Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors.

PURPOSE: This study aimed to investigate the incidence and risk factors for secondary malignant neoplasms (SMN) in pediatric solid tumors, focusing on the effects of tandem high-dose chemotherapy (HDCT). MATERIALS AND METHODS: Patients (aged < 19 years) diagnosed with or treated for pediatric solid tumors between 1994 and 2014 were retrospectively analyzed. The cumulative incidence of SMN was estimated using competing risk methods by considering death as a competing risk. RESULTS: A total of 1,435 patients (413 with brain tumors and 1,022 with extracranial solid tumors) were enrolled. Seventy-one patients developed 74 SMNs, with a 10-year and 20-year cumulative incidence of 2.680±0.002% and 10.193±0.024%, respectively. The types of SMN included carcinoma in 28 (37.8%), sarcoma in 24 (32.4%), and hematologic malignancy in 15 (20.3%) cases. Osteosarcoma and thyroid carcinoma were the most frequently diagnosed tumors. Multivariate analysis showed that radiotherapy (RT) > 2, 340 cGy, and tandem HDCT were significant risk factors for SMN development. The SMN types varied according to the primary tumor type; carcinoma was the most frequent SMN in brain tumors and neuroblastoma, whereas hematologic malignancy and sarcomas developed more frequently in patients with sarcoma and retinoblastoma, respectively. CONCLUSION: The cumulative incidence of SMN in pediatric patients with solid tumors was considerably high, especially in patients who underwent tandem HDCT or in those who received RT > 2,340 cGy. Therefore, the treatment intensity should be optimized based on individual risk assessment and the long-term follow-up of pediatric cancer survivors.

Management of Stroke in Patients With Chronic Liver Disease: A Practical Review.

Chronic liver disease (CLD) is a highly prevalent condition. There is burgeoning recognition that there are many people with subclinical liver disease that may nonetheless be clinically significant. CLD has a variety of systemic aberrations relevant to stroke, including thrombocytopenia, coagulopathy, elevated liver enzymes, and altered drug metabolism. There is a growing body of literature on the intersection of CLD and stroke. Despite this, there have been few efforts to synthesize these data, and stroke guidelines provide scant guidance on this topic. To fill this gap, this multidisciplinary review provides a contemporary overview of CLD for the vascular neurologist while appraising data regarding the impact of CLD on stroke risk, mechanisms, and outcomes. Finally, the review addresses acute and chronic treatment considerations for patients with stroke-ischemic and hemorrhagic-and CLD.

Thrombocytopenia and liver disease: pathophysiology and periprocedural management.

Abnormal bleeding in patients with liver disease may result from elevated portal pressure and varix formation, reduced hepatic synthesis of coagulation proteins, qualitative platelet dysfunction, and/or thrombocytopenia. Major mechanisms of thrombocytopenia in liver disease include splenic sequestration and impaired platelet production due to reduced thrombopoietin production. Alcohol and certain viruses may induce marrow suppression. Immune thrombocytopenia (ITP) may co-occur in patients with liver disease, particularly those with autoimmune liver disease or chronic hepatitis C. Drugs used for the treatment of liver disease or its complications, such as interferon, immunosuppressants, and antibiotics, may cause thrombocytopenia. Periprocedural management of thrombocytopenia of liver disease depends on both individual patient characteristics and the bleeding risk of the procedure. Patients with a platelet count higher than or equal to 50 000/µL and those requiring low-risk procedures rarely require platelet-directed therapy. For those with a platelet count below 50 000/µL who require a high-risk procedure, platelet-directed therapy should be considered, especially if the patient has other risk factors for bleeding, such as abnormal bleeding with past hemostatic challenges. We often target a platelet count higher than or equal to 50 000/µL in such patients. If the procedure is elective, we prefer treatment with a thrombopoietin receptor agonist; if it is urgent, we use platelet transfusion. In high-risk patients who have an inadequate response to or are otherwise unable to receive these therapies, other strategies may be considered, such as a trial of empiric ITP therapy, spleen-directed therapy, or transjugular intrahepatic portosystemic shunt placement.

Controllable fabrication of silver-deposited polyurethane acrylate nanopillar array film as a flexible surface-enhanced Raman scattering (SERS) substrate with high sensitivity and reproducibility.

