Improved survival of patients receiving immunotherapy and chemotherapy following curative-intent resection of colorectal liver metastases.

BACKGROUND: Despite significant advancements in the treatment of patients with colorectal liver metastases (CRLMs), only a minority will experience long-term survival. This study aimed to determine the effect of chemotherapy (CT) and immunotherapy (IT) compared with that of CT alone on patient survival after surgical resection. METHODS: Patients undergoing curative-intent liver resection followed by adjuvant systemic therapy for stage IV colon cancer were identified using the National Cancer Database. Patients were stratified into type of therapy (CT alone vs CT + IT) and microsatellite status. Propensity score-weighted analysis was performed through 1:1 matching based on the nearest neighbor method. RESULTS: Of 9943 patients who underwent resection of CRLMs, 7971 (80%) received systemic adjuvant therapy. Of 7971 patients, 1432 (18%) received a combination of CT and IT. Microsatellite status was not associated with overall survival (OS). Adjuvant CT + IT was associated with increased 3-year OS compared with that of CT alone in both the unmatched cohort (55% vs 48%, respectively; P < .001) and matched cohort (52% vs 48%, respectively; P = .050). On multivariate analysis, older age, positive resection margins, and KRAS mutation were independent predictors of poor survival, whereas the administration of adjuvant CT + IT was an independent predictor of improved survival. CONCLUSION: IT combined with CT was associated with improved survival compared with that of CT alone after curative-intent resection of CRLMs, regardless of microsatellite instability status. Clinical trials to determine optimal patient selection, IT regimen, and long-term efficacy to improve outcomes of patients with CRLMs are warranted.

Cytotoxic Programming of CD4+ T Cells Is Regulated by Opposing Actions of the Related Transcription Factors Eos and Aiolos.

In contrast to the "helper" activities of most CD4+ T effector subsets, CD4+ cytotoxic T lymphocytes (CD4-CTLs) perform functions normally associated with CD8+ T and NK cells. Specifically, CD4-CTLs secrete cytotoxic molecules and directly target and kill compromised cells in an MHC class II-restricted fashion. The functions of these cells have been described in diverse immunological contexts, including their ability to provide protection during antiviral and antitumor responses, as well as being implicated in autoimmunity. Despite their significance to human health, the complete mechanisms that govern their programming remain unclear. In this article, we identify the Ikaros zinc finger transcription factor Eos (Ikzf4) as a positive regulator of CD4-CTL differentiation during murine immune responses against influenza virus infection. We find that the frequency of Eos+ cells is elevated in lung CD4-CTL populations and that the cytotoxic gene program is compromised in Eos-deficient CD4+ T cells. Consequently, we observe a reduced frequency and number of lung-residing, influenza virus-responsive CD4-CTLs in the absence of Eos. Mechanistically, we determine that this is due, at least in part, to reduced expression of IL-2 and IL-15 cytokine receptor subunits on the surface of Eos-deficient CD4+ T cells, both of which support the CD4-CTL program. Finally, we find that Aiolos, a related Ikaros family member and known CD4-CTL antagonist, represses Eos expression by antagonizing STAT5-dependent activation of the Ikzf4 promoter. Collectively, our findings reveal a mechanism wherein Eos and Aiolos act in opposition to regulate cytotoxic programming of CD4+ T cells.

A perfused multi-well bioreactor platform to assess tumor organoid response to a chemotherapeutic gradient.

There is an urgent need to develop new therapies for colorectal cancer that has metastasized to the liver and, more fundamentally, to develop improved preclinical platforms of colorectal cancer liver metastases (CRCLM) to screen therapies for efficacy. To this end, we developed a multi-well perfusable bioreactor capable of monitoring CRCLM patient-derived organoid response to a chemotherapeutic gradient. CRCLM patient-derived organoids were cultured in the multi-well bioreactor for 7 days and the subsequently established gradient in 5-fluorouracil (5-FU) concentration resulted in a lower IC50 in the region near the perfusion channel versus the region far from the channel. We compared behaviour of organoids in this platform to two commonly used PDO culture models: organoids in media and organoids in a static (no perfusion) hydrogel. The bioreactor IC50 values were significantly higher than IC50 values for organoids cultured in media whereas only the IC50 for organoids far from the channel were significantly different than organoids cultured in the static hydrogel condition. Using finite element simulations, we showed that the total dose delivered, calculated using area under the curve (AUC) was similar between platforms, however normalized viability was lower for the organoid in media condition than in the static gel and bioreactor. Our results highlight the utility of our multi-well bioreactor for studying organoid response to chemical gradients and demonstrate that comparing drug response across these different platforms is nontrivial.

