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AbstractAs a result of treatment and diagnosis, adults with primary or metastatic brain tumors experience comorbidities that impacts their health and well-being. The Children’s Oncology Group has guideline recommendations for childhood survivors of brain tumors; however, guidelines for monitoring long-term sequela among adult brain tumor survivors are lacking. The purpose of this review is to present the screening recommendations for the long-term complications after brain tumor treatment from a multidisciplinary panel of healthcare professionals. Chronic complications identified include cognitive dysfunction, vasculopathy, endocrinopathy, ophthalmic, ototoxicity, physical disability, sleep disturbance, mood disorder, unemployment, financial toxicity, and secondary malignancy. We invited specialists across disciplines to perform a literature search and provide expert recommendations for surveillance for long-term complications for adult brain tumor survivors. The Brain Tumor Center Survivorship Committee recommends routine screening using laboratory testing, subjective assessment of symptoms, and objective evaluations to appropriately monitor the complications of brain tumor treatments. Effective monitoring and treatment should involve collaboration with primary care providers and may require referral to other specialties and support services to provide patient-centered care during neuro-oncology survivorship. Further research is necessary to document the incidence and prevalence of medical complications as well as evaluate the efficacy of screening and neuro-oncology survivorship programs.

To identify recurrent inflammation in hemophilia, we assessed the acute-phase response in the blood of patients with hemophilia A and B. Compared to age- and weight-matched controls, blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and LPS-binding protein (LBP) were significantly elevated in the entire cohort of hemophilia patients but exhibited a particularly pronounced increase in obese hemophilia patients with a body mass index (BMI) ≥30. Subgroup analysis of the remaining nonobese hemophilia patients (BMI: 18–29.9) revealed a significant spike of IL-6, CRP, and LBP in connection with a de-novo increase of soluble IL-6 receptor α (sIL-6Rα) in patients with bleeding events within the last month. Hemophilia patients who did not experience recent bleeding had IL-6, CRP, and sIL-6Rα blood levels similar to healthy controls. We did not find increased IL-6 or acute-phase reactants in hemophilia patients with arthropathy or infectious disease. The role of IL-6 as a marker of bleeding in hemophilia was confirmed in hemophilia patients with acute bleeding events as well as in transgenic hemophilia mice after needle puncture of the knee, which exhibited an extensive hematoma and a 150-fold increase of IL-6 blood levels within 7 days of the injury compared to needle-punctured control mice. Notably, IL-6 blood levels shrunk to a fourfold elevation in hemophilia mice over controls after 28 days, when the hematoma was replaced by arthrofibrosis. These findings indicate that acute-phase reactants in combination with sIL-6Rα could be sensitive biomarkers for the detection of acute and recent bleeding events in hemophilia.

Live cell imaging of fibrin-embedded shSCR 786-O cells.

Live cell imaging of fibrin-embedded shCLIC1 786-O cells.

Supplementary Data from HGF and c-Met Participate in Paracrine Tumorigenic Pathways in Head and Neck Squamous Cell Cancer

Supplementary data Table S1. Ex vivo biodistribution (24 h p.i.) of antibody fragments in SCID mice bearing 38C13-huCD20, blocked or CD20-negative 38C13 subcutaneous allografts. Data are presented as mean (%ID/g) with standard deviation ({plus minus} SEM). Table S2. Ex vivo biodistribution (24 h p.i.) of GA101 cys-diabody and cys-minibody fragments in human CD20 transgenic mice (huCD20TM). Data are presented as mean (%ID/g) with standard deviation ({plus minus} SEM). Figure S1 Biochemical characterization. (A) SDS-PAGE analysis of purified rituximab-based cys-diabody (RxcDb, 52 kDa) and cys-minibody (RxcMb, 82 kDa) shows correctly assembled dimers under non-reducing conditions (NR) and monomeric fragments under reducing conditions. (B) Size exclusion chromatography of engineered antibody fragments in comparison to full-length rituximab IgG. Rx cMb eluted as a single peak corresponding to the expected molecular weight. Rx cDb eluted slightly later, corresponding to the 52 kDa dimer but also showed a smaller second peak of higher molecular weight. Figure S2. (A) Schematic representation of site-specific conjugation to the C-terminal cys-tag of cys-diabody and cys-minibody antibody fragments, respectively. (B) Reduction and conjugation of Alexa Fluor 488 Maleimide (using the example of the cys-diabody) results in monomeric fragments migrating under non-reducing conditions in SDS-PAGE shown as Coomassie stain (left panel) and fluorescence (right panel). (C) Size exclusion chromatography analysis comparing unconjugated (black) and mal-DFo conjugated (grey) antibody fragments (using Superdex 75 column for cys-diabodies and Superdex 200 column for cys-minibodies. Figure S3. Obinutuzumab (GA101)-based antibody fragments retain type II binding characteristics. Figure S4. Immunoreactive fractions of radiolabeled antibody fragments were determined by cell binding studies using CD20 positive Ramos cells and CD20 negative Bc-1 cells. Shown is one representative plot for 124I-GAcDb. Immunoreactive fractions for obinutuzumab (GA1010)-based fragments ranged from 65-85 %. Figure S5 89Zr-GAcMb immunoPET imaging of huCD20TM. Figure S6 Immunohistochemical staining of human CD20 expression in murine 38C13 B-cell lymphoma allografts.

