International Prognostic Score for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

PURPOSE: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

Impact of Time-to-Antibiotic Delivery in Pediatric Patients With Cancer Presenting With Febrile Neutropenia.

PURPOSE: Febrile neutropenia (FN) in pediatric patients with cancer can cause severe infections, and prompt antibiotics are warranted. Extrapolated from other populations, a time-to-antibiotic (TTA) metric of <60 minutes after medical center presentation was established, with compliance data factoring into pediatric oncology program national rankings. METHODS: All FN episodes occurring at Vanderbilt Children's Hospital (2007-February 2022) and a sample of episodes from Colorado Children's Hospital (2012-2019) were abstracted, capturing TTA and clinical outcomes including major complications (intensive care unit [ICU] admission, vasopressors, intubation, or infection-related mortality). Odds ratios (ORs) were adjusted for age, treatment center, absolute neutrophil count, hypotension presence, stem-cell transplant status, and central line type. RESULTS: A total of 2,349 episodes were identified from Vanderbilt (1,920) and Colorado (429). Only 0.6% (n = 14) episodes required immediate ICU management, with a median TTA of 28 minutes (IQR, 20-37). For the remaining patients, the median TTA was 56 minutes (IQR, 37-90), and 54.3% received antibiotics in <60 minutes. There were no significant associations between TTA (<60 or ≥60 minutes) and major complications (adjusted OR, 0.99 [95% CI, 0.62 to 1.59]; P = .98), and a TTA ≥60 minutes was not associated with any type of complication. Similarly, TTA, when evaluated as a continuous variable, was not associated with a major (OR, 0.99 [95% CI, 0.94 to 1.04]; P = .69) nor any other complication in adjusted analysis. CONCLUSION: There is no clear evidence that a reduced TTA improves clinical outcomes in pediatric oncology FN and thus it should not be used as a primary quality measure.

Designing and Conducting Scholarly Quality Improvement: A Practical Guide for Improvers Everywhere.

Successful publication of quality improvement (QI) work is predicated on the use of established QI frameworks and rigorous analytical methods that allow teams to understand the impact of interventions over time. This article is meant to help QI teams disseminate their work more broadly through publication by providing tangible methods that many journals desire in QI articles with specific examples of published works referenced throughout the article. We introduce improvement frameworks that teams should identify early and use as a foundation throughout their projects. We review vital aspects of QI projects, such as team formation, creation of a succinct and clear aim statement, defining primary, process, and balancing measures, as well as QI tools like key driver diagrams, Ishikawa (fishbone) diagrams, and Pareto charts. Finally, we highlight the importance of analyzing data over time to understand the impacts of plan-do-study-act cycles on data. Annotated run charts or, more preferably, annotated statistical process control (or Shewhart) charts are both statistically sound methods to identify significant changes over time. Deliberate planning and execution of QI projects using these concepts will lead to improved chances of QI teams finding success in their project and eventual article acceptance.

Oncologist counseling practice and COVID-19 vaccination outcomes for patients with history of PEG-asparaginase hypersensitivity.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an effective strategy to prevent serious coronavirus disease 2019 (COVID-19) and is important for oncology patients. mRNA-based COVID-19 vaccines are contraindicated in those with a history of severe or immediate allergy to any vaccine component, including polyethylene glycol (PEG)2000. Patients with acute lymphoblastic leukemia/lymphoma receive asparaginase conjugated to PEG5000 (PEG-ASNase) and those with PEG-ASNase-associated hypersensitivity may be unnecessarily excluded from receiving mRNA COVID-19 vaccines. We, therefore, surveyed oncologists on COVID-19 vaccine counseling practice and vaccination outcomes in COVID-19 vaccination-eligible patients and show safe receipt of mRNA vaccines despite PEG-ASNase hypersensitivity.

Clinician collaboration to improve clinical decision support: the Clickbusters initiative.

OBJECTIVE: We describe the Clickbusters initiative implemented at Vanderbilt University Medical Center (VUMC), which was designed to improve safety and quality and reduce burnout through the optimization of clinical decision support (CDS) alerts. MATERIALS AND METHODS: We developed a 10-step Clickbusting process and implemented a program that included a curriculum, CDS alert inventory, oversight process, and gamification. We carried out two 3-month rounds of the Clickbusters program at VUMC. We completed descriptive analyses of the changes made to alerts during the process, and of alert firing rates before and after the program. RESULTS: Prior to Clickbusters, VUMC had 419 CDS alerts in production, with 488 425 firings (42 982 interruptive) each week. After 2 rounds, the Clickbusters program resulted in detailed, comprehensive reviews of 84 CDS alerts and reduced the number of weekly alert firings by more than 70 000 (15.43%). In addition to the direct improvements in CDS, the initiative also increased user engagement and involvement in CDS. CONCLUSIONS: At VUMC, the Clickbusters program was successful in optimizing CDS alerts by reducing alert firings and resulting clicks. The program also involved more users in the process of evaluating and improving CDS and helped build a culture of continuous evaluation and improvement of clinical content in the electronic health record.