Eos Promotes TH2 Differentiation by Interacting with and Propagating the Activity of STAT5.

The Ikaros zinc-finger transcription factor Eos has largely been associated with sustaining the immunosuppressive functions of regulatory T cells. Paradoxically, Eos has more recently been implicated in promoting proinflammatory responses in the dysregulated setting of autoimmunity. However, the precise role of Eos in regulating the differentiation and function of effector CD4+ T cell subsets remains unclear. In this study, we find that Eos is a positive regulator of the differentiation of murine CD4+ TH2 cells, an effector population that has been implicated in both immunity against helminthic parasites and the induction of allergic asthma. Using murine in vitro TH2 polarization and an in vivo house dust mite asthma model, we find that EosKO T cells exhibit reduced expression of key TH2 transcription factors, effector cytokines, and cytokine receptors. Mechanistically, we find that the IL-2/STAT5 axis and its downstream TH2 gene targets are one of the most significantly downregulated pathways in Eos-deficient cells. Consistent with these observations, we find that Eos forms, to our knowledge, a novel complex with and supports the tyrosine phosphorylation of STAT5. Collectively, these data define a regulatory mechanism whereby Eos propagates STAT5 activity to facilitate TH2 cell differentiation.

Metastatic colorectal adenocarcinoma tumor purity assessment from whole exome sequencing data.

Tumors rich in stroma are associated with advanced stage and poor prognosis in colorectal adenocarcinoma (CRC). Abundance of stromal cells also has implications for genomic analysis of patient tumors as it may prevent detection of somatic mutations. As part of our efforts to interrogate stroma-cancer cell interactions and to identify actionable therapeutic targets in metastatic CRC, we aimed to determine the proportion of stroma embedded in hepatic CRC metastases by performing computational tumor purity analysis based on whole exome sequencing data (WES). Unlike previous studies focusing on histopathologically prescreened samples, we used an unbiased in-house collection of tumor specimens. WES from CRC liver metastasis samples were utilized to evaluate stromal content and to assess the performance of three in silico tumor purity tools, ABSOLUTE, Sequenza and PureCN. Matching tumor derived organoids were analyzed as a high purity control as they are enriched in cancer cells. Computational purity estimates were compared to those from a histopathological assessment conducted by a board-certified pathologist. According to all computational methods, metastatic specimens had a median tumor purity of 30% whereas the organoids were enriched for cancer cells with a median purity estimate of 94%. In line with this, variant allele frequencies (VAFs) of oncogenes and tumor suppressor genes were undetectable or low in most patient tumors, but higher in matching organoid cultures. Positive correlation was observed between VAFs and in silico tumor purity estimates. Sequenza and PureCN produced concordant results whereas ABSOLUTE yielded lower purity estimates for all samples. Our data shows that unbiased sample selection combined with molecular, computational, and histopathological tumor purity assessment is critical to determine the level of stroma embedded in metastatic colorectal adenocarcinoma.

Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity.

During intracellular infection, T follicular helper (TFH) and T helper 1 (TH1) cells promote humoral and cell-mediated responses, respectively. Another subset, CD4-cytotoxic T lymphocytes (CD4-CTLs), eliminate infected cells via functions typically associated with CD8+ T cells. The mechanisms underlying differentiation of these populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key TFH transcription factors, and consequently reduced TFH differentiation and antibody production, during influenza virus infection. Conversely, CD4-CTL programming is elevated, including enhanced Eomes and cytolytic molecule expression. We further demonstrate that Aiolos deficiency allows for enhanced IL-2 sensitivity and increased STAT5 association with CD4-CTL gene targets, including Eomes, effector molecules, and IL2Ra. Thus, our collective findings identify Aiolos as a pivotal regulator of CD4-CTL and TFH programming and highlight its potential as a target for manipulating CD4+ T cell responses.

HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane.

PURPOSE: To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel). METHODS: Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score). RESULTS: Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea. CONCLUSION: Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

Oak Galls Exhibit Ant Dispersal Convergent with Myrmecochorous Seeds.