Purpose: The inability to visualize cancer during prostatectomy contributes to positive margins, cancer recurrence, and surgical side effects. A molecularly targeted fluorescent probe offers the potential for real-time intraoperative imaging. The goal of this study was to develop a probe for image-guided prostate cancer surgery.Experimental Design: An antibody fragment (cys-diabody, cDb) against prostate stem cell antigen (PSCA) was conjugated to a far-red fluorophore, Cy5. The integrity and binding of the probe to PSCA was confirmed by gel electrophoresis, size exclusion, and flow cytometry, respectively. Subcutaneous models of PSCA-expressing xenografts were used to assess the biodistribution and in vivo kinetics, whereas an invasive intramuscular model was utilized to explore the performance of Cy5-cDb–mediated fluorescence guidance in representative surgical scenarios. Finally, a prospective, randomized study comparing surgical resection with and without fluorescent guidance was performed to determine whether this probe could reduce the incidence of positive margins.Results: Cy5-cDb demonstrated excellent purity, stability, and specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 6 hours. In mice carrying PSCA+ and negative (−) dual xenografts, the mean fluorescence ratio of PSCA+/− tumors was 4.4:1. In surgical resection experiments, residual tumors Conclusions: Fluorescently labeled cDb enables real-time in vivo imaging of prostate cancer xenografts in mice, and facilitates more complete tumor removal than conventional white light surgery alone. Clin Cancer Res; 22(6); 1403–12. ©2015 AACR.See related commentary by van Leeuwen and van der Poel, p. 1304

Supplemental Figure 1: Transfection of 22rv1 with FLuc-IRES-mCherry and 22rv1_PSCA with Fluc-IRES-GFP and FACS sorting created FLuc expressing PSCA positive and negative cell lines. Supplemental Figure 2: H&E Staining of 22rv1 and 22rv1_PSCA intratibial xenografts shows mixed osteolytic (blue dashed arrows) and osteoblastic (solid red arrows) type tumor formation. Supplemental Figure 3: Comparison of optical imaging, 18F-Fluoride Bone Scan, and A11 immunoPET in mice bearing 22rv1 intratibial xenograft 6 weeks post-xenograftimplantation. Supplemental Figure 4: Comparison of optical imaging, 18F-Fluoride Bone Scan, and A11 immunoPET in a mouse bearing a 22rv1_PSCA intratibial xenograft at 2 and 6 weeks postxenograft- implantation. Supplemental Figure 5: Quantification of tumor necrosis using ImageJ based color Segmentation. Supplemental Figure 6: H&E staining of LAPC-9 tumors treated with either MDV-3100 or vehicle control. Supplemental Table 1: 44 hour biodistribution of mice bearing 22rv1 and 22rv1_PSCA intratibial xenografts. Histologic analysis of control and MDV-3100 treated tumors.

Figure S1. Biochemical characterization of Cy5 conjugated anti-PSCA cys-Diabody. Figure S2. Validation of in vivo tumor detection using endogenously PSCA-expressing line LAPC-9 Figure S3. Determining the optimal time point for in vivo Cy5-cDb imaging. Figure S4. Cy5-cDb enabled fluorescence-guided surgical resection of PSCA-expressing tumors. Figure S5. LAPC-9 intramuscular tumor extent was not readily detectable under white light (A-B), but was clearly visible under fluorescence guidance (C). Figure S6. Intraoperative white light and florescent images of 22Rv1 intramuscular xenografts utilizing anti-PSCA Cy5-cDb. Figure S7. Additional H&E histopathology of tumor margins from the prospective, randomized trial.

