Assessing the Utility of Toe Arm Index and Toe Pressure in Predicting Wound Healing in Patients Undergoing Vascular Intervention.

BACKGROUND: Objective measures of perfusion such as an ankle-brachial index (ABI) and toe pressure remain important in prognosticating wound healing. However, the use of ABI is limited in patients with incompressible vessels and toe pressure may not be comparable across patients. While a toe arm index (TAI) may be of value in this setting, its role as clinical indicator of perfusion for healing in patients with lower-extremity wounds has not been well established. METHODS: A retrospective review was performed of all vascular patients with lower-extremity wounds that underwent peripheral vascular intervention between 2014-2019. Data regarding patient demographics, comorbidities, TAI, ABI, toe pressures, and the wound, ischemia, and foot infection (WIfI) score were collected. Associations between patient variables and wound healing at various time points were evaluated. RESULTS: A total of 173 patients (67.7 ± 10.9 years; 71.1% male) were identified with lower-extremity wounds. Most patients underwent endovascular intervention (77.5%). Patients were followed for a median of 416 (IQR 129-900) days. Mean postoperative TAI was 0.35 ± 0.19 and mean WIfI score was 2.60 ± 1.17. Nine percent (15) of patients healed within 1 month, 44.8% (69) healed within 6 months, and 65.5% (97) healed within 1 year of revascularization without need for major amputation. Those that healed within 1 year without any major amputation did not differ from those that did not heal based on age, gender, race, comorbidities, periprocedural medications, or procedures performed. However, patients that healed without major amputation had a higher postoperative TAI (0.38 vs. 0.30, P = 0.02), higher toe pressure (53 vs. 40 mm Hg, P = 0.004), and lower WIfI score (2.26 vs. 3.12, P < 0.001). Patients that healed with 1 year without requiring any amputation had similar associations with postoperative TAI, toe pressure, and WIfI. Additionally, they were more likely to be White (P = 0.019) and have an open surgical procedure (P < 0.001) and less likely to have chronic kidney disease (P = 0.001) or diabetes (P = 0.008). A Youden index was calculated and identified a TAI value of 0.30 that optimized sensitivity and specificity for wound healing. The area under the curve for TAI as a predictor of wound healing was 0.62. CONCLUSIONS: Higher postoperative TAI is associated with higher odds of wound healing without need for major amputation. Toe arm index is therefore a useful tool to identify patients with adequate arterial perfusion to heal lower-extremity wounds. However, the area under the curve is poor for TAI when used as a sole predictor of wound healing potential suggesting that TAI should be one of multiple factors to considered when prognosticating wound healing potential.

Defining Vascular Deserts to Describe Access to Care and Identify Sites for Targeted Limb Preservation Outreach.

BACKGROUND: Access to care plays a critical role in limb salvage in chronic limb-threatening ischemia (CLTI). A "medical desert" describes a community lacking access to medical necessities, resulting in increased morbidity and mortality. We sought to describe vascular deserts, which we defined as regions with decreased access to specialty care. METHODS: All California providers performing vascular surgery procedures were identified through online provider and health care facility searches. Facility participation in the Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) lower extremity bypass (LEB) and peripheral vascular intervention (PVI) modules was also determined. Addresses were geocoded with a 30-mile surrounding buffer using ArcGIS (Geographic information systems), creating maps based on care type, including all providers performing vascular procedures, board-certified vascular surgeons, and facilities participating in VQI modules. Public census data overlayed on the maps demonstrated population composition in desert versus nondesert regions. Subsequently, data from the Healthy Places Index (HPI) was overlayed, providing data regarding 25 social factors, comprising an overall HPI score and percent, with lower scores corresponding to poorer health and outcomes. RESULTS: Maps depicting care regions demonstrated decreased provider coverage with increasing specialty care, with the VQI provider map showing the most prominent "desert" regions. When comparing nondesert versus desert regions by care type, demographics including race, the percentage of the population 200% below the poverty line, and the rate of uninsured residents were described. Social determinants of health were then described for desert and nondesert regions by care type, including the HPI percentage and specific domain factors. The percentage of uninsured residents was significant only in the desert and nondesert areas served by board-certified vascular surgeons (19.6 vs. 16.8%, P < 0.001). The mean HPI percentile was significantly lower in board-certified provider and VQI facility deserts than nondeserts (50.48% vs. 40.65%, P < 0.001 and 52.68% vs. 43.12%, P < 0.001, respectively). The economic and education factor percentiles were significantly lower in all desert populations, while the housing, social, and pollution factors were significantly higher in nondesert regions. Health care access, transportation, and neighborhood factor percentiles were significantly lower in board-certified and VQI facility deserts than in the nondesert areas. CONCLUSIONS: Access to vascular care plays a significant role in limb salvage. Through mapping vascular deserts, patient demographics, and social factors in desert regions are better understood, and areas that would benefit most from targeted outreach and limb preservation programs for CLTI are identified.