Respiratory failure and shock in an infant with severe anemia.

Patients with severe anemia can present with non-specific symptoms, including shock and respiratory distress. Ensuring a rapid, targeted workup is initiated and providing prompt transfusions as necessary are critical for both diagnostic success and clinical improvement.

Pediatric Hodgkin Lymphoma, Version 3.2021.

Hodgkin lymphoma (HL) is a highly curable form of cancer, and current treatment regimens are focused on improving treatment efficacy while decreasing the risk of late effects of treatment. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric HL provide recommendations on the workup, diagnostic evaluation, and treatment of classic HL, including principles of pathology, imaging, staging, systemic therapy, and radiation therapy. This portion of the NCCN Guidelines focuses on the management of pediatric classic HL in the upfront and relapsed/refractory settings.

Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.

Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.

Functional genomics resources for the North Atlantic copepod, Calanus finmarchicus: EST database and physiological microarray.

The copepod, Calanus finmarchicus is a keystone species for the North Atlantic. Because of recent changes in the geographic distribution of this species, there are questions as to how this organism responds physiologically to environmental cues. Molecular techniques allow for examination and new understanding of these physiological changes. Here, we describe the development of a microarray for high-throughput studies of the physiological ecology of C. finmarchicus. An EST database was generated for this species using a normalized cDNA library derived from adult and sub-adult individuals. Sequence data were clustered into contigs and annotated using Blastx. Target transcripts were selected, and unique, 50 base-pair, oligomer probes were generated for 995 genes. Blast2GO processing provided detailed information on gene function. The selected targets included broad representation of biological processes, cellular components, and molecular functions. The microarray was tested in two sets of comparisons: adult females maintained at different food concentrations and field-caught sub-adults showing differences in lipid storage. Up-regulated and down-regulated transcripts were identified for both comparisons. Only a small subset of the genes up-regulated in low food individuals were also up-regulated in lipid-poor animals; no overlap was seen between the genes down-regulated in the two comparisons.

Using knowledge structures to redesign an instructor-operator station.

Frequently, user interface (UI) designers must choose between modifying an established, but suboptimal and familiar, UI or to avoid such changes. Changing the UI's, organization may frustrate users who have become familiar with the original design, whereas failing to make changes may force users to perform at an unsatisfactory level. This paper presents two studies that investigate whether users familiar with a poorly designed UI would find items faster, and prefer a reorganized UI that conformed to domain expert knowledge, or would their familiarity with the original UI yield faster performance and higher satisfaction. This paper describes activities to redesign a menu structure in a simulator instructor-operator station (IOS) using hierarchical card sorting and cluster analysis (Romesburg, 2004). This analysis was used to reorganize the menu structure to reflect the knowledge representations of domain experts in accordance with the principle of proximity compatibility (Wickens and Carswell, 1995; Rothrock et al., 2006). The new design was validated with a separate set of users by a reaction time experiment and preference selection.

Characterization of the Carcinus maenas neuropeptidome by mass spectrometry and functional genomics.

Carcinus maenas, commonly known as the European green crab, is one of the best-known and most successful marine invasive species. While a variety of natural and anthropogenic mechanisms are responsible for the geographic spread of this crab, its ability to adapt physiologically to a broad range of salinities, temperatures and other environmental factors has enabled its successful establishment in new habitats. To extend our understanding of hormonal control in C. maenas, including factors that allow for its extreme adaptability, we have undertaken a mass spectral/functional genomics investigation of the neuropeptides used by this organism. Via a strategy combining MALDI-based high resolution mass profiling, biochemical derivatization, and nanoscale separation coupled to tandem mass spectrometric sequencing, 122 peptide paracrines/hormones were identified from the C. maenas central nervous system and neuroendocrine organs. These peptides include 31 previously described Carcinus neuropeptides (e.g. NSELINSILGLPKVMNDAamide [beta-pigment dispersing hormone] and PFCNAFTGCamide [crustacean cardioactive peptide]), 49 peptides only described in species other than the green crab (e.g. pQTFQYSRGWTNamide [Arg(7)-corazonin]), and 42 new peptides de novo sequenced here for the first time (e.g. the pyrokinins TSFAFSPRLamide and DTGFAFSPRLamide). Of particular note are large collections of FMRFamide-like peptides (25, including nine new isoforms sequenced de novo) and A-type allatostatin peptides (25, including 10 new sequences reported here for the first time) in this study. Also of interest is the identification of two SIFamide isoforms, GYRKPPFNGSIFamide and VYRKPPFNGSIFamide, the latter peptide known previously only from members of the astacidean genus Homarus. Using transcriptome analyses, 15 additional peptides were characterized, including an isoform of bursicon beta and a neuroparsin-like peptide. Collectively, the data presented in this study not only greatly expand the number of identified C. maenas neuropeptides, but also provide a framework for future investigations of the physiological roles played by these molecules in this highly adaptable species.