Purpose: The B-cell antigen CD20 provides a target for antibody-based positron emission tomography (immunoPET). We engineered antibody fragments targeting human CD20 and studied their potential as immunoPET tracers in transgenic mice (huCD20TM) and in a murine lymphoma model expressing human CD20.Experimental Design: Anti-CD20 cys-diabody (cDb) and cys-minibody (cMb) based on rituximab and obinutuzumab (GA101) were radioiodinated and used for immunoPET imaging of a murine lymphoma model. Pairwise comparison of obinutuzumab-based antibody fragments labeled with residualizing (89Zr) versus non-residualizing (124I) radionuclides by region of interest analysis of serial PET images was conducted both in the murine lymphoma model and in huCD20TM to assess antigen modulation in vivo.Results:124I-GAcDb and 124I-GAcMb produced high-contrast immunoPET images of B-cell lymphoma and outperformed the respective rituximab-based tracers. ImmunoPET imaging of huCD20TM showed specific uptake in lymphoid tissues. The use of the radiometal 89Zr as alternative label for GAcDb and GAcMb yielded greater target-specific uptake and retention compared with 124I-labeled tracers. Pairwise comparison of 89Zr- and 124I-labeled GAcDb and GAcMb allowed assessment of in vivo internalization of CD20/antibody complexes and revealed that CD20 internalization differs between malignant and endogenous B cells.Conclusions: These obinutuzumab-based PET tracers have the ability to noninvasively and quantitatively monitor CD20-expression and have revealed insights into CD20 internalization upon antibody binding in vivo. Because they are based on a humanized mAb they have the potential for direct clinical translation and could improve patient selection for targeted therapy, dosimetry prior to radioimmunotherapy, and prediction of response to therapy. Clin Cancer Res; 23(23); 7242–52. ©2017 AACR.

Purpose: We determined hepatocyte growth factor (HGF) and c-Met expression and signaling in human head and neck squamous cell carcinoma (HNSCC) cells and primary tissues and tested the ability of c-Met tyrosine kinase inhibitors (TKI) to block HGF-induced biological signaling.Experimental Design: Expression and signaling were determined using immunoblotting, ELISA, and immunohistochemistry. Biological end points included wound healing, cell proliferation, and invasion. c-Met TKIs were tested for their ability to block HGF-induced signaling and biological effects in vitro and in xenografts established in nude mice.Results: c-Met was expressed and functional in HNSCC cells. HGF was secreted by HNSCC tumor-derived fibroblasts, but not by HNSCC cells. Activation of c-Met promoted phosphorylation of AKT and mitogen-activated protein kinase as well as release of the inflammatory cytokine interleukin-8. Cell growth and wound healing were also stimulated by HGF. c-Met TKIs blocked HGF-induced signaling, interleukin-8 release, and wound healing. Enhanced invasion of HNSCC cells induced by the presence of tumor-derived fibroblasts was completely blocked with a HGF-neutralizing antibody. PF-2341066, a c-Met TKI, caused a 50% inhibition of HNSCC tumor growth in vivo with decreased proliferation and increased apoptosis within the tumors. In HNSCC tumor tissues, both HGF and c-Met protein were increased compared with expression in normal mucosa.Conclusions: These results show that HGF acts mainly as a paracrine factor in HNSCC cells, the HGF/c-Met pathway is frequently up-regulated and functional in HNSCC, and a clinically relevant c-Met TKI shows antitumor activity in vivo. Blocking the HGF/c-Met pathway may be clinically useful for the treatment of HNSCC.

Supplementary Figure Legends 1-4 from Plasma Fibronectin Promotes Lung Metastasis by Contributions to Fibrin Clots and Tumor Cell Invasion

PDF file, 893K, Supplementary table, figures, figure legends and methods Files in this Data Supplement: � Supplementary Movie 1 - WMV file, 12420 K. Live cell imaging (phase contrast, 10x) of 786-0 cells over 72 hours after embedding in fibrin. � Supplementary Movie 2 - WMV file, 11607 K. Live cell imaging (phase contrast, 10x) of MDA-MB-231 cells over 72 hours after embedding in fibrin. � Supplementary Table, Figures and Legends - PDF file, 893 K. Supplementary Table 1: Clinicopathological data of patients with RCC. Figure S1A: Colony formation of 786-0 and MDA-MB-231 cells. Figure S1B: Cell surface expression of integrin �v�3 analyzed by flow cytometry. Figure S2: Effect of integrin �1 and �3 knockdown. Figure S3: Tumor cell spreading on fibrinogen-coated surface. Figure S4: Effect of fibronectin knockdown. Figure S5: Effect of Slug knockdown or inhibition with the TGF-�RII inhibitor SB431542 (EMD Millipore).