A controllable method for fabricating flexible surface-enhanced Raman scattering (SERS) substrates is demonstrated by depositing silver onto a flexible nanopillar array film. The flexible nanopillar array film was cost-effectively prepared by replicating an anodic aluminum oxide (AAO) template with UV-curable polyurethane acrylate (PUA) over a large area. Then, the deposition of silver was done by an Ar-assisted thermal evaporation. In the deposition process, the partial pressure of Ar was optimized because it has a significant influence on the SERS intensity through the microstructural changes of silver deposited on PUA nanopillars. In addition, the increase in the nanopillar diameter and height enhanced the SERS intensity obtained at 785-nm excitation because of the increased number of hot spots. However, the agglomeration of Ag-deposited nanopillars, which is caused by high aspect ratios, negatively affected the SERS performance in terms of intensity and standard deviation. The optimized Ag-deposited nanopillar array film with nanopillar diameters and heights of 80 nm and 200 nm exhibited excellent SERS sensitivity and signal reproducibility with stable mechanical flexibility. For application in food and biomedical analysis, it was used for detecting saccharin and peptide and showed a good linear relationship between the SERS intensity and concentration. These findings demonstrate the suitability of our method for the controllable fabrication and optimization of flexible SERS substrates with high sensitivity and reproducibility.

Postchemotherapy gross residual tumor in non-high-risk neuroblastoma: Clinical significance and the role of adjuvant therapy.

BACKGROUND: Although survival rate among patients with non-high-risk neuroblastoma is excellent, a gross residual tumor (GRT) is often present at the end of treatment. However, reliable data do not exist on the relevance of a GRT for the risk of progression and the role of adjuvant therapy for patients with GRT. METHODS: A retrospective review of 131 patients with non-high-risk neuroblastoma who underwent chemotherapy was performed. GRT was defined as >1 cm3 residual soft tissue density on end-of-chemotherapy scans. Progression-free survival (PFS) and overall survival (OS) rates were compared between patients with GRT and those without GRT. A proportional hazards model was also used to assess the effects of GRT and adjuvant therapies, including radiation and isotretinoin therapy on outcomes. RESULTS: GRT was found in 52 (40%) patients in the study cohort. Correlation was not found between GRT and outcomes (PFS; p = .954, OS; p = .222). In multivariable analysis, GRT remained a nonsignificant predictor of outcome after adjusting for confounders. Local radiation and isotretinoin therapy did not affect outcome for patients with GRT. However, within GRT subgroups, the degree of volume reduction, as well as absolute residual volume in the primary tumor after induction treatment, were significantly associated with outcomes. CONCLUSION: GRT in non-high-risk neuroblastoma may not indicate active disease that requires additional treatment. However, risk of progression is increased in patients with GRT whose response to treatment was less prominent, thus adjuvant therapy should be reserved only for those patients.

Improving the Performance of Aqueous Zinc-ion Batteries by Inhibiting Zinc Dendrite Growth: Recent Progress.

Aqueous zinc-ion batteries (ZIBs) are promising candidates for the next-generation high-energy storage devices, owing to their resource availability, low cost, eco-friendliness, and high safety. The zinc (Zn) metal anode in a suitable battery system, including an electrolyte and a high-performance cathode electrode, can deliver an excellent electrochemical performance. However, several obstacles must be overcome to utilize aqueous ZIBs. Among these, Zn dendrite growth, corrosion, and side reactions severely impair the performance of rechargeable ZIBs. To deal with these issues, a profound understanding of the mechanism of the matter occurring in electrochemical cycles is essential to thoroughly solve the challenges. Instead of focusing solely on techniques for improving the performance of Zn metal anodes, this review delves into and summarizes the causes of side reactions and dendrite formation, thereby establishing a logical system of methodologies for improving the electrochemical performance of mild aqueous ZIBs. The correlation between the Zn metal anode, aqueous electrolyte, separators and the performance of ZIBs is also discussed in detail. There is also a brief perspective on the future development of Zn metal anodes in aqueous solutions. This study sheds a light on the challenges associated with the construction of high-performance ZIBs, which will significantly aid in their practical implementation.

Management and outcomes of mild hemophiliacs and hemophilia carriers during pregnancy and peripartum period: a hemophilia treatment center experience in the United States.