Identification and cardiotropic actions of brain/gut-derived tachykinin-related peptides (TRPs) from the American lobster Homarus americanus.

Two tachykinin-related peptides (TRPs) are known in decapods, APSGFLGMRamide and TPSGFLGMRamide. The former peptide appears to be ubiquitously conserved in members of this taxon, while the latter has been suggested to be a genus (Cancer)- or infraorder (Brachyura)-specific isoform. Here, we characterized a cDNA from the American lobster Homarus americanus (infraorder Astacidea) that encodes both TRPs: six copies of APSGFLGMRamide and one of TPSGFLGMRamide. Mass spectral analyses of the H. americanus supraoesophageal ganglion (brain) and commissural ganglia confirmed the presence of both peptides in these neural tissues; both isoforms were also detected in the midgut. Physiological experiments showed that both APSGFLGMRamide and TPSGFLGMRamide are cardioactive in H. americanus, eliciting identical increases in both heart contraction frequency and amplitude. Collectively, our data represent the first genetic confirmation of TRPs in H. americanus and of TPSGFLGMRamide in any species, demonstrate that TPSGFLGMRamide is not restricted to brachyurans, and show that both this peptide and APSGFLGMRamide are brain-gut isoforms, the first peptides thus far confirmed to possess this dual tissue distribution in H. americanus. Our data also suggest a possible role for TRPs in modulating the output of the lobster heart.

SIFamide peptides in clawed lobsters and freshwater crayfish (Crustacea, Decapoda, Astacidea): a combined molecular, mass spectrometric and electrophysiological investigation.

Recently, we identified the peptide VYRKPPFNGSIFamide (Val(1)-SIFamide) in the stomatogastric nervous system (STNS) of the American lobster Homarus americanus using matrix-assisted laser desorption/ionization-Fourier transform mass spectrometry (MALDI-FTMS). Given that H. americanus is the only species thus far shown to possess this peptide, and that a second SIFamide isoform, Gly(1)-SIFamide, is broadly conserved in other decapods, including another astacidean, the crayfish Procambarus clarkii, we became interested both in confirming our identification of Val(1)-SIFamide via molecular methods and in determining the extent to which this isoform is conserved within other members of the infraorder Astacidea. Here, we present the identification and characterization of an H. americanus prepro-SIFamide cDNA that encodes the Val(1) isoform. Moreover, we demonstrate via MALDI-FTMS the presence of Val(1)-SIFamide in a second Homarus species, Homarus gammarus. In contrast, only the Gly(1) isoform was detected in the other astacideans investigated, including the lobster Nephrops norvegicus, a member of the same family as Homarus, and the crayfish Cherax quadricarinatus, P. clarkii and Pacifastacus leniusculus, which represent members of each of the extant families of freshwater astacideans. These results suggest that Val(1)-SIFamide may be a genus (Homarus)-specific isoform. Interestingly, both Val(1)- and Gly(1)-SIFamide possess an internal dibasic site, Arg(3)-Lys(4), raising the possibility of the ubiquitously conserved isoform PPFNGSIFamide. However, this octapeptide was not detected via MALDI-FTMS in any of the investigated species, and when applied to the isolated STNS of H. americanus possessed little bioactivity relative to the full-length Val(1) isoform. Thus, it appears that the dodeca-variants Val(1)- and Gly(1)-SIFamide are the sole bioactive isoforms of this peptide family in clawed lobsters and freshwater crayfish.

Identification of A-type allatostatins possessing -YXFGI/Vamide carboxy-termini from the nervous system of the copepod crustacean Calanus finmarchicus.