AbstractAnts disperse oak galls of some cynipid wasp species similarly to how they disperse seeds with elaiosomes. We conducted choice assays in field and laboratory settings with ant-dispersed seeds and wasp-induced galls found in ant nests and found that seed-dispersing ants retrieve these galls as they do myrmecochorous seeds. We also conducted manipulative experiments in which we removed the putative ant-attracting appendages ("kapéllos") from galls and found that ants are specifically attracted to kapéllos. Finally, we compared the chemical composition and histology of ant-attracting appendages on seeds and galls and found that they both have similar fatty acid compositions as well as morphology. We also observed seed-dispersing ants retrieving oak galls to their nests and rodents and birds consuming oak galls that were not retrieved by ants. These results suggest convergence in ant-mediated dispersal between myrmecochorous seeds and oak galls. Based on our observations, a protective advantage for galls retrieved to ant nests seems a more likely benefit than dispersal distance, as has also been suggested for myrmecochorous seeds. These results require reconsideration of established ant-plant research assumptions, as ant-mediated seed and gall dispersal appear strongly convergent and galls may be far more abundant in eastern North American deciduous forests than myrmecochorous seeds.

STAT3 regulates inflammatory cytokine production downstream of TNFR1 by inducing expression of TNFAIP3/A20.

Tumour Necrosis Factor (TNF) potently induces a transient inflammatory response that must be downregulated once any invasive stimulus has resolved. Yet, how TNF-induced inflammation is shut down in normal cells is incompletely understood. The present study shows that STAT3 was activated in mouse embryo fibroblasts (MEFs) by treatment with TNF or an agonist antibody to TNFR1. STAT3 activation was inhibited by pharmacological inhibition of the Jak2 tyrosine kinase that associates with TNFR1. To identify STAT3 target genes, global transcriptome analysis by RNA sequencing was performed in wild-type MEFs and MEFs from STAT3 knockout (STAT3KO ) mice that were stimulated with TNF, and the results were validated at the protein level by using multiplex cytokine assays and immunoblotting. After TNF stimulation, STAT3KO MEFs showed greater gene and protein induction of the inflammatory chemokines Ccl2, Cxcl1 and Cxcl10 than WT MEFs. These observations show that, by activating STAT3, TNF selectively modulates expression of a cohort of chemokines that promote inflammation. The greater induction by TNF of chemokines in STAT3KO than WT MEFs suggested that TNF induced an inhibitory protein in WT MEFs. Consistent with this possibility, STAT3 activation by TNFR1 increased the expression of Tnfaip3/A20, a ubiquitin modifying enzyme that inhibits inflammation, in WT MEFs but not in STAT3KO MEFs. Moreover, enforced expression of Tnfaip3/A20 in STAT3KO MEFs suppressed proinflammatory chemokine expression induced by TNF. Our observations identify Tnfaip3/A20 as a new downstream target for STAT3 which limits the induction of Ccl2, Cxcl1 and Cxcl10 and inflammation induced by TNF.

Diffuse optical spectroscopic method for tissue and body composition assessment.

SIGNIFICANCE: Growing levels of obesity and metabolic syndrome have driven demand for more advanced forms of body composition assessment. While various techniques exist to measure body composition, devices are typically expensive and not portable, involve radiation [in the case of dual-energy x-ray absorptiometry (DXA)], and are limited to analysis of adiposity while metabolic information from blood supply and oxygenation are not considered. AIM: We evaluate whether diffuse optical spectroscopic imaging (DOSI) can be used to predict site-specific adiposity and percent fat (whole body) while simultaneously providing information about local tissue hemoglobin levels and oxygenation. APPROACH: DOSI measures of tissue composition in gastrocnemius, quadriceps, abdomen, and biceps, DXA whole-body composition, and ultrasound-derived skin and adipose tissue thickness (SATT) in the quadriceps were obtained from 99 individuals aged 7 to 34 years old. RESULTS: Various DOSI-derived parameters were correlated with SATT and an optical method is proposed for estimating SATT using a newly defined parameter, the optical fat fraction (OFF), which considers all parameters that correlate with SATT. Broadband absorption and scattering spectra from study participants with the thinnest (SATT ≈ 0.25 ± 0.02 cm) and thickest SATT (SATT ≈ 1.55 ± 0.14 cm), representing best estimates for pure in vivo lean and fatty tissue, respectively, are reported. Finally, a trained prediction model is developed which allows DOSI assessment of OFF to predict DXA body-fat percentage, demonstrating that DOSI can be used to quantify body composition. CONCLUSIONS: This study shows that DOSI can be used to assess the adiposity of specific tissues or the entire human body, and the OFF parameter is defined for corroboration and further evaluation in future research.