BACKGROUND: Pregnancy, peripartum management, and outcomes of mild hemophiliacs and hemophilia carriers in the United States are not well established. AIM: To describe the management and outcomes of mild hemophiliacs and hemophilia carriers during assisted conception, pregnancy, peripartum and post-partum period at our hemophilia treatment center (HTC). METHODS: Retrospective review of electronic medical records of pregnant women with mild hemophilia A or B (Factor VIII [FVIII] or Factor IX [FIX] level <0.4 IU/mL) and hemophilia A and B carriers followed at our HTC from January 2008 to October 2020. Demographics, the reason for diagnosis, FVIII and FIX levels at baseline and third trimester, bleeding phenotype and genotype were obtained. Method of conception, factor replacement, iron supplementation, mode of delivery, type of anesthesia, peripartum complications, and offspring outcomes was recorded. RESULTS: There was a total of 18 pregnancies in 12 women (2 with mild hemophilia A, 2 mild hemophilia B, 6 hemophilia A carriers, and 2 hemophilia B carriers). Eleven pregnancies (61%) were conceived naturally and 7 (39%) via in-vitro fertilization (IVF). Eight (44.4%) and 10 (55.6%) pregnancies were vaginal and C-section deliveries, respectively. Neuraxial anesthesia was administered in 17 (94.4%) deliveries without complications. Four pregnancies (22.2%) had bleeding complications, 2 of which were post-partum hemorrhages not requiring transfusion. CONCLUSION: In our case series of pregnant hemophilia carriers and mild hemophiliacs, successful outcomes were achieved with a carefully detailed multidisciplinary-driven approach.

Clinical implication of residual MIBG-positive disease in the follow-up of high-risk neuroblastoma treated with tandem high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND: The implication of residual metaiodobenzylguanidine (MIBG)-positive disease in the era of tandem high-dose chemotherapy (HDCT) with autologous stem cell transplantation (auto-SCT) has not yet been established in neuroblastoma. Moreover, most published studies have not evaluated the long-term prognosis of patients with residual MIBG-positive disease following treatment completion. Therefore, we investigated the prognostic significance of residual MIBG-positive disease at each treatment phase and after treatment completion. METHODS: We assessed MIBG scans labeled with either iodine-123 (123 I) or 131 I from 150 patients with MIBG-avid and high-risk neuroblastoma enrolled in the NB-2004, -2009, and -2014 trials at postinduction, posttandem HDCT/auto-SCT, and completion of treatment. RESULTS: The residual MIBG-positive disease at postinduction and posttandem HDCT/auto-SCT evaluation was highly correlated with the risk of progression. However, at treatment completion, there was no significant difference in survival and risk of progression between patients with residual MIBG-positive disease and MIBG-negative patients. Patients with persistent MIBG-positive disease at the end of treatment were more likely to have indolent tumor characteristics, such as favorable histology at diagnosis, lower incidence of MYCN amplification, and slow response to chemotherapy. CONCLUSION: Residual MIBG-positive disease during treatment predicted unfavorable outcomes for patients with high-risk neuroblastoma, even under tandem HDCT/auto-SCT. However, persistent MIBG uptake at the completion of all treatments may not always indicate an active disease.

Annexin A2 in Fibrinolysis, Inflammation and Fibrosis.

As a cell surface tissue plasminogen activator (tPA)-plasminogen receptor, the annexin A2 (A2) complex facilitates plasmin generation on the endothelial cell surface, and is an established regulator of hemostasis. Whereas A2 is overexpressed in hemorrhagic disease such as acute promyelocytic leukemia, its underexpression or impairment may result in thrombosis, as in antiphospholipid syndrome, venous thromboembolism, or atherosclerosis. Within immune response cells, A2 orchestrates membrane repair, vesicle fusion, and cytoskeletal organization, thus playing a critical role in inflammatory response and tissue injury. Dysregulation of A2 is evident in multiple human disorders, and may contribute to the pathogenesis of various inflammatory disorders. The fibrinolytic system, moreover, is central to wound healing through its ability to remodel the provisional matrix and promote angiogenesis. A2 dysfunction may also promote tissue fibrogenesis and end-organ fibrosis.

Topical Delivery of Nanosized Hydroxycitric Acid Enriched Extract-Loaded Ethosomes for Suppression of Lipid Droplet Deposition.

The aim of this study was to improve the skin accumulation of hydroxycitric acid by using ethosomes with nanosize. We fabricated nanosized ethosome for the topical delivery of hydrophilic hydroxycitric acid and evaluated their physical properties and furthermore cytotoxicity. As results, in cell-based experiments, the use of ethosomes encapsulating hydroxycitric acid extract reduced the lipid droplet deposition in differentiated adipocytes, which was visualized by Oil Red O staining assay and also quantitatively measured by a triglyceride assay. The observed reduction in lipid droplet deposition occurred in a hydroxycitric acid extract concentration-dependent manner. In addition, the high accumulation of hydroxycitric acid in murine skin (66.28%) was observed following treatment with hydroxycitric acid extract-loaded ethosomes compared with treatment with hydroxycitric acid alone (1.19%) without ethosome as a nanocarrier. Based on these results, our findings showed that nanosized ethosomes improved the topical delivery of hydroxycitric acid and thus reduced lipid droplet deposition in adipocytes.