Supplementary Figure 2 from Plasma Fibronectin Promotes Lung Metastasis by Contributions to Fibrin Clots and Tumor Cell Invasion

Supplementary Figure 3 from Plasma Fibronectin Promotes Lung Metastasis by Contributions to Fibrin Clots and Tumor Cell Invasion

The attachment of circulating tumor cells to the blood vessels of distant organs is an important step in metastasis. We show here that experimental lung metastasis by two cell lines, B16F1 melanoma and 3LL lung carcinoma, is greatly reduced in transgenic mice that lack plasma fibronectin. This multifunctional adhesive glycoprotein becomes cross-linked to fibrin during clotting. Here, we report that eliminating plasma fibronectin from the blood circulation reverses the prometastatic effects of blood clotting and tumor cell integrin αvβ3. In vitro studies showed that fibrin-fibronectin complexes, but not purified fibrin, supported tumor cell attachment and invasion. These functions correlate with the ability of fibrin-fibronectin complexes to induce the activation of integrin αvβ3. Our findings reveal an important contribution of plasma fibronectin in lung metastasis. Furthermore, they suggest that the previously noted effects of blood clotting on lung metastasis might be mediated in part by a fibronectin-αvβ3 integrin axis, in which plasma fibronectin has to be incorporated into the blood clot. Cancer Res; 70(11); 4327–34. ©2010 AACR.

WMV file, 11607K, MDA-MB-231 in 3D fibrin.

WMV file, 12420K, 786-0 in 3D fibrin.

Supplementary Figure 1 from Plasma Fibronectin Promotes Lung Metastasis by Contributions to Fibrin Clots and Tumor Cell Invasion

Supplementary Figure 4 from Plasma Fibronectin Promotes Lung Metastasis by Contributions to Fibrin Clots and Tumor Cell Invasion

The blood clotting cascade is selectively involved in lung metastasis, but the reason for this selectivity is unclear. Here, we show that tumor cells that metastasize predominantly to the lung, such as renal cell carcinoma (RCC) and soft tissue sarcoma (STS), have an inherent capacity to generate extensive invadopodia when embedded in a blood clot. Compared with other metastatic cancer cells tested, RCC and STS cells exhibited increased levels of expression of fibronectin and an activated form of the integrin αvβ3, which coordinately supported the generation of an elaborate fibronectin matrix and actin stress fibers in fibrin-embedded tumor cells. Together, fibronectin and αvβ3 induced upregulation of the transcription factor Slug, which mediates epithelial–mesenchymal transition as well as fibrin invasion and lung metastasis. This mechanism is clinically significant, because primary cancer cells from patients with metastatic RCC strongly invaded fibrin and this correlated with fibronectin matrix formation and Slug expression. In contrast, tumor cells from patients with localized RCC were largely noninvasive. Together, our findings establish that activated integrin αvβ3 and fibronectin promote lung metastasis by upregulating Slug, defining a mechanism through which cancer cells can colonize blood clots in the lung vasculature. Cancer Res; 73(20); 6175–84. ©2013 AACR.

Objective To describe pain intensity and interference in people with progressive multiple sclerosis (MS), compare these with people with relapsing-remitting multiple sclerosis (RRMS), and identify common and unique factors associated with pain intensity in people with progressive MS and RRMS. Design Observational, cross-sectional analysis using baseline data from a longitudinal survey on quality of life in participants with MS. Setting Community. Participants A total of 573 adults with MS (N=573; progressive MS, n=142; RRMS, n=431). Interventions Not applicable. Main Outcome Measures Average pain intensity was measured by an 11-point numeric rating scale, and pain interference was measured by the Patient-Reported Outcomes Measurement Information System Pain Interference Short Form. Results Participants with progressive MS reported moderate average pain intensity (3.22±2.50) and elevated pain interference (T score of 55.55±9.13). They did not differ significantly from those with RRMS in average pain intensity or pain interference. Common factors associated with higher average pain intensity were more severe disability, lower education level, unemployment, and current smoking. In those with progressive MS, older age was associated with lower average pain intensity. Conclusions Pain intensity and interference are similar across MS types. In addition to assessing and treating pain, it is important to screen for modifiable pain-related factors, such as smoking cessation, in this population.

Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS). A recent randomized controlled trial comparing a fatigue self-management program and a general MS education program found that both programs improved fatigue in participants with MS. Participants were randomized to a self-management program (Fatigue: Take Control, n = 109) or an MS education program (MS: Take Control, n = 109). This secondary analysis of that trial used multilevel moderation analysis to examine moderators of treatment-related effects on fatigue (Modified Fatigue Impact Scale) from baseline through the 6-month follow-up. The following potential treatment moderators were examined: age, sex, cohabitation/marital status, and baseline levels of self-efficacy, depression symptoms, and sleep quality. Cohabitation status (living with or without a spouse/partner) interacted with intervention group and time to predict fatigue impact (p = .04). Fatigue: Take Control participants who lived with a spouse/partner showed a marginal effect in greater rate of improvement in fatigue compared to those who lived alone (p = .08). However, rates of improvement in fatigue in MS: Take Control participants were similar in those living with or without a spouse/partner. These findings suggest that living with a spouse or partner may facilitate benefit from self-management interventions for MS-related fatigue. Future research should investigate the contribution of supportive others in self-management of fatigue in MS.

Control of Ag electro chemical migration is crucial for long–term reliability of electrical components in high–voltage applications. In this work, Cu was bonded onto an AlN substrate at temperatures between 650 °C and 950 °C for 1 h using a Ag free Cu–P–Sn–Ni brazing filler metal with Ti as an active metal addition. The interfacial structure between the Cu and the AlN and the mechanical properties of the bond were both investigated. Three different phases which contain Ti and O were observed during the growth process of the Cu/AlN interfacial reaction layer: an amorphous P–Ti–O phase, an amorphous Ti–O phase and rutile, TiO2. The most stable Cu/AlN interfacial structure occurred when rutile was present, and where a particular orientation relationship with AlN was observed: TiO2 (101)//AlN (0001), TiO2 [010]//AlN [ $$11\overline{2}0$$ ]. The probability of Cu/AlN interfacial fracture decreased as the bonding temperature was increased. Cu/AlN interfacial fracture was completely suppressed above 850 °C where rutile was the dominant phase at the Cu/AlN interface.

CME/CNE Information Activity Available Online: To access the article, post-test, and evaluation online, go to https://www.highmarksce.com/mscare. Target Audience: The target audience for this activity is physicians, physician assistants, nursing professionals, rehabilitation professionals, mental health care clinicians, and other health care providers involved in the management of patients with multiple sclerosis (MS). Learning Objectives: 1) Describe the potential benefits of outdoor adventure programs as well as the similarities and differences between outdoor adventure programs and established nonpharmacologic treatments for mood, function, and quality of life in MS. 2) Describe future directions for research on outdoor adventure programs tailored to individuals with MS. Accreditation Statement: In support of improving patient care, this activity has been planned and implemented by the Consortium of Multiple Sclerosis Centers (CMSC) and Delaware Media Group. The CMSC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physician Credit: The CMSC designates this journal-based activity for a maximum of 0.75 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Credit: The CMSC designates this enduring material for 0.75 contact hour (none in the area of pharmacology). Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has disclosed relationships with Springer Publishing (royalty), Qr8 (receipt of intellectual property rights/patent holder), Biogen (receipt of intellectual property rights/patent holder, speakers’ bureau), GW Pharmaceuticals (consulting fee), MedRhythms (consulting fee, contracted research), Genentech (consulting fee), Helius Medical Technologies (consulting fee), Osmotica (consulting fee), Ipsen (consulting fee), and Adamas Pharmaceuticals (contracted research). Laurie Scudder, DNP, NP, has served as Reviewer for this activity. She has disclosed no relevant financial relationships. Tracy E. Herring, PhD, has disclosed no relevant financial relationships. Lindsey M. Knowles, PhD, has disclosed no relevant financial relationships. Kevin N. Alschuler, PhD, has disclosed no relevant financial relationships. The peer reviewers for IJMSC have disclosed no relevant financial relationships. The staff at IJMSC, CMSC, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Note: Financial relationships may have changed in the interval between listing these disclosures and publication of the article. Method of Participation: Release Date: August 1, 2021 Valid for Credit Through: August 1, 2022 In order to receive CME/CNE credit, participants must: 1) Review the continuing education information, including learning objectives and author disclosures.2) Study the educational content.3) Complete the post-test and evaluation, which are available at https://www.highmarksce.com/mscare. Statements of Credit are awarded upon successful completion of the evaluation and the post-test with a passing score of >70%. The post-test may be retaken if necessary. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. The CMSC and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the CMSC or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health care professionals without first evaluating their patients’ conditions, considering possible contraindications or risks, reviewing any applicable manufacturer’s product information, and comparing any therapeutic approach with the recommendations of other authorities.

