR 1.3, p = 0.7), non-relapse mortality (p = 0.81) or overall survival (p = 0.74). Based on this single center retrospective study, pre-transplant hepatic steatosis is associated with development of chronic GVHD. Further, prospective study with other imaging modalities including non-contrasted CT scans is needed to determine if this association is reproducible.

Targeting and monitoring several acute myeloid leukemia mutations sequentially provides insights into optimal treatment plans.

Background Gastrointestinal (GI) toxicity and acute graft versus host disease (GVHD) are significant morbidities associated with allogeneic hematopoietic stem cell transplantation (HSCT). The somatostatin analogue Octreotide ameliorates mucosal injury from radiation damage in pre-clinical mouse models. We hypothesized that administration of the longer-acting synthetic somatostatin analogue, Pasireotide, in the peri-transplant period would decrease acute GI toxicity and acute GVHD related to allogeneic HSCT. Methods Adult patients who underwent matched allogeneic HSCT with myeloablative conditioning were eligible for this study. Exclusion criteria included severe cardiac and endocrine abnormalities. Pasireotide was administered at 0.9mg twice daily from the day before conditioning began to day +4. The co-primary endpoints were 1) Acute GI toxicity, defined as GI toxicity occurring from the day prior to conditioning to day +30, and 2) Acute GVHD. Results were compared with 50 historical controls matched by Transplant diagnosis, Donor, Graft, GVHD prophylaxis, and Conditioning regimen. Results 36 patients were consented for the study, 25 patients received the study drug (5 screen failures, 1 insurance denial, 3 withdrew consent, 1 switched trials, 1 enrolled at an alternate center without available follow-up). There was no difference in Acute GI toxicity, which occurred in all patients in both the Pasireotide and Control groups. Grade 3 or 4 GI toxicity was similar, occurring in 20 patients (80%) in the Pasireotide group and 35 patients (70%) in the Control group. Specific GI toxicities varied in incidence between the Control and Pasireotide study groups (Figure 1), most notable for numerically higher rates of the expected toxicities abdominal pain, bloating, and vomiting in the Pasireotide group. Other common toxicities that occurred in the Pasireotide and Control groups are listed in Figure 1. There was no significant difference in incidence of overall Acute GVHD or Acute GI GVHD (Figure 2). The subset of patients who received Total Body Irradiation (TBI) conditioning had numerically lower Acute GVHD in the Pasireotide group (5/9, 55%) compared to the Control group (16/20, 80%), however this was not statistically significant (Fisher's Exact Test, p=0.21); these patients also had a lower rate of combined upper and lower GI GVHD (3/9, 33% in the Pasireotide group versus 11/20, 55% in the Control group), though this was not statistically significant (Fisher's Exact Test, p=0.43). Conclusions In this Phase 2 study, the somatostatin analogue Pasireotide did not decrease GI toxicity in allogeneic HSCT; however, in the subset of patients who received TBI conditioning, there was a numerically (but not statistically) significant decrease in overall and GI Acute GVHD. Further study in a larger cohort of patients undergoing TBI conditioning is warranted.

e14108 Background: Oncology has unique characteristics that predict early benefit from digital technologies including a culture of patient involvement in trials, genetic testing, and longitudinal assessments including objective measures. However, implementation of digital tools is slow for many reasons including lack of incentives/interoperability, and high-profile cases highlighting inadequate data governance. We report results from the Digital Medicine Society’s study of the stakeholders involved in using digital technologies to optimize health, with a focus on oncology. Methods: We performed 16 interviews with diverse Key Opinion Leaders (KOLs) including physicians, executives, senior government officials, patients, payers, tech innovators, and investors. KOLs received a pre-interview list of topics. We used the Delphi method, an evidence-based approach to compile expert opinions, to iteratively refine recommendations. Results: We identified priorities for 5 stakeholder groups to facilitate digital tool implementation (Table); all groups must also act now to develop a framework for data governance. We describe 4 categories of early success in oncologic digital tools: regimen/drug choice, drug approval efficiency, digital user training, and patient generated health data. Conclusions: Data and technology have great potential to improve cancer care. Multi-stakeholder involvement and a framework for US health data governance are needed. [Table: see text]

Introduction Although metastatic NSCLC is widely treated in both academic centers (ACs) and community-based centers (CCs), it is unclear whether outcomes are similar across both settings. A growing variety of chemotherapies and targeted agents for an increasingly histology- and molecular-based treatment strategy could provide an advantage to patients treated in ACs. Using the National Cancer Database, we investigated whether treatment at ACs was associated with a survival advantage in metastatic NSCLC. Methods We conducted a retrospective analysis of the National Cancer Database after the introduction of novel NSCLC chemotherapy agents from 1998 to 2010. The primary outcome was 2-year survival, which was analyzed by using a multivariable regression model controlling for age, year of diagnosis, sex, primary payer, histologic type, facility type (AC versus CC), and an interaction term allowing a time-based comparison of survival between ACs and CCs. Alpha was set to 0.001 because of the size of the data set. Results There were 193,279 patients included in this study. The percentage of patients achieving 2-year survival was higher in ACs versus in CCs in 1998 (11.5% versus 9.2% [+2.3%]), and by 2010, the difference had increased to 17.4% versus 13.1% (+4.3%). Multivariable analysis confirmed a significant relative increase in 2-year survival associated with ACs versus with CCs from 1998 to 2010 (p = 0.0005). A histology-dependent survival difference was also noted in adenocarcinoma versus in squamous cell carcinoma (10.2% versus 9.9% in 1998 [+0.3%], increasing to 17.3% versus 10.1% in 2010 [+7.2%]). Adenocarcinoma survival also varied by treatment facility, with the difference in 2-year survival in ACs versus in CCs increasing from 12.3% versus 9.1% (+3.2%) in 1998 to 20.5% versus 15.5% (+5%) in 2010, with a trend toward significance in our multivariable model (p = 0.005). Conclusions A greater increase in survival was noted in ACs than in CCs over this time period, and it was particularly pronounced among patients with adenocarcinoma versus in those with squamous cell carcinoma. Given the known advances in adenocarcinoma treatment compared with in squamous cell lung cancer over this time period, our study suggests that potential treatment-related disparities may exist between ACs and CCs. Further study will be needed to validate this disparity in health care and address opportunities to improve survival in patients with stage IV NSCLC across treatment settings.