Provider ankle brachial index and wound classification teaching as part of a comprehensive limb preservation outreach program.

OBJECTIVE: Utilization of evidence-based specialty guidelines is low in primary care settings. Early use of ankle-brachial index (ABI) testing and a validated wound classification system allows prompt referral of patients for specialty care. We implemented a program to teach providers ABI testing and the use of the Wound, Ischemia, and foot Infection (WIfI) classification tool. Here, we report program outcomes and provider perceptions. METHODS: Physicians and non-physicians from wound care centers, nursing and physician education programs, primary care offices, and federally qualified health centers were invited to participate in the educational program teaching ABI testing and the use of the WIfI tool. Pretest and posttest responses and intention to use content in the future were assessed with descriptive statistics. RESULTS: A total of 101 subjects completed the ABI module, and 84 indicated their occupation (59 physicians, 25 non-physicians). Seventy-nine subjects completed the WIfI module, and 89% indicated their occupation (50 physicians, 20 non-physicians). Physicians had lower pre-test knowledge scores for the ABI module than non-physicians (mean scores of 7.9 and 8.2, respectively). Both groups had improved knowledge scores on the post-test (physicians, 13.4; non-physicians, 13.8; P < .001). Non-physicians in practice longer than 10 years at wound care centers had the lowest baseline knowledge scores, whereas physicians in practice for over 10 years had the highest. In the ABI module, the largest knowledge gap included accurately calculating the ABI, followed by the correct use of the Doppler, and management of incompressible vessels. For the WIfI module, providers struggled to accurately score patients based on wound classification. The greatest barriers to the implementation of ABI testing were the availability of trained personnel, followed by limited time for testing. Barriers to the use of the WIfI tool for physicians included lack of time and national guideline support. For non-physicians, the most notable barrier was a lack of training. CONCLUSIONS: Provider understanding of ABI and WIfI tools are limited in wound care centers, primary care offices, and federally qualified health centers. Further barriers include a lack of training in the use of tools, limited potential for point-of-care testing reimbursement, and insufficient dissemination of WIfI guidelines. Such barriers discourage widespread adoption and result in delayed diagnosis of arterial insufficiency.

Stroke Severity in Ischemic Stroke Patients with a History of Diastolic Blood Pressure Treated in a Telestroke Network.

Background: The relationship between diastolic blood pressure (DBP), risk factors, and stroke severity in acute ischemic stroke (AIS) patients treated in a telestroke network is not fully understood. The present study aims to determine the effect of risk factors on stroke severity in AIS patients with a history of elevated DBP. Material and Methods: We retrospectively analyzed data on stroke severity for AIS patients treated between January 2014 and June 2016 treated in the PRISMA Health telestroke network. Data on the severity of stroke on admission were evaluated using NIHSS scores ≤7 for reduced, and >7 for increased, stroke severity. DBP was stratified as ≤80 mmHg for reduced DBP and >80 mmHg for elevated DBP. The study's primary outcomes were risk factors associated with improving neurologic functions or reduced stroke severity and deteriorating neurologic functions or increased stroke severity. The associations between risk factors and stroke severity for AIS with elevated DBP were determined using multi-level logistic and regression models. Results: In the adjusted analysis, AIS patients with a DBP ≤ 80 mmHg, obesity (OR = 0.388, 95% Cl, 0.182−0.828, p = 0.014) was associated with reduced stroke severity, while an increased heart rate (OR = 1.025, 95% Cl, 1.001−1.050, p = 0.042) was associated with higher stroke severity. For AIS patients with a DBP > 80 mmHg, hypertension (OR = 3.453, 95% Cl, 1.137−10.491, p = 0.029), history of smoking (OR = 2.55, 95% Cl, 1.06−6.132, p = 0.037), and heart rate (OR = 1.036, 95% Cl, 1.009−1.064, p = 0.009) were associated with higher stroke severity. Caucasians (OR = 0.294, 95% Cl, 0.090−0.964, p = 0.002) and obesity (OR = 0.455, 95% Cl, 0.207−1.002, p = 0.05) were more likely to be associated with reduced stroke severity. Conclusions: Our findings reveal specific risk factors that can be managed to improve the care of AIS patients with elevated DBP treated in the telestroke network.