Personality metatraits predict resilience among family caregivers responsible for a dependent youth's chronic respiratory management.

BACKGROUND: Family caregivers of children and youth with severe neurodisabilities that require chronic respiratory management often report a compromised quality of life. In this cross-sectional study, we used DeYoung's (Psychol Inq 21(1): 26-33, 2010. https://doi.org/10.1080/10478401003648674 ) conceptualization of two personality metatraits, Alpha and Beta, to test their theorized role in facilitating resilience among these family caregivers. We expected higher Alpha and Beta would exhibit direct, beneficial effects on caregiver mental and physical health quality of life (QoL), and they would operate through self-reported resilience and coping to exert positive, indirect effects on caregiver QoL. METHODS: Family caregivers of children and youth at an outpatient chronic respiratory management clinic were informed of the study. Of the 68 who consented, 61 provided complete data on measures of personality traits, coping styles, and physical and mental health-related QoL. Factor analytic techniques verified the two personality metatraits, consistent with the DeYoung model. The metatraits were then used as predictor variables in a path model to predict physical and mental health-related QoL. Self-reported resilience and a coping variable were examined as possible mediators of the personality-QoL relationship. RESULTS: Correlational analyses isolated a coping variable that met criteria as a possible mediator. The path model exhibited good fit to the data. The Alpha metatrait-characterized by emotional stability, self-regulation, perseverance, and intrinsic motivation-was directly predictive of caregiver mental health. The Beta metatrait, reflecting a disposition for adaptive flexibility, responsiveness, and interpersonal initiative, demonstrated significant indirect effects to physical and mental health through its positive association with coping efforts to maintain social support and a sense of self. CONCLUSIONS: Consistent with DeYoung's conceptualization, higher Alpha and Beta predicted caregiver resilience, albeit through different pathways. The emotional stability, perseverance and emotional regulation associated with Alpha likely accounted for its positive association with caregiver mental health. Beta, in contrast, may operate through their adaptive flexibility, personal resourcefulness and social engagement to augment coping efforts that involve others and support family activities, which, in turn, promote their own physical and mental health. Limitations of the cross-sectional design, and potential theoretical and clinical implications of the personality metatraits and their relation to resilience are discussed.

Antibody-suppressor CXCR5+ CD8+ T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice.

CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2b ) were transplanted with A/J kidneys (H-2a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+ CD8+ T cells and CD8-mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+ CD8+ T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5+ CD8+ T cells (but not alloprimed CXCR5- CD8+ or third-party primed CXCR5+ CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+ CD8+ T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.

Laurentian Great Lakes warming threatens northern fruit belt refugia.

Climate refugia are anomalous "pockets" of spatially or temporally disjunct environmental conditions that buffer distinct flora and fauna against prevailing climatic conditions. Physiographic landscape features, such as large water bodies, can create these micro-to-macro-scale terrestrial habitats, such as the prevailing westerly winds across the Laurentian Great Lakes that create relatively cooler leeward conditions in spring and relatively warmer leeward conditions in autumn. The leeward Great Lakes climate effects create refugia (popularly known as a "fruit belt") favorable for fruit-bearing trees and shrubs. These fruit belt refugia owe their existence to seasonal inversions whereby spring cooling prevents early flower budding that leaves fruit trees susceptible to late spring killing frosts, and autumn warming prevents early killing frosts. With global climate change, however, warmer summers and milder winters, and corresponding warmer waters, might erode the leeward delaying effect on spring flowering, creating a paradoxical situation in which warming increases the risk of frost damage to plants. We evaluated the success of regional agriculture in the Great Lakes fruit belt to test our hypothesis that warmer spring climate (and concomitant warmer lake waters) correspond with degraded fruit production. We also examined long-term trends in Great Lakes climate conditions. We found that the cold-sensitive fruit tree (apple, grape, peach, and cherry) refugia were destabilized by relatively warmer springs. Moreover, we found several indicators that lake waters are warming across the Great Lakes, which portends negative consequences for agricultural and natural plant communities in the Great Lakes region and in similar "fruit belt" refugia worldwide.