Successful outcome with eculizumab treatment in a patient with antiphospholipid syndrome presenting with an unusual thrombotic storm.

Catastrophic Antiphospholipid Syndrome (CAPS) is a life-threatening complication of APS requiring complex management to optimize patient outcome. We describe a 54-year-old man with APS with history of splanchnic vein thrombosis, a Factor II G20210A heterozygote, autoimmune hemolytic anemia and thrombocytopenia. He developed sudden onset of severe flank pain due to spontaneous bilateral adrenal hemorrhage while on warfarin with a therapeutic INR. Despite unfractionated heparin and initial clinical improvement, severe thrombocytopenia developed requiring dexamethasone, rituximab, and romiplostim. Hospitalization was complicated further by thrombosis of the inferior vena cava, pulmonary embolism, and painful violaceous patches on his neck and ear cartilages. Punch biopsy of lesions revealed C5b-C9 deposition of small vessel thromboses. Although the inciting event for his thrombotic storm remains uncertain, anti-complement therapy with eculizumab provided rapid and durable lesion resolution. Eculizumab was discontinued after 6 months and patient remains in remission without recurrent thrombosis. This case provides insight on the management of CAPS, including the use of eculizumab.

Decisions in the Dark: An Educational Intervention to Promote Reflection and Feedback on Night Float Rotations.

BACKGROUND: Night float rotations, where residents admit patients to the hospital, are opportunities for practice-based learning. However, night float residents receive little feedback on their diagnostic and management reasoning, which limits learning. AIM: Improve night float residents' practice-based learning skills through feedback solicitation and chart review with guided reflection. SETTING/PARTICIPANTS: Second- and third-year internal medicine residents on a 1-month night float rotation between January and August 2017. PROGRAM DESCRIPTION: Residents performed chart review of a subset of patients they admitted during a night float rotation and completed reflection worksheets detailing patients' clinical courses. Residents solicited feedback regarding their initial management from day team attending physicians and senior residents. PROGRAM EVALUATION: Sixty-eight of 82 (83%) eligible residents participated in this intervention. We evaluated 248 reflection worksheets using content analysis. Major themes that emerged from chart review included residents' identification of future clinical practice changes, evolution of differential diagnoses, recognition of clinical reasoning gaps, and evaluation of resident-provider interactions. DISCUSSION: Structured reflection and feedback during night float rotations is an opportunity to improve practice-based learning through lessons on disease progression, clinical reasoning, and communication.

Selective Nonenzymatic Amperometric Detection of Lactic Acid in Human Sweat Utilizing a Multi-Walled Carbon Nanotube (MWCNT)-Polypyrrole Core-Shell Nanowire.

Lactic acid plays an important role as a biochemical indicator for sports medicine and clinical diagnosis. The detection of lactic acid in sweat is a promising technique without any intrusive inconvenience or risk of infection. In this study, we present a selective nonenzymatic amperometric detection method for lactic acid in human sweat utilizing a multi-wall carbon nanotube (MWCNT)-polypyrrole core-shell nanowire. Because polypyrrole is a p-type conducting polymer, onto which anions are exclusively doped, leading to charge transfer, it offers selective detection for lactate anions at a specific potential, while being inert to the neutral and cationic species contained in human sweat. A chronoamperometric study reveals good sensing performance for lactic acid with a high sensitivity of 2.9 µA mM-1 cm-2 and detection limit of 51 µM. Furthermore, the MWCNT-polypyrrole nanowire exhibits excellent selectivity for lactic acid over interfering species, such as sodium chloride, glucose, urea, and riboflavin, which coexist with lactic acid in sweat. Finally, a nonenzymatic amperometric sensor for the selective detection of lactic acid in human sweat is demonstrated on commercial flexible electrodes. The results demonstrate the potential applications of the MWCNT-polypyrrole core-shell nanowire as a nonenzymatic amperometric lactate sensor.

Prevalence and characterisation of diagnostic error among 7-day all-cause hospital medicine readmissions: a retrospective cohort study.