The copepod crustacean Calanus finmarchicus plays a critical role in the ecology of the Gulf of Maine and other regions of the North Atlantic. To increase our understanding of the physiology of this species, a normalized, whole organism cDNA library was constructed, and expressed sequence tags (ESTs) of the clones were generated. Among these ESTs was one with homology to known cDNAs encoding prepro-A-type allatostatins (A-type ASTs), a well-known family of arthropod peptides that regulate juvenile hormone production in insects. Sequence analysis of the clone from which the EST was generated, with subsequent translation of its open reading frame, showed it to encode five novel A-type ASTs, whose mature structures were predicted to be APYGFGIamide, pE/EPYGFGIamide, ALYGFGIamide, pE/EPYNFGIamide, and pQ/QPYNFGVamide. Each of the peptides is present as a single copy within the prepro-hormone with the exception of APYGFGIamide, which is present in three copies. Surprisingly, the organization of the Calanus prepro-A-type AST, specifically the number of encoded A-type peptides, is more similar to those of insects than it is to the known decapod crustacean prepro-hormones. Moreover, the Calanus A-type ASTs possess isoleucine or valine residues at their carboxy (C)-termini rather than leucine, which is present in most other family members. Wholemount immunohistochemistry suggests that six pairs of somata produce the native Calanus A-type ASTs: five in the protocerebrum and one in the suboesophageal region. To the best of our knowledge, our report is the first characterization of a neuropeptidergic system in a copepod, the first identification of A-type ASTs from a non-decapod crustacean, the first report of crustacean A-type ASTs possessing isoleucine C-terminal residues, and the first report from any species of an A-type peptide possessing a valine C-terminal residue.

Identification and cardiotropic actions of sulfakinin peptides in the American lobster Homarus americanus.

In arthropods, a group of peptides possessing a -Y((SO3H))GHM/LRFamide carboxy-terminal motif have been collectively termed the sulfakinins. Sulfakinin isoforms have been identified from numerous insect species. In contrast, members of this peptide family have thus far been isolated from just two crustaceans, the penaeid shrimp Penaeus monodon and Litopenaeus vannamei. Here, we report the identification of a cDNA encoding prepro-sulfakinin from the American lobster Homarus americanus. Two sulfakinin-like sequences were identified within the open-reading frame of the cDNA. Based on modifications predicted by peptide modeling programs, and on homology to the known isoforms of sulfakinin, particularly those from shrimp, the mature H. americanus sulfakinins were hypothesized to be pEFDEY((SO3H))GHMRFamide (Hoa-SK I) and GGGEY((SO3H))DDY((SO3H))GHLRFamide (Hoa-SK II). Hoa-SK I is identical to one of the previously identified shrimp sulfakinins, while Hoa-SK II is a novel isoform. Exogenous application of either synthetic Hoa-SK I or Hoa-SK II to the isolated lobster heart increased both the frequency and amplitude of spontaneous heart contractions. In preparations in which spontaneous contractions were irregular, both peptides increased the regularity of the heartbeat. Our study provides the first molecular characterization of a sulfakinin-encoding cDNA from a crustacean, as well as the first demonstration of bioactivity for native sulfakinins in this group of arthropods.

Identification and characterization of a cDNA encoding a crustin-like, putative antibacterial protein from the American lobster Homarus americanus.

Pathogenic challenges in decapod crustaceans are combated by innate immune responses, including the production and secretion of soluble antibacterial proteins into the hemolymph. Among the antibacterials that have been identified in decapod species are the crustins, a group of four-disulfide core/whey-acidic-protein (WAP) domain-containing proteins, which target marine/salt tolerant Gram-positive bacteria. To begin to assess the possible role of crustins in combating bacterial invasion in the American lobster Homarus americanus, we identified and sequenced a 744 base pair cDNA that encodes a novel 96 amino acid crustin-like protein. Comparison of H. americanus crustin (Hoa-crustin) with crustins from other decapod species showed that it is most similar to an isoform predicted from the European lobster Homarus gammarus ( approximately 86% identity). With our identification of the Hoa-crustin cDNA, we are positioned to begin molecular and physiological investigations of the regulation and function of this putative antibacterial protein in H. americanus.

Adaptation of the Carter method to adjust lumbar spine bone mineral content for age and body size: application to children who were born preterm.

In adults, the Carter method allows the separation of the lumbar spine bone mineral content (BMC) into its constituents; bone volume (BV) and volumetric density (bone mineral apparent density [BMAD]). However, this method is not widely used in pediatric studies and does not account for the effects of body habitus on bone mass. The aims of this study were to modify the Carter method for use in children by developing an approach that adjusts separately for age and body height, and to test whether lumbar spine bone