Retrospective Outcomes of a New Acupuncture Service at a Comprehensive Cancer Center.

Introduction: Among cancer centers, patients' interest in acupuncture is growing, in addition to clinical research in the intervention. Their National Cancer Institute-designated comprehensive cancer center piloted an acupuncture service. Their aim was to assess whether acupuncture impacted patient self-reported symptoms as delivered clinically and discuss their implementation strategy. Methods: Patients undergoing acupuncture at a comprehensive cancer center from June 2019 to March 2020 were asked to complete a modified Edmonton Symptom Assessment Scale (ESAS) before and after each session. The authors evaluated symptom changes after acupuncture in both outpatient and inpatient settings. A change of ≥1 U, on the 0-10 scale, was considered clinically significant. Results: Three hundred and nine outpatient and 394 inpatient acupuncture sessions were provided to patients at the comprehensive cancer center during this period, of which surveys from 186 outpatient (34 patients) and 124 inpatient (57 patients) sessions were available for analysis. The highest pretreatment symptoms reported by outpatients were neuropathy (5.78), pain (5.58), and tiredness (5.59). Outpatients receiving acupuncture reported clinically significant improvements in pain (ESAS score change of -2.97), neuropathy (-2.68), decreased lack of well-being (-2.60), tiredness (-1.85), nausea (-1.83), anxiety (-1.56), activities of daily living issues (-1.32), depression (-1.23), anorexia (-1.19), insomnia (-1.14), and shortness of breath (-1.14). The most severe pretreatment symptoms reported by inpatients were pain (6.90), insomnia (6.16), and constipation (5.44). Inpatients receiving acupuncture reported clinically significant improvements in anxiety (-3.69), nausea (-3.61), insomnia (-3.26), depression (-2.98), pain (-2.77), neuropathy (-2.68), anorexia (-2.20), constipation (-1.95), and diarrhea (-1.26). Conclusion: Both outpatient and inpatient participants in this pilot acupuncture program reported clinically significant improvements in symptoms after a single acupuncture treatment. Some differences between the outpatient and inpatient settings warrant further investigation.

Are NCI Cancer Centers Providing Adolescents and Young Adults With Cancer Focused Clinical Services? A National Survey.

BACKGROUND: This study sought to evaluate the current services and delivery models of adolescent and young adult oncology (AYAO)-specific programs at NCI-designated Cancer Centers (NCI-CCs). PATIENTS AND METHODS: NCI, academic, and community cancer centers were electronically sent surveys from October to December 2020 and administered via REDCap. RESULTS: Survey responses were received from 50 of 64 (78%) NCI-CCs, primarily completed by pediatric oncologists (53%), adult oncologists (11%), and social workers (11%). Half (51%) reported an existing AYAO program, with most (66%) started within the past 5 years. Although most programs combined medical and pediatric oncology (59%), 24% were embedded within pediatrics alone. Most programs saw patients aged 15 (55%) to 39 years (66%) mainly via outpatient clinic consultation (93%). Most centers reported access to a range of medical oncology and supportive services, but dedicated services specifically for adolescent and young adults (AYAs) were available at a much lower extent, such as social work (98% vs 58%) and psychology (95% vs 54%). Although fertility preservation was offered by all programs (100%), only two-thirds of NCI centers (64%) reported providing sexual health services to AYAs. Most NCI-CCs (98%) were affiliated with a research consortium, and a lesser extent (73%) reported collaboration between adult and pediatric researchers. Nearly two-thirds (60%) reported that AYA oncology care was important/very important to their respective institution and reported providing good/excellent care to AYAs with cancer (59%), but to a lesser extent reported good/excellent research (36%), sexual health (23%), and education of staff (21%). CONCLUSIONS: Results of this first-ever national survey to assess AYAO programs showed that only half of NCI-CCs report having a dedicated AYAO program, and that areas of improvement include staff education, research, and sexual health services for patients.

Associations between symptoms with healthcare utilization and death in advanced cancer patients.