Effectiveness of Intranasal Dexmedetomidine with Nitrous Oxide Compared to Other Pediatric Dental Sedation Drug Regimens.

Purpose: The purpose of this study was to compare the effectiveness of intranasal dexmedetomidine (DEX), oral midazolam (MID), and oral midazolam combined with oral hydroxyzine (MIDHYD) with nitrous oxide when used for sedation during pediatric dental procedures. Methods: The charts of 146 patients who underwent dental procedures using moderate sedation with DEX, MID, or MIDHYD, all with nitrous oxide, from January 2014 to December 2019, were reviewed retrospectively. Sedations were evaluated for effectiveness based on sedation level and behavior using a modified University of Michigan Sedation Scale and behavior using the American Academy of Pediatric Dentistry sedation behavior scale. Procedures planned and completed were evaluated for each sedation regimen. Results: Overall, the effectiveness was not statistically different between sedation regimens (P=0.71). More stainless steel crowns were planned and completed with DEX, more resins were planned and completed with MIDHYD, and more extractions were planned and completed with MID. The onset of action and working time were found to be statistically significant between sedation regimens; DEX had the longest working time. Conclusions: This retrospective study found that intranasal dexmedetomidine with nitrous oxide showed no statistical difference in effectiveness, compared with oral midazolam or oral midazolam combined with oral hydroxyzine and nitrous oxide, in moderate sedation for pediatric dental procedures. The majority of stimulating time-consuming procedures were completed in the DEX sedation regimen.

Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection.

Hepatocyte transplant represents a treatment for metabolic disorders but is limited by immunogenicity. Our prior work identified the critical role of CD8+ T cells, with or without CD4+ T cell help, in mediating hepatocyte rejection. In this study, we evaluated the influence of invariant NKT (iNKT) cells, uniquely abundant in the liver, upon CD8-mediated immune responses in the presence and absence of CD4+ T cells. To investigate this, C57BL/6 (wild-type) and iNKT-deficient Jα18 knockout mice (cohorts CD4 depleted) were transplanted with allogeneic hepatocytes. Recipients were evaluated for alloprimed CD8+ T cell subset composition, allocytotoxicity, and hepatocyte rejection. We found that CD8-mediated allocytotoxicity was significantly decreased in iNKT-deficient recipients and was restored by adoptive transfer of iNKT cells. In the absence of both iNKT cells and CD4+ T cells, CD8-mediated allocytotoxicity and hepatocyte rejection was abrogated. iNKT cells enhance the proportion of a novel subset of multipotent, alloprimed CXCR3+CCR4+CD8+ cytolytic T cells that develop after hepatocyte transplant and are abundant in the liver. Alloprimed CXCR3+CCR4+CD8+ T cells express cytotoxic effector molecules (perforin/granzyme and Fas ligand) and are distinguished from alloprimed CXCR3+CCR4-CD8+ T cells by a higher proportion of cells expressing TNF-α and IFN-γ. Furthermore, alloprimed CXCR3+CCR4+CD8+ T cells mediate higher allocytotoxicity and more rapid allograft rejection. Our data demonstrate the important role of iNKT cells in promoting the development of highly cytotoxic, multipotent CXCR3+CCR4+CD8+ T cells that mediate rapid rejection of allogeneic hepatocytes engrafted in the liver. Targeting iNKT cells may be an efficacious therapy to prevent rejection of intrahepatic cellular transplants.

Multi-modal diffuse optical spectroscopy for high-speed monitoring and wide-area mapping of tissue optical properties and hemodynamics.