In response to the host environment, Cryptococcus neoformans must rapidly reprogram its translatome from one which promotes growth to one which is responsive to host temperature and oxidative stress. This reprogramming is primarily driven through the Gcn2-mediated repression of translation initiation and Ccr4-mediated removal of abundant pro-growth mRNAs from the translating pool. Here we investigate the contributions of these two pathways to the translational response to stress, and show that the response to oxidative stress is primarily driven by Gcn2 whereas temperature and oxidative stress both require Ccr4. Temperature stress, but not oxidative stress, result in an increase in RNase I resistant disome. Further, eIF2α phosphorylation varies in response to the type and magnitude of stress, yet all tested conditions induce translation of integrated stress response (ISR) transcription factor Gcn4, but not necessarily the Gcn4-dependent transcription. Finally, we define the ISR regulon in response to oxidative stress in C. neoformans. Together this study identifies the differential response to host-relevant stressors in an environmental fungus which can adapt to the environment inside the human host.

Antifibrinolytic agents, tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA), are often used during cardiac surgery to decrease the number of allogenic blood transfusions and to prevent perioperative bleeding. Weight-based TXA dosing regimens have been compared to fixed-dose regimens of EACA with variable outcomes in perioperative blood product transfusions and chest tube output. Serious adverse events, including seizures, have been reported with higher doses of TXA. Fixed-dose TXA regimens have been evaluated in trauma and orthopedic surgery but there is a paucity of evidence in the cardiac surgery population.To compare the safety and efficacy of fixed-dose TXA versus EACA in patients undergoing cardiac surgery.A single-center, retrospective chart review was conducted at a 793-bed tertiary care academic teaching hospital comparing cardiac surgery patients receiving either fixed-dose TXA 1000 mg followed by a 500-1000 mg infusion or EACA-7.5 g intravenous boluses followed by a 1-1.25 g/h infusion for the duration of the surgery. The major endpoint included chest tube output at 12 h, 24 h, and 7 days postoperatively. Minor endpoints included quantity and incidence of blood product transfusions and reported safety events.There were 1544 patients included. Chest tube output was similar between groups and the TXA group required more intraoperative blood product transfusions (22.7% vs. 18.2%, p = .03). There were no differences in the median quantity of total blood products administered postoperatively at 24 h or at 7 days. Reported safety events were similar between groups.Both fixed-dose TXA and EACA may be considered safe and effective options for antifibrinolytic therapy in cardiac surgery patients.

Weld residual stress and fracture behavior of 316L electron beam weldments, which are of particular interest in power generation industry, were investigated in this work. Two butt‐weld joints were manufactured in stainless steel 316L plates of 6 mm and 25.4 mm thicknesses. Three complementary methods were used to measure the three orthogonal components of the residual stress in the weld coupons, and fracture tests were conducted on single edge notched bending specimens extracted from different regions of the welds and parent metals.The residual stress measurements showed a maximum value of 450 MPa in longitudinal direction, while it was less than 150 MPa in the other two orthogonal directions, revealing that in our material, and with the chosen weld parameters, the residual stresses were biaxial. The fracture resistance of the weldment and parent material was similar, with material microstructure differences being more significant than the measured residual stresses.The study suggests that 316L electron beam weldments are not susceptible to fracture failure due to their high ductility and ability to relieve residual stresses through gross plasticity. Electron beam welding may therefore be suggested as a reliable manufacturing technology for safety critical 316L components.

Regulatory T cells (Tregs) play an important role in maintaining immune homeostasis by preventing excessive inflammation in normal tissues. In cancer, Tregs hamper antitumor immunosurveillance and may be a resistance mechanism to anti-PD-1 therapies. In preclinical cancer models, Treg depletion enhances antitumor cytotoxic immune responses, but systemic and persistent Treg removal can elicit immunopathology. Therapeutic strategies that selectively deplete highly suppressive activated intratumoral Tregs may avoid immune-related toxicities and amplify the activity of antitumor CD8 T cells during PD-1 blockade. CD30 is a member of the TNF receptor superfamily and is expressed by a subset of activated lymphocytes and various lymphomas. Here, transcriptomics and flow cytometry data from tumor and peripherally derived Tregs demonstrated CD30 is enriched on intratumoral Tregs. Among peripheral Tregs, CD30 expression was associated with an activated effector phenotype (FoxP3hiCD45RA-, fraction II). Further, treatment of dissociated NSCLC tumor spheroids with anti-PD-1 resulted in upregulated CD30 expression by Tregs but not intratumoral CD4 or CD8 T cells, which is consistent with Treg reactivation and supports CD30 as an activated Treg target. In vitro, CD30 expression on Tregs was dependent on signaling through the TCR and was significantly amplified by IL-2 and IL-15, suggesting CD30 may identify a subpopulation of activated antigen-specific Tregs. Brentuximab vedotin (BV) is an antibody-drug conjugate approved for clinical use in multiple types of lymphomas including cHL and PTCL. BV consists of a CD30-directed monoclonal antibody conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE). The activity of BV in lymphomas is thought to primarily result from tumor-directed intracellular MMAE release leading to apoptosis, though multiple immunomodulatory effects of BV have also been suggested. We have demonstrated through in vitro and in vivo preclinical model systems of human T cell activation that BV can selectively deplete CD30-expressing Tregs, amplifying cytotoxic CD8 T cell expansion. These and Treg CD30 expression data motivated the clinical exploration of BV plus pembrolizumab in metastatic PD-1 refractory melanoma and NSCLC (NCT04609566). Consistent with preclinical data, preliminary biomarker analysis from these studies showed a small but significant decrease in Tregs (CD4+CD25+CD127low/-) in peripheral blood after treatment with BV plus pembrolizumab. Further, limited on-treatment biopsies showed a trend toward increased intratumoral CD8:Treg (FoxP3) ratio in some patients receiving combination therapy. These data support the ongoing evaluation of BV in combination with PD-1 inhibitors in solid tumors and a potential additional mechanism of action for BV. Citation Format: Ryan A. Heiser, Bryan M. Grogan, Reice D. James, Michelle L. Ulrich, Jason D. Berndt, Brian P. O'Connor, Shyra J. Gardai, Hailing Lu, Scott M. Knowles. CD30 is a marker of activated effector regulatory T cells in solid tumors providing clinical rationale for the combination of brentuximab vedotin and PD-1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3253.

Background Depression, fatigue, and pain commonly co-occur in multiple sclerosis (MS) and are positively associated with one another. However, it is unclear whether treatment-related improvement in one of these symptoms is associated with improvements in the other two symptoms. Purpose This study examined whether early improvements in depressive symptoms, fatigue impact, and pain interference during a multisymptom intervention in persons with MS were associated with overall improvements in the other two symptoms. Methods Secondary analysis of a randomized controlled trial in which both treatments improved depressive symptoms, fatigue, and pain interference. Adults with MS experiencing chronic pain, chronic fatigue, and/or moderate depressive symptoms (N = 154, 86% women) participated in an 8-week, telephone-delivered intervention: self-management (n = 69) or education (n = 85); intervention groups were combined for the current study. Outcome measures were depressive symptoms (PHQ-9), fatigue impact (Modified Fatigue Impact Scale), and pain interference (Brief Pain Inventory). Path analysis examined associations between pre-to-mid intervention improvement in one symptom (i.e., depression, fatigue, pain interference) and pre-to-post (overall) improvement in the other two symptoms. Results Early reduction in depressive symptoms was associated with an overall reduction in pain interference and fatigue impact (p’s < .01). Early reduction in fatigue impact was associated with an overall reduction in depressive symptom severity (p = .04) but not pain interference. Early reduction in pain interference was not associated with reductions in fatigue impact or depressive symptoms. Conclusions These findings suggest the potential importance of reducing depressive symptoms to overall improvement in fatigue and pain interference in persons with MS. Clinical Trial Registrations NCT00944190.