INTRODUCTION: There is limited data about assessments that are associated with increased utilization of medical services among advanced oncology patients (AOPs). We aimed to identify factors related to healthcare utilization and death in AOP. METHODS: AOPs at a comprehensive cancer center were enrolled in a Center for Medicare and Medicaid Innovation program. Participants completed the Edmonton Symptom Assessment Scale (ESAS) and the Functional Assessment of Cancer Therapy-General (FACT-G) scale. We examined factors associated with palliative care (PC), acute care (AC), emergency room (ER), hospital admissions (HA), and death. RESULTS: In all, 817 AOPs were included in these analyses with a median age of 69. They were generally female (58.7%), white (61.4%), stage IV (51.6%), and represented common cancers (31.5% GI, 25.2% thoracic, 14.3% gynecologic). ESAS pain, anxiety, and total score were related to more PC visits (B=0.31, 95% CI [0.21, 0.40], p<0.001; B=0.24 [0.12, 0.36], p<0.001; and B=0.038 [0.02, 0.06], p=0.001, respectively). Total FACT-G score and physical subscale were related to total PC visits (B=-0.021 [-0.037, -0.006], p=0.008 and B=-0.181 [-0.246, -0.117], p<0.001, respectively). Lower FACT-G social subscale scores were related to more ER visits (B=-0.03 [-0.53, -0.004], p=0.024), while increased tiredness was associated with fewer AC visits (B=-0.039 [-0.073, -0.006], p=0.023). Higher total ESAS scores were related to death within 30 days (OR=0.87 [0.76, 0.98], p=0.027). CONCLUSIONS: The ESAS and FACT-G assessments were linked to PC and AC visits and death. These assessments may be useful for identifying AOPs that would benefit from routine PC.

The perspectives of oncology healthcare providers on the role of palliative care in a comprehensive cancer center.

BACKGROUND: Palliative care (PC) is an essential part of oncologic care, but its optimal role within a cancer center remains unclear. This study examines oncology healthcare providers' perspectives about the role of PC at a comprehensive cancer center (CCC). METHODS: Physicians, nurses, and other oncology healthcare providers at a CCC were surveyed for their opinions about the role of inpatient and outpatient PC, preferences for PC services, and barriers to referral. Chi-squared tests and multiple regression analyses were performed to explore associations. RESULTS: We received 137/221 completed questionnaires (61% response rate). Respondents were generally female (78%), had ≤ 10 years of service (69%), and included physicians (32%), nurses (32%), and advanced practice providers (17%). Most respondents (82%) agreed that more patients could benefit from PC. They also agreed that PC is beneficial for both outpatient and inpatient management of complex pain (96 and 88%), complex symptoms (84 and 74%), and advanced cancer patients (80 and 64%). Transition to hospice (64 vs. 42%, p = 0.007) and goals of care (62 vs. 49%, p = 0.011) provided by PC services were more valued by respondents for the inpatient than for the outpatient setting. Barriers to utilizing PC included lack of availability, unsure of when to refer, and poor communication. The majority of respondents (83%) preferred a cancer focused PC team to provide high-quality care. CONCLUSIONS: Overall, the majority of oncology health care providers believe that more patients could benefit from PC, but opinions vary regarding the roles of inpatient and outpatient PC. Barriers and areas for improvement include availability, referral process, and improved communication.

Fabrication and maturation of integrated biphasic anatomic mesenchymal stromal cell-laden composite scaffolds for osteochondral repair and joint resurfacing.

Articular cartilage injury can lead to joint-wide erosion and the early onset of osteoarthritis. To address this, we recently developed a rapid fabrication method to produce patient-specific engineered cartilage tissues to replace an entire articular surface. Here, we extended that work by coupling a mesenchymal stromal cell-laden hydrogel (methacrylated hyaluronic acid) with the porous polycaprolactone (PCL) bone integrating phase and assessed the composition and mechanical performance of these constructs over time. To improve initial construct stability, PCL/hydrogel interface parameters were first optimized by varying PCL pretreatment (with sodium hydroxide before ethanol) before hydrogel infusion. Next, cylindrical osteochondral constructs were formed and cultured in media containing transforming growth factor ß3 for up to 8 weeks, with constructs evaluated for viability, histological features, and biochemical content. Mechanical properties were also assessed in axial compression and via an interface shear strength assay. Results showed that the fabrication process was compatible with cell viability, and that construct biochemical content and mechanical properties increased with time. Interestingly, compressive properties peaked at 5 weeks, while interfacial shear properties continued to improve beyond this time point. Finally, these fabrication methods were combined with a custom mold developed from limb-specific computed tomography imaging data to create an anatomic implantable cell-seeded biologic joint surface, which showedmaturation similar to the osteochondral cylinders. Future work will apply these advances in large animal models of critically sized osteochondral defects to study repair and whole joint resurfacing.

EAST Multicenter Trial on targeted temperature management for hanging-induced cardiac arrest.