Osteoarthritis (OA) is a progressive degenerative disease of articular cartilage and surrounding tissues, and is associated with both advanced age and joint injury. Biomechanical factors play a critical role in the onset and progression of OA, yet the mechanisms through which physiologic or pathologic mechanical signals are transduced into a cellular response are not well understood. Defining the role of mechanosensory pathways in cartilage during OA pathogenesis may yield novel strategies or targets for the treatment of OA. The transient receptor potential vanilloid 4 (TRPV4) ion channel transduces mechanical loading of articular cartilage via the generation of intracellular calcium ion transients. Using tissue-specific, inducible Trpv4 gene-targeted mice, we demonstrate that loss of TRPV4-mediated cartilage mechanotransduction in adulthood reduces the severity of aging-associated OA. However, loss of chondrocyte TRPV4 did not prevent OA development following destabilization of the medial meniscus (DMM). These results highlight potentially distinct roles of TRPV4-mediated cartilage mechanotransduction in age-related and post-traumatic OA, and point to a novel disease-modifying strategy to therapeutically target the TRPV4-mediated mechanotransduction pathway for the treatment of aging-associated OA.

The inability to identify, isolate, and culture intestinal epithelial stem cells (IESCs) has been prohibitive to the study and therapeutic utilization of these cells. Using a Sox9EGFPmouse model, we demonstrate that Sox9EGFPfluorescence signatures can be used to differentiate between and enrich for progenitors ( Sox9EGFPsubLo) and multipotent IESCs ( Sox9EGFPlo). Sox9EGFPlocells generate “organoids” in a recently defined culture system that mimics the native IESC niche. These organoids possess all four differentiated cell types of the small intestine epithelium, demonstrating the multipotent capacity of Sox9EGFPlocells. Our results are consistent with the previously reported observation that single IESCs generate cryptlike units without a detectable mesenchymal cell component. A prospective search revealed that CD24 is expressed in the Sox9EGFPlopopulation and marks IESCs that form organoids in culture. CD24 represents the first cell surface marker that facilitates fluorescence-activated cell sorting enrichment of IESCs with widely available antibodies without requiring a specialized fluorescent reporter gene mouse model.

Though relatively uncommon, median nerve injury following bony trauma of the upper extremity has been described in the literature following humeral fracture [4], forearm fracture [5], and combined dislocation of the shoulder and elbow [6]. Previous reports of median nerve injury from elbow dislocation describe injuries in which the median nerve remains in continuity and functional recovery is spontaneous [8, 9]. In this manuscript, we report a case of a complete, closed, median nerve rupture, requiring repair after elbow dislocation.

Sox9 is an high-mobility group box transcription factor that is expressed in the stem cell zone of the small intestine and colon. We have previously used a Sox9EGFP mouse model to demonstrate that discrete levels of Sox9 expression mark small intestine epithelial stem cells that form crypt/villus-like structures in a three-dimensional culture system (Formeister EJ, Sionas AL, Lorance DK, Barkley CL, Lee GH, Magness ST. Am J Physiol Gastrointest Liver Physiol 296: G1108–G1118, 2009; Gracz AD, Ramalingam S, Magness ST. Am J Physiol Gastrointest Liver Physiol 298: G590–G600, 2010). In the present study, we hypothesized that discrete levels of Sox9 expression would also mark colonic epithelial stem cells (CESCs). Using the Sox9EGFP mouse model, we show that lower levels of Sox9 mark cells in the transit-amplifying progenitor cell zone, while higher levels of Sox9 mark cells in the colonic crypt base. Furthermore, we demonstrate that variable SOX9 levels persist in cells of colonic adenomas from mice and humans. Cells expressing lower Sox9 levels demonstrate gene expression profiles consistent with more differentiated populations, and cells expressing higher Sox9 levels are consistent with less differentiated populations. When placed in culture, cells expressing the highest levels of Sox9 formed “colonoids,” which are defined as bodies of cultured colonic epithelial cells that possess multiple cryptlike structures and a pseudolumen. Cells expressing the highest levels of Sox9 also demonstrate multipotency and self-renewal in vitro, indicating functional stemness. These data suggest a dose-dependent role for Sox9 in normal CESCs and cells comprising colon tumors. Furthermore, distinct Sox9 levels represent a new biomarker to study CESC and progenitor biology in physiological and disease states.