BACKGROUND: The prevalence and aetiology of diagnostic error among hospitalised adults is unknown, though likely contributes to patient morbidity and mortality. We aim to identify and characterise the prevalence and types of diagnostic error among patients readmitted within 7 days of hospital discharge. METHODS: Retrospective cohort study at a single urban academic hospital examining adult patients discharged from the medical service and readmitted to the same hospital within 7 days between January and December 2018. The primary outcome was diagnostic error presence, identified through two-physician adjudication using validated tools. Secondary outcomes included severity of error impact and characterisation of diagnostic process failures contributing to error. RESULTS: There were 391 cases of unplanned 7-day readmission (5.2% of 7507 discharges), of which 376 (96.2%) were reviewed. Twenty-one (5.6%) admissions were found to contain at least one diagnostic error during the index admission. The most common problem areas in the diagnostic process included failure to order needed test(s) (n=11, 52.4%), erroneous clinician interpretation of test(s) (n=10, 47.6%) and failure to consider the correct diagnosis (n=8, 38.1%). Nineteen (90.5%) of the diagnostic errors resulted in moderate clinical impact, primarily due to short-term morbidity or contribution to the readmission. CONCLUSION: The prevalence of diagnostic error among 7-day medical readmissions was 5.6%. The most common drivers of diagnostic error were related to clinician diagnostic reasoning. Efforts to reduce diagnostic error should include strategies to augment diagnostic reasoning and improve clinician decision-making around diagnostic studies.

Clinical Significance of Segmental Chromosomal Aberrations in Patients with Neuroblastoma: First Report in Korean Population.

BACKGROUND: This study aimed to investigate the incidence and clinical significance of segmental chromosomal aberrations (SCAs) in Korean patients with neuroblastoma. METHODS: Patients diagnosed with neuroblastoma from 2012 to 2018 were included for retrospective review. Fluorescence in situ hybridization (FISH) was used to analyze four SCAs (MYCN amplification, 1p deletion, 11q deletion, and 17q gain). Clinical characteristics at diagnosis, early tumor response (reduction in primary tumor volume and neuron-specific enolase level after the first three cycles of chemotherapy), and survival rates were compared according to SCAs. RESULTS: Among 173 patients with FISH results, 92 (53.2%) had at least one of the four SCAs, while 25 (14.5%) had two co-aberrations, and eight (4.6%) had three co-aberrations. SCAs detected in our study were MYCN amplification (n = 17, 9.8%), 1p deletion (n = 26, 15.2%), 11q deletion (n = 44, 25.6%), and 17q gain (n = 46, 27.1%). Patients with MYCN amplification showed a better early response but a worse survival than those without (5-year overall survival: 46.2% ± 13.1% vs. 88.6% ± 3.4%). Furthermore, 1p deletion was associated with a better early response but a worse survival; however, it was not an independent factor for survival. We could not find any prognostic significance associated with 11q deletion or 17q gain. CONCLUSION: This is the first study investigating SCAs in Korean neuroblastoma patients. Prognostic significance of SCAs other than MYCN amplification was different from those reported in western countries. Further study with a larger cohort and longer follow-up is needed to confirm our findings.

De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort.

De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH), and 6 with R-CHOP with methotrexate, 3 g/m(2) . The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients.

Characterization of IgA and IgM binding and internalization by surface-expressed human Fcα/µ receptor.

The Fcα/µ receptor (Fcα/µR) is an unusual Fc receptor in that it binds to two different antibody isotypes, IgA and IgM. This receptor is of interest because it is thought to be involved in the capture of IgA- and IgM-immune complexes and antigen presentation. To further characterize this receptor, we were able to stably express human Fcα/µR on the surface of the 293T cell line. Using this system, we determined the affinity of the interactions of the receptor with IgA and IgM, which led to novel insights including the important finding that IgM polymers can bind to human Fcα/µR in the absence of J chain. This is in contrast to the polymeric immunoglobulin receptor (pIgR), which requires the presence of J chain to bind to polymeric IgA and IgM. The dissociation constants (K(d)) of all of the different human IgA isotypes and allotypes for human Fcα/µR were determined, and we show that the N-linked glycans on IgA1 are not required for binding to the receptor. In addition, we demonstrate that IgA can be rapidly internalized by human Fcα/µR in the presence of cross-linking antibody.

Heterobifunctional modification of DNA for conjugation to solid surfaces.

Many biosensors, DNA arrays, and next-generation DNA sequencing technologies need common methods for end modification of random DNA sequences generated from a sample of DNA. Surface immobilization of chemically modified DNA is often the first step in creating appropriate sensing platforms. We describe a simple technique for efficient heterobifunctional modification of arbitrary double-stranded DNA fragments with chosen chemical groups. The modification requires the use of short (10-20 base pairs) synthetic adaptors having desired terminal functional groups and installs known sequences, which can be used for hybridization of primers in the sequencing-by-synthesis approaches. The method, based on ligation under optimized conditions, is selective and provides high yields of the target heterobifunctional DNA product. An additional two-step procedure can be applied to select further for the desired bifunctionalized product using PCR amplification with a chemically modified primer. Both functional groups in the modified DNA are chemically active and can be used in surface immobilization of the DNA strands to create the surface of a biosensor or sequencing chip.