BACKGROUND: We sought to determine the outcome of suicidal hanging and the impact of targeted temperature management (TTM) on hanging-induced cardiac arrest (CA) through an Eastern Association for the Surgery of Trauma (EAST) multicenter retrospective study. METHODS: We analyzed hanging patient data and TTM variables from January 1992 to December 2015. Cerebral performance category score of 1 or 2 was considered good neurologic outcome, while cerebral performance category score of 3 or 4 was considered poor outcome. Classification and Regression Trees recursive partitioning was used to develop multivariate predictive models for survival and neurologic outcome. RESULTS: A total of 692 hanging patients from 17 centers were analyzed for this study. Their overall survival rate was 77%, and the CA survival rate was 28.6%. The CA patients had significantly higher severity of illness and worse outcome than the non-CA patients. Of the 175 CA patients who survived to hospital admission, 81 patients (46.3%) received post-CA TTM. The unadjusted survival of TTM CA patients (24.7% vs 39.4%, p < 0.05) and good neurologic outcome (19.8% vs 37.2%, p < 0.05) were worse than non-TTM CA patients. However, when subgroup analyses were performed between those with an admission Glasgow Coma Scale score of 3 to 8, the differences between TTM and non-TTM CA survival (23.8% vs 30.0%, p = 0.37) and good neurologic outcome (18.8% vs 28.7%, p = 0.14) were not significant. Targeted temperature management implementation and post-CA management varied between the participating centers. Classification and Regression Trees models identified variables predictive of favorable and poor outcome for hanging and TTM patients with excellent accuracy. CONCLUSION: Cardiac arrest hanging patients had worse outcome than non-CA patients. Targeted temperature management CA patients had worse unadjusted survival and neurologic outcome than non-TTM patients. These findings may be explained by their higher severity of illness, variable TTM implementation, and differences in post-CA management. Future prospective studies are necessary to ascertain the effect of TTM on hanging outcome and to validate our Classification and Regression Trees models. LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic study, level III.

A Cost and Quality Analysis of Utilizing a Rectal Catheter for Medication Administration in End-of-Life Symptom Management.

Technology that can improve the ability to provide quick symptom control while decreasing the cost and burden of care could help hospice agencies deal with current hospice industry challenges. This paper describes how the use of a new rectal medication delivery technology at a large hospice in western New York has improved patient care and nursing efficiency while at the same time decreasing the cost of care.

A microengineered model of RBC transfusion-induced pulmonary vascular injury.

Red blood cell (RBC) transfusion poses significant risks to critically ill patients by increasing their susceptibility to acute respiratory distress syndrome. While the underlying mechanisms of this life-threatening syndrome remain elusive, studies suggest that RBC-induced microvascular injury in the distal lung plays a central role in the development of lung injury following blood transfusion. Here we present a novel microengineering strategy to model and investigate this key disease process. Specifically, we created a microdevice for culturing primary human lung endothelial cells under physiological flow conditions to recapitulate the morphology and hemodynamic environment of the pulmonary microvascular endothelium in vivo. Perfusion of the microengineered vessel with human RBCs resulted in abnormal cytoskeletal rearrangement and release of intracellular molecules associated with regulated necrotic cell death, replicating the characteristics of acute endothelial injury in transfused lungs in vivo. Our data also revealed the significant effect of hemodynamic shear stress on RBC-induced microvascular injury. Furthermore, we integrated the microfluidic endothelium with a computer-controlled mechanical stretching system to show that breathing-induced physiological deformation of the pulmonary microvasculature may exacerbate vascular injury during RBC transfusion. Our biomimetic microsystem provides an enabling platform to mechanistically study transfusion-associated pulmonary vascular complications in susceptible patient populations.

Enhanced nutrient transport improves the depth-dependent properties of tri-layered engineered cartilage constructs with zonal co-culture of chondrocytes and MSCs.

Biomimetic design in cartilage tissue engineering is a challenge given the complexity of the native tissue. While numerous studies have generated constructs with near-native bulk properties, recapitulating the depth-dependent features of native tissue remains a challenge. Furthermore, limitations in nutrient transport and matrix accumulation in engineered constructs hinders maturation within the central core of large constructs. To overcome these limitations, we fabricated tri-layered constructs that recapitulate the depth-dependent cellular organization and functional properties of native tissue using zonally derived chondrocytes co-cultured with MSCs. We also introduced porous hollow fibers (HFs) and HFs/cotton threads to enhance nutrient transport. Our results showed that tri-layered constructs with depth-dependent organization and properties could be fabricated. The addition of HFs or HFs/threads improved matrix accumulation in the central core region. With HF/threads, the local modulus in the deep region of tri-layered constructs nearly matched that of native tissue, though the properties in the central regions remained lower. These constructs reproduced the zonal organization and depth-dependent properties of native tissue, and demonstrate that a layer-by-layer fabrication scheme holds promise for the biomimetic repair of focal cartilage defects. STATEMENT OF SIGNIFICANCE: Articular cartilage is a highly organized tissue driven by zonal heterogeneity of cells, extracellular matrix proteins and fibril orientations, resulting in depth-dependent mechanical properties. Therefore, the recapitulation of the functional properties of native cartilage in a tissue engineered construct requires such a biomimetic design of the morphological organization, and this has remained a challenge in cartilage tissue engineering. This study demonstrates that a layer-by-layer fabrication scheme, including co-cultures of zone-specific articular CHs and MSCs, can reproduce the depth-dependent characteristics and mechanical properties of native cartilage while minimizing the need for large numbers of chondrocytes. In addition, introduction of a porous hollow fiber (combined with a cotton thread) enhanced nutrient transport and depth-dependent properties of the tri-layered construct. Such a tri-layered construct may provide critical advantages for focal cartilage repair. These constructs hold promise for restoring native tissue structure and function, and may be beneficial in terms of zone-to-zone integration with adjacent host tissue and providing more appropriate strain transfer after implantation.