DNA Damage and Oxidative Stress of Tobacco Smoke Condensate in Human Bladder Epithelial Cells.

Smoking is a major risk factor for bladder cancer (BC), with up to 50% of BC cases being attributed to smoking. There are 70 known carcinogens in tobacco smoke; however, the principal chemicals responsible for BC remain uncertain. The aromatic amines 4-aminobiphenyl (4-ABP) and 2-naphthylamine (2-NA) are implicated in BC pathogenesis of smokers on the basis of the elevated BC risk in factory workers exposed to these chemicals. However, 4-ABP and 2-NA only occur at several nanograms per cigarette and may be insufficient to induce BC. In contrast, other genotoxicants, including acrolein, occur at 1000-fold or higher levels in tobacco smoke. There is limited data on the toxicological effects of tobacco smoke in human bladder cells. We have assessed the cytotoxicity, oxidative stress, and DNA damage of tobacco smoke condensate (TSC) in human RT4 bladder cells. TSC was fractionated by liquid-liquid extraction into an acid-neutral fraction (NF), containing polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs, phenols, and aldehydes, and a basic fraction (BF) containing aromatic amines, heterocyclic aromatic amines, and N-nitroso compounds. The TSC and NF induced a time- and concentration-dependent cytotoxicity associated with oxidative stress, lipid peroxide formation, glutathione (GSH) depletion, and apurinic/apyrimidinic (AP) site formation, while the BF showed weak effects. LC/MS-based metabolomic approaches showed that TSC and NF altered GSH biosynthesis pathways and induced more than 40 GSH conjugates. GSH conjugates of several hydroquinones were among the most abundant conjugates. RT4 cell treatment with synthetic hydroquinones and cresol mixtures at levels present in tobacco smoke accounted for most of the TSC-induced cytotoxicity and the AP sites formed. GSH conjugates of acrolein, methyl vinyl ketone, and crotonaldehyde levels also increased owing to TSC-induced oxidative stress. Thus, TSC is a potent toxicant and DNA-damaging agent, inducing deleterious effects in human bladder cells at concentrations of <1% of a cigarette in cell culture media.

Human primitive mesenchymal stem cell-derived retinal progenitor cells improved neuroprotection, neurogenesis, and vision in rd12 mouse model of retinitis pigmentosa.

BACKGROUND: Currently, there is no treatment for retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP). Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. Thus far, primarily adult mesenchymal stem cells (MSCs) have been investigated in preclinical and clinical studies, and the results have not been convincing. We applied a new approach in which primitive (p) MSC-derived retinal progenitor cells (RPCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. METHODS: Well-characterized pMSCs and RPCs labeled with PKH26 were intravitreally injected into rd12 mice. The vision and retinal function of transplanted animals were analyzed using electroretinography. Animals were killed 4 and 8 weeks after cell transplantation for histological, immunological, molecular, and transcriptomic analyses of the retina. RESULTS: Transplanted RPCs significantly improved vision and retinal thickness as well as function in rd12 mice. pMSCs and RPCs homed to distinct retinal layers. pMSCs homed to the retinal pigment epithelium, and RPCs migrated to the neural layers of the retina, where they improved the thickness of the respective layers and expressed cell-specific markers. RPCs induced anti-inflammatory and neuroprotective responses as well as upregulated the expression of genes involved in neurogenesis. The transcriptomic analysis showed that RPCs promoted neurogenesis and functional recovery of the retina through inhibition of BMP and activation of JAK/STAT and MAPK signaling pathways. CONCLUSIONS: Our study demonstrated that RPCs countered inflammation, provided retinal protection, and promoted neurogenesis resulting in improved retinal structure and physiological function in rd12 mice.

Catastrophic chemotherapy toxicity leading to diagnosis of Fanconi anaemia due to FANCD1/BRCA2 during adulthood: description of an emerging phenotype.

Fanconi anaemia due to biallelic loss of BRCA2 (Fanconi anaemia subtype D1) is traditionally diagnosed during childhood with cancer rates historically reported as 97% by 5.2 years. This report describes an adult woman with a history of primary ovarian failure, who was diagnosed with gastrointestinal adenocarcinoma and BRCA2-associated Fanconi anaemia at 23 years of age, only after she suffered severe chemotherapy toxicity. The diagnostic challenges include atypical presentation, initial false-negative chromosome fragility testing and variant classification. It highlights gastrointestinal adenocarcinoma as a consideration for adults with biallelic BRCA2 pathogenic variants with implications for surveillance. After over 4 years, the patient has no evidence of gastrointestinal cancer recurrence although the tumour was initially considered only borderline resectable. The use of platinum-based chemotherapy, to which heterozygous BRCA2 carriers are known to respond, may have had a beneficial anticancer effect, but caution is advised given its extreme immediate toxicity at standard dosing. Fanconi anaemia should be considered as a cause for women with primary ovarian failure of unknown cause and referral to cancer genetic services recommended when there is a family history of cancer in the hereditary breast/ovarian cancer spectrum.

Management and Outcomes of Diffuse Large B-cell Lymphoma Post-transplant Lymphoproliferative Disorder in the Era of PET and Rituximab: A Multicenter Study From the Australasian Lymphoma Alliance.

There are limited data on post-transplant lymphoproliferative disorder (PTLD) in the era of positron emission tomography (PET) and rituximab (R). Furthermore, there is limited data on the risk of graft rejection with modern practices in reduction in immunosuppression (RIS). We studied 91 patients with monomorphic diffuse large B-cell lymphoma PTLD at 11 Australian centers: median age 52 years, diagnosed between 2004 and 2017, median follow-up 4.7 years (range, 0.5-14.5 y). RIS occurred in 88% of patients. For patients initially treated with R-monotherapy, 45% achieved complete remission, rising to 71% with the addition of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) for those not in complete remission. For patients initially treated with R-CHOP, the complete remission rate was 76%. There was no difference in overall survival (OS) between R-monotherapy and R-chemotherapy patients. There was no difference in OS for patients with systemic lymphoma (n = 68) versus central nervous system (CNS) involvement (n = 23) (3-y OS 72% versus 73%; P = 0.78). Treatment-related mortality was 7%. End of treatment PET was prognostic for patients with systemic lymphoma with longer OS in the PET negative group (3-y OS 91% versus 57%; P = 0.01). Graft rejection occurred in 9% (n = 4 biopsy-proven; n = 4 suspected) during the entire follow-up period with no cases of graft loss. RIS and R-based treatments are safe and effective with a low likelihood of graft rejection and high cure rate for patients achieving complete remission with CNS or systemic PTLD.