SIGNIFICANCE: Diffuse optical spectroscopic imaging (DOSI) is a versatile technology sensitive to changes in tissue composition and hemodynamics and has been used for a wide variety of clinical applications. Specific applications have prompted the development of versions of the DOSI technology to fit specific clinical needs. This work describes the development and characterization of a multi-modal DOSI (MM-DOSI) system that can acquire metabolic, compositional, and pulsatile information at multiple penetration depths in a single hardware platform. Additionally, a 3D tracking system is integrated with MM-DOSI, which enables registration of the acquired data to the physical imaging area. AIM: We demonstrate imaging, layered compositional analysis, and metabolism tracking capabilities using a single MM-DOSI system on optical phantoms as well as in vivo human tissue. APPROACH: We characterize system performance with a silicone phantom containing an embedded object. To demonstrate multi-layer sensitivity, we imaged human calf tissue with a 4.8-mm skin-adipose thickness. Human thenar tissue was also measured using a combined broadband DOSI and continuous-wave near-infrared spectroscopy method (∼15 Hz acquisition rate). RESULTS: High-resolution optical property maps of absorption (µa) and reduced scattering (µs ' ) were recovered on the phantom by capturing over 1000 measurement points in under 5 minutes. On human calf tissue, we show two probing depth layers have significantly different (p < 0.001) total-hemo/myoglobin and µs ' composition. On thenar tissue, we calculate tissue arterial oxygen saturation, venous oxygen saturation, and tissue metabolic rate of oxygen consumption during baseline and after release of an arterial occlusion. CONCLUSIONS: The MM-DOSI can switch between collection of broadband spectra, high-resolution images, or multi-depth hemodynamics without any hardware reconfiguration. We conclude that MM-DOSI enables acquisition of high resolution, multi-modal data consolidated in a single platform, which can provide a more comprehensive understanding of tissue hemodynamics and composition for a wide range of clinical applications.

Belowground community turnover accelerates the decomposition of standing dead wood.

Standing dead trees (snags) decompose more slowly than downed dead wood and provide critical habitat for many species. The rate at which snags fall therefore influences forest carbon dynamics and biodiversity. Fall rates correlate strongly with mean annual temperature, presumably because warmer climates facilitate faster wood decomposition and hence degradation of the structural stability of standing wood. These faster decomposition rates coincide with turnover from fungal-dominated wood decomposer communities in cooler forests to codomination by fungi and termites in warmer regions. A key question for projecting forest dynamics is therefore whether temperature effects on wood decomposition arise primarily because warmer conditions facilitate faster decomposer metabolism, or are also influenced indirectly by belowground community turnover (e.g., termites exert additional influence beyond fungal-plus-bacterial mediated decomposition). To test between these possibilities, we simulate standing dead trees with untreated wooden posts and follow them in the field across 5 yr at 12 sites, before measuring buried, soil-air interface and aerial post sections to quantify wood decomposition and organism activities. High termite activities at the warmer sites are associated with rates of postfall that are three times higher than at the cooler sites. Termites primarily consume buried wood, with decomposition rates greatest where termite activities are highest. However, where higher microbial and termite activities co-occur, they appear to compensate for one another first, and then to slow decomposition rates at their highest activities, suggestive of interference competition. If the range of microbial and termite codomination of wood decomposer communities expands under climate warming, our data suggest that expansion will accelerate snag fall with consequent effects on forest carbon cycling and biodiversity in forests previously dominated by microbial decomposers.

Hematologic safety of palbociclib in combination with endocrine therapy in patients with benign ethnic neutropenia and advanced breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. METHODS: PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. RESULTS: Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). CONCLUSIONS: These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

PURPOSE: HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5 years. METHODS: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40-49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients. RESULTS: Median follow-up as of June 2020 is 42 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines. CONCLUSIONS: Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

DEFINING THE MEDICAL RECORD: RELATIONSHIPS OF THE LEGAL MEDICAL RECORD, THE DESIGNATED RECORD SET, AND THE ELECTRONIC HEALTH RECORD.

Not so long ago, defining the "medical record" was simple. It was the paper chart-volume upon volume that captured the serial, dutifully recorded events of a person's health care at a hospital or physician's office. Entries were typically handwritten, dated and timed, and signed in ink with title (i.e., authenticated). Errors were easily identified by an authenticated strike-through. Similarly, the paper chart was synonymous with the legal medical record (LMR). In other words, a patient's paper chart was that patient's LMR by definition, even if critical data was omitted or irrelevant data was included. Fast-forward to 2021 and the use of technology for capturing the record of a patient's care. Technology has brought new challenges as well as successes. For example, pervasive and persistent mythologies include that 1) a patient's electronic health record (EHR) is the LMR, and 2) patient-specific EHR printouts to paper or disc-or displays on monitors-are necessarily equivalents to the paper chart of the 1980s. Neither are true. We now must define at the outset what is included in the LMR/designated record set to ensure the accuracy of what is retained and released.