Single-cell differences in matrix gene expression do not predict matrix deposition.

Mesenchymal stem cells (MSCs) display substantial cell-to-cell heterogeneity, complicating their use in regenerative medicine. However, conventional bulk assays mask this variability. Here we show that both chondrocytes and chondrogenically induced MSCs exhibit substantial mRNA expression heterogeneity. Single-molecule RNA FISH to measure mRNA expression of differentiation markers in single cells reveals that sister cell pairs have high levels of mRNA variability, suggesting that marker expression is not heritable. Surprisingly, this variability does not correlate with cell-to-cell differences in cartilage-like matrix production. Transcriptome-wide analysis suggests that no combination of markers can predict functional potential. De-differentiating chondrocytes also show a disconnect between mRNA expression of the cartilage marker aggrecan and cartilage-like matrix accumulation. Altogether, these quantitative analyses suggest that sorting subpopulations based on these markers would only marginally enrich the progenitor population for 'superior' MSCs. Our results suggest that instantaneous mRNA abundance of canonical markers is tenuously linked to the chondrogenic phenotype at the single-cell level.

Functional properties of bone marrow-derived MSC-based engineered cartilage are unstable with very long-term in vitro culture.

The success of stem cell-based cartilage repair requires that the regenerate tissue reach a stable state. To investigate the long-term stability of tissue engineered cartilage constructs, we assessed the development of compressive mechanical properties of chondrocyte and mesenchymal stem cell (MSC)-laden three dimensional agarose constructs cultured in a well defined chondrogenic in vitro environment through 112 days. Consistent with previous reports, in the presence of TGF-ß, chondrocytes outperformed MSCs through day 56, under both free swelling and dynamic culture conditions, with MSC-laden constructs reaching a plateau in mechanical properties between days 28 and 56. Extending cultures through day 112 revealed that MSCs did not simply experience a lag in chondrogenesis, but rather that construct mechanical properties never matched those of chondrocyte-laden constructs. After 56 days, MSC-laden constructs underwent a marked reversal in their growth trajectory, with significant declines in glycosaminoglycan content and mechanical properties. Quantification of viability showed marked differences in cell health between chondrocytes and MSCs throughout the culture period, with MSC-laden construct cell viability falling to very low levels at these extended time points. These results were not dependent on the material environment, as similar findings were observed in a photocrosslinkable hyaluronic acid (HA) hydrogel system that is highly supportive of MSC chondrogenesis. These data suggest that, even within a controlled in vitro environment that is conducive to chondrogenesis, there may be an innate instability in the MSC phenotype that is independent of scaffold composition, and may ultimately limit their application in functional cartilage repair.

High mesenchymal stem cell seeding densities in hyaluronic acid hydrogels produce engineered cartilage with native tissue properties.

Engineered cartilage based on adult mesenchymal stem cells (MSCs) is an alluring goal for the repair of articular defects. However, efforts to date have failed to generate constructs with sufficient mechanical properties to function in the demanding environment of the joint. Our findings with a novel photocrosslinked hyaluronic acid (HA) hydrogel suggest that stiff gels (high HA concentration, 5% w/v) foster chondrogenic differentiation and matrix production, but limit overall functional maturation due to the inability of the formed matrix to diffuse away from the point of production and form a contiguous network. In the current study, we hypothesized that increasing the MSC seeding density would decrease the required diffusional distance, and so expedite the development of functional properties. To test this hypothesis bovine MSCs were encapsulated at seeding densities of either 20,000,000 or 60,000,000 cells ml(-1) in 1%, 3%, and 5% (w/v) HA hydrogels. Counter to our hypothesis the higher concentration HA gels (3% and 5%) did not develop more rapidly with increased MSC seeding density. However, the biomechanical properties of the low concentration (1%) HA constructs increased markedly (nearly 3-fold with a 3-fold increase in seeding density). To ensure that optimal nutrient access was delivered, we next cultured these constructs under dynamic culture conditions (with orbital shaking) for 9 weeks. Under these conditions 1% HA seeded at 60,000,000 MSCs ml(-1) reached a compressive modulus in excess of 1 MPa (compared with 0.3-0.4 MPa for free swelling constructs). This is the highest level we have reported to date in this HA hydrogel system, and represents a significant advance towards functional stem cell-based tissue engineered cartilage.