Neural stem cells derived from primitive mesenchymal stem cells reversed disease symptoms and promoted neurogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). MS affects millions of people and causes a great economic and societal burden. There is no cure for MS. We used a novel approach to investigate the therapeutic potential of neural stem cells (NSCs) derived from human primitive mesenchymal stem cells (MSCs) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: MSCs were differentiated into NSCs, labeled with PKH26, and injected into the tail vein of EAE mice. Neurobehavioral changes in the mice assessed the effect of transplanted cells on the disease process. The animals were sacrificed two weeks following cell transplantation to collect blood, lymphatic, and CNS tissues for analysis. Transplanted cells were tracked in various tissues by flow cytometry. Immune infiltrates were determined and characterized by H&E and immunohistochemical staining, respectively. Levels of immune regulatory cells, Treg and Th17, were analyzed by flow cytometry. Myelination was determined by Luxol fast blue staining and immunostaining. In vivo fate of transplanted cells and expression of inflammation, astrogliosis, myelination, neural, neuroprotection, and neurogenesis markers were investigated by using immunohistochemical and qRT-PCR analysis. RESULTS: MSC-derived NSCs expressed specific neural markers, NESTIN, TUJ1, VIMENTIN, and PAX6. NSCs improved EAE symptoms more than MSCs when transplanted in EAE mice. Post-transplantation analyses also showed homing of MSCs and NSCs into the CNS with concomitant induction of an anti-inflammatory response, resulting in reducing immune infiltrates. NSCs also modulated Treg and Th17 cell levels in EAE mice comparable to healthy controls. Luxol fast blue staining showed significant improvement in myelination in treated mice. Further analysis showed that NSCs upregulated genes involved in myelination and neuroprotection but downregulated inflammatory and astrogliosis genes more significantly than MSCs. Importantly, NSCs differentiated into neural derivatives and promoted neurogenesis, possibly by modulating BDNF and FGF signaling pathways. CONCLUSIONS: NSC transplantation reversed the disease process by inducing an anti-inflammatory response and promoting myelination, neuroprotection, and neurogenesis in EAE disease animals. These promising results provide a basis for clinical studies to treat MS using NSCs derived from primitive MSCs.

Cytotoxicity and genotoxicity of the carcinogen aristolochic acid I (AA-I) in human bladder RT4 cells.

Aristolochic acid (AA-I) induces upper urothelial tract cancer (UUTC) and bladder cancer (BC) in humans. AA-I forms the 7-(2'-deoxyadenosin-N6-yl)aristolactam I (dA-AL-I) adduct, which induces multiple A:T-to-T:A transversion mutations in TP53 of AA-I exposed UTUC patients. This mutation is rarely reported in TP53 of other transitional cell carcinomas and thus recognized as an AA-I mutational signature. A:T-to-T:A transversion mutations were recently detected in bladder tumors of patients in Asia with known AA-I-exposure, implying that AA-I contributes to BC. Mechanistic studies on AA-I genotoxicity have not been reported in human bladder. In this study, we examined AA-I DNA adduct formation and mechanisms of toxicity in the human RT4 bladder cell line. The biological potencies of AA-I were compared to 4-aminobiphenyl, a recognized human bladder carcinogen, and several structurally related carcinogenic heterocyclic aromatic amines (HAA), which are present in urine of smokers and omnivores. AA-I (0.05-10 µM) induced a concentration- and time-dependent cytotoxicity. AA-I (100 nM) DNA adduct formation occurred at over a thousand higher levels than the principal DNA adducts formed with 4-ABP or HAAs (1 µM). dA-AL-I adduct formation was detected down to a 1 nM concentration. Studies with selective chemical inhibitors provided evidence that NQO1 is the major enzyme involved in AA-I bio-activation in RT4 cells, whereas CYP1A1, another enzyme implicated in AA-I toxicity, had a lesser role in bio-activation or detoxification of AA-I. AA-I DNA damage also induced genotoxic stress leading to p53-dependent apoptosis. These biochemical data support the human mutation data and a role for AA-I in BC.

Transcriptomic Analysis of Naïve Human Embryonic Stem Cells Cultured in Three-Dimensional PEG Scaffolds.

Naïve human embryonic stem cells (ESCs) are characterized by improved viability, proliferation, and differentiation capacity in comparison to traditionally derived primed human ESCs. However, currently used two-dimensional (2-D) cell culture techniques fail to mimic the three-dimensional (3-D) in vivo microenvironment, altering morphological and molecular characteristics of ESCs. Here, we describe the use of 3-D self-assembling scaffolds that support growth and maintenance of the naïve state characteristics of ESC line, Elf1. Scaffolds were formed via a Michael addition reaction upon the combination of two 8-arm polyethylene glycol (PEG) polymers functionalized with thiol (PEG-8-SH) and acrylate (PEG-8-Acr) end groups. 3-D scaffold environment maintained the naïve state and supported the long-term growth of ESCs. RNA-sequencing demonstrated significant changes in gene expression profiles between 2-D and 3-D grown cells. Gene ontology analysis revealed upregulation of biological processes involved in the regulation of transcription and translation, extracellular matrix organization, and chromatin remodeling in 3-D grown cells. 3-D culture conditions also induced upregulation of genes associated with Wnt and focal adhesion signaling, while p53 signaling pathway associated genes were downregulated. Our findings, for the first time, provide insight into the possible mechanisms of self-renewal of naïve ESCs stimulated by the transduction of mechanical signals from the 3-D microenvironment.

Inverse relationship between oligoclonal expanded CD69- TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients.

CD8+CD57+ terminal effector T (TTE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed TTE cells in the bone marrow (BM) and peripheral blood (PB) of age-matched controls and patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed (ND) MM using flow cytometry, mass cytometry, and FlowSOM clustering. TTE cells are heterogeneous in all subjects, with BM containing both CD69- and CD69+ subsets, while only CD69- cells are found in PB. Within the BM-TTE compartment, CD69- and CD69+ cells are found in comparable proportions in controls, while CD69- cells are dominant in MGUS and SMM and predominantly either CD69- or CD69+ cells in NDMM. A positive relationship between CD69+TTE and CD69-TTE cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69-TTE cells include multiple oligoclonal expansions of T-cell receptor/Vß families shared between BM and PB of NDMM. Oligoclonal expanded CD69-TTE cells from the PB include myeloma-reactive cells capable of killing autologous CD38hi plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69-TTE cells, oligoclonal expansions are not evident within CD69+TTE cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69-TTE and CD69+TTE cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-γ and tumor necrosis factor α. The balance between CD69- and CD69+ cells within the BM-TTE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease.

Virtual Visits in Ophthalmology: Timely Advice for Implementation During the COVID-19 Public Health Crisis.

Virtual visits (VVs) are necessitated due to the public health crisis and social distancing mandates due to COVID-19. However, these have been rare in ophthalmology. Over 3.5 years of conducting >350 ophthalmological VVs, our group has gained numerous insights into best practices. This communication shares these experiences with the medical community to support patient care during this difficult time and beyond. We highlight that mastering the technological platform of choice, optimizing lighting, camera positioning, and "eye contact," being thoughtful and creative with the virtual eye examination, and ensuring good documenting and billing will make a successful and efficient VV. Moreover, we think these ideas will stimulate further VV creativity and expertise to be developed in ophthalmology and across medicine. This approach, holds promise for increasing its adoption after the crisis has passed.

Desmoplastic Small Round Cell Tumor: Long-Term Complications After Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare intra-abdominal soft tissue sarcoma affecting adolescents and young adults. Cytoreduction, hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), and adjuvant radiotherapy may improve local control. We review our experience with patients who undergo CRS/HIPEC and adjuvant radiotherapy for DSRCT. METHODS: A retrospective review was performed for patients with DSRCT from 2013 to 2017 who underwent CRS/HIPEC. Clinicopathologic, operative, and outcome data were reviewed. RESULTS: Ten CRS/HIPEC procedures were performed for nine patients (7 males, 6 Caucasian, median age 19 years (range 10-24)). Four patients presented with extra-abdominal disease; five had liver involvement. The median peritoneal cancer index was 16 (range 5-20). All received neoadjuvant chemotherapy. CCR 0/1 resection was possible in nine patients. Major complications occurred in four with no operative mortalities. All received adjuvant chemotherapy, seven received radiation therapy, and three received stem-cell transplant. All but one patient recurred after treatment. The median recurrence-free and overall survival (OS) were 12 and 45 months (95% confidence interval 35.1-54.9) respectively, with a 3-year OS of 55%. Long-term parenteral nutrition was required in eight for a median of 261 days (range 37-997). Clinically significant long-term complications requiring further surgery included gastroparesis (N = 1), small bowel obstruction (N = 3) and hemorrhagic cystitis (N = 2). CONCLUSIONS: Multimodal therapy for DSRCT consisting of multiagent neoadjuvant chemotherapy, CRS/HIPEC, adjuvant chemotherapy, and radiation therapy is associated with potential cumulative toxicity. Recurrence after resection is common. Prolonged parenteral nutrition may be necessary, and late gastrointestinal and genitourinary complications may require additional treatment.

A multi-center randomized controlled trial to reduce unmet needs, depression, and anxiety among hematological cancer patients and their support persons.

Purpose: Individuals diagnosed with a high-grade hematological malignancy are at high risk for psychosocial distress. This study aimed to examine the effectiveness of a web-based information tool and nurse delivered telephone support in reducing: (i) unmet information needs; (ii) depression; and (iii) anxiety, among hematological cancer patients and their support persons (SPs).Methods: Patients with a new diagnosis of acute myeloid leukemia, acute lymphoblastic leukemia, Burkitt lymphoma, or lymphoblastic lymphoma and their SPs were enrolled in a prospective multi-site randomized trial. Participants received either access to an online information tool and telephone support from a hematology nurse, or usual care. Outcome data were collected 2, 4, 8, and 12 weeks post-recruitment. The primary endpoint was unmet information needs.Results: Data from 60 patients and 15 SPs were included in the analysis. There were no statistically significant differences in unmet information needs, depression or anxiety between intervention and control groups for patients. Patients in both groups demonstrated a decrease in information needs over the intervention period. Post hoc analyses revealed that patients who did not achieve remission with the first cycle of treatment experienced increased anxiety from 4 weeks until the end of the study (p = 0.008).Conclusions: A web-based information tool and nurse delivered telephone support did not reduce unmet information needs, depression or anxiety among hematological cancer patients, however this finding is inconclusive given the low power of the study.Implications for Psychosocial Providers or Policy: Patients who do not achieve remission are at high risk of anxiety, and may benefit from targeted psychological intervention.

Mass Cytometry Discovers Two Discrete Subsets of CD39-Treg Which Discriminate MGUS From Multiple Myeloma.

Multiple Myeloma (MM) is preceded by the clinically stable condition monoclonal gammopathy of undetermined significance (MGUS). Critical immune events that discriminate MGUS from newly diagnosed MM (ND)MM patients remain unknown, but may involve changes in the regulatory T cell (Treg) compartment that favor myeloma growth. To address this possibility, we used mass cytometry and the unsupervised clustering algorithm Flow self-organizing map (FlowSOM) to interrogate the distribution of multiple subsets within CD25+CD127low/negTreg in matched bone marrow (BM) and peripheral blood (PB) of MGUS and NDMM patients. Both mass cytometry and flow cytometry confirmed a trend toward prevalence of CD39-Treg within the Treg compartment in BM and PB of NDMM patients compared to CD39-Treg in MGUS patients. FlowSOM clustering displayed a phenotypic organization of Treg into 25 metaclusters that confirmed Treg heterogeneity. It identified two subsets which emerged within CD39-Treg of NDMM patients that were negligible or absent in CD39-Treg of MGUS patients. One subset was found in both BM and PB which phenotypically resembled activated Treg based on CD45RO, CD49d, and CD62L expression; another subset resembled BM-resident Treg based on its tissue-resident CD69+CD62L-CD49d- phenotype and restricted location within the BM. Both subsets co-expressed PD-1 and TIGIT, but PD-1 was expressed at higher levels on BM-resident Treg than on activated Treg. Within BM, both subsets had limited Perforin and Granzyme B production, whilst activated Treg in PB acquired high Perforin and Granzyme B production. In conclusion, the use of mass cytometry and FlowSOM clustering discovered two discrete subsets of CD39-Treg which are discordant in MGUS and NDMM patients and may be permissive of myeloma growth which warrants further study. Understanding the regulatory properties of these subsets may also advance MGUS and MM diagnosis, prognosis, and therapeutic implications for MM patients.

Mesenchymal stem cells: Cell therapy and regeneration potential.

Rapid advances in the isolation of multipotent progenitor cells, routinely called mesenchymal stromal/stem cells (MSCs), from various human tissues and organs have provided impetus to the field of cell therapy and regenerative medicine. The most widely studied sources of MSCs include bone marrow, adipose, muscle, peripheral blood, umbilical cord, placenta, fetal tissue, and amniotic fluid. According to the standard definition of MSCs, these clonal cells adhere to plastic, express cluster of differentiation (CD) markers such as CD73, CD90, and CD105 markers, and can differentiate into adipogenic, chondrogenic, and osteogenic lineages in vitro. However, isolated MSCs have been reported to vary in their potency and self-renewal potential. As a result, the MSCs used for clinical applications often lead to variable or even conflicting results. The lack of uniform characterization methods both in vitro and in vivo also contributes to this confusion. Therefore, the name "MSCs" itself has been increasingly questioned lately. As the use of MSCs is expanding rapidly, there is an increasing need to understand the potential sources and specific potencies of MSCs. This review discusses and compares the characteristics of MSCs and suggests that the variations in their distinctive features are dependent on the source and method of isolation as well as epigenetic changes during maintenance and growth. We also discuss the potential opportunities and challenges of MSC research with the hope to stimulate their use for therapeutic and regenerative medicine.

Anesthesia and Pain Management for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Desmoplastic Small Round Cell Tumors in Children, Adolescents, and Young Adults.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may improve survival. METHODS: A retrospective review of anesthetic management and postoperative pain control strategies after CRS/HIPEC for DSRCT from 2013 to 2017 was performed. RESULTS: The review analyzed 10 CRS/HIPEC procedures performed for nine DSRCT patients with a median age of 19 years (range 10-24 years). Six of these patients were Caucasian, and seven were men. The median operative duration was 551 min (range 510-725 min), and the median anesthesia duration was 621 min (range 480-820 min). Postoperative mechanical ventilation was necessary in 5 patients for a median duration of 1 day (range 0-2 days). The median intraoperative intravenous fluid administration was 13 ml/kg/h (range 6.3-24.4 ml/kg/h), and the colloid administration was 12 ml/kg (range 0.0-53.0 ml/kg). The median blood loss was 15 ml/kg (range 6.3-77.2 ml/kg). Nine patients received intraoperative transfusion with a median red blood cell transfusion volume of 14 ml/kg (range 10.1-58.5 ml/kg). The median intraoperative urine output was 2 ml/kg/h (range 0.09-8.40 ml/kg/h), and half of the patients received intraoperative diuretics. Cisplatin was used during HIPEC for eight surgeries. Acute kidney injury was observed in two patients, one of whom required short-term dialysis. Epidural infusions were used in eight cases for a median of 4 days (range 3-5 days). Postoperative intravenous opioid use (morphine equivalent) was 0.67 mg/kg/day (range 0.1-9.2 mg/kg/day) administered for a median of 11 days (range 2-35 days). CONCLUSION: Cytoreduction and HIPEC for DSRCT are associated with significant perioperative fluid requirements and potentially challenging pain management. Renal protective strategies should be considered for reduction of cisplatin-associated nephrotoxicity. Further investigation for a more effective, less systemically toxic HIPEC agent is warranted.

Toxicity of JQ1 in neuronal derivatives of human umbilical cord mesenchymal stem cells.

Bromodomain and extra-terminal domain (BET) proteins regulate the transcription of many genes including c-MYC, a proto-oncogene, which is upregulated in many types of cancers. The thienodiazepine class of BET inhibitors, such as JQ1, inhibits growth of cancer cells and triggers apoptosis. However, the effects of BET inhibitors on normal cells and mesenchymal stem cells (MSCs), which are important in routine maintenance or regeneration of damaged cells and tissues, are poorly investigated. Previously, we have shown that JQ1 causes human umbilical cord MSCs to undergo cell cycle arrest and neural differentiation. In this study, we determined that JQ1 is more deleterious to neuronal derivatives (NDs) than adipogenic, chondrogenic or osteogenic derivatives of MSCs. NDs treated with JQ1 showed a significant decrease in cell proliferation, viability, and neuronal markers. JQ1 caused cell death through the intrinsic apoptotic pathway in NDs as determined by activation of Caspase 9 and increased expression of Cytochrome C. A comparative analysis showed differential action of JQ1 on MSCs and NDs. The results showed selective neuronal toxicity of JQ1 in NDs but not in the undifferentiated MSCs. These findings suggest a more careful examination of the selection and use of BET inhibitors as therapeutic agents, as they may cause unwanted damage to non-target cells and tissues.