Gelatin microspheres crosslinked with genipin for local delivery of growth factors.

A main challenge in tissue engineering and regenerative medicine is achieving local and efficient growth factor release to guide cell function. Gelatin is a denatured form of collagen that cells can bind to and degrade through enzymatic action. In this study, gelatin microspheres were used to release bone morphogenetic protein 2 (BMP2). Spherical microparticles with diameters in the range of 2-6 µm were created by an emulsification process and were stabilized by crosslinking with the small molecule genipin. The degree of crosslinking was varied by controlling the incubation time in genipin solution. Loading rate studies, using soy bean trypsin inhibitor as a model protein, showed rapid protein uptake over the first 24 h, followed by a levelling off and then a further increase after approximately 3 days, as the microspheres swelled. Growth factor release studies using microspheres crosslinked to 20%, 50% and 80% of saturation and then loaded with BMP2 showed that higher degrees of crosslinking resulted in higher loading efficiency and slower protein release. After 24 h, the concentration profiles produced by all microsphere formulations were steady and approximately equal. Microspheres incubated with adult human mesenchymal stem cells accumulated preferentially on the cell surface, and degraded over time in culture. BMP2-loaded microspheres caused a three- to eight-fold increase in expression of the bone sialoprotein gene after 14 days in culture, with more crosslinked beads producing a greater effect. These results demonstrate that genipin-crosslinked gelatin microspheres can be used to deliver growth factors locally to cells in order to direct their function.

Long-term dynamic loading improves the mechanical properties of chondrogenic mesenchymal stem cell-laden hydrogel.

Mesenchymal stem cells (MSCs) are an attractive cell source for cartilage tissue engineering given their ability to undergo chondrogenesis in 3D culture systems. Mechanical forces play an important role in regulating both cartilage development and MSC chondrogenic gene expression, however, mechanical stimulation has yet to enhance the mechanical properties of engineered constructs. In this study, we applied long-term dynamic compression to MSC-seeded constructs and assessed whether varying pre-culture duration, loading regimens and inclusion of TGF-beta3 during loading would influence functional outcomes and these phenotypic transitions. Loading initiated before chondrogenesis decreased functional maturation, although chondrogenic gene expression increased. In contrast, loading initiated after chondrogenesis and matrix elaboration further improved the mechanical properties of MSC-based constructs, but only when TGF-beta3 levels were maintained and under specific loading parameters. Although matrix quantity was not affected by dynamic compression, matrix distribution, assessed histologically and by FT-IRIS analysis, was significantly improved on the micro- (pericellular) and macro- (construct expanse) scales. Further, whole genome expression profiling revealed marked shifts in the molecular topography with dynamic loading. These results demonstrate, for the first time, that dynamic compressive loading initiated after a sufficient period of chondro-induction and with sustained TGF-beta exposure enhances matrix distribution and the mechanical properties of MSC-seeded constructs.

Mechanics and mechanobiology of mesenchymal stem cell-based engineered cartilage.

In this review, we outline seminal and recent work highlighting the potential of mesenchymal stem cells (MSCs) in producing cartilage-like tissue equivalents. Specific focus is placed on the mechanical properties of engineered MSC-based cartilage and how these properties relate to that of engineered cartilage based on primary chondrocytes and to native tissue properties. We discuss current limitations and/or concerns that must be addressed for the clinical realization of MSC-based cartilage therapeutics, and provide some insight into potential underpinnings for the observed deviations from chondrocyte-based engineered constructs. We posit that these differences reveal specific deficits in terms of our description of chondrogenesis, and suggest that new benchmarks must be developed towards this end. Further, we describe the growing body of literature on the mechanobiology of MSC-based cartilage, highlighting positive findings with regards to the furtherance of the chondrogenic phenotype. We likewise discuss the failure of early molecular changes to translate directly into engineered constructs with improved mechanical properties. Finally, we highlight recent work from our group and others that may point to new strategies for enhancing the formation of engineered cartilage based on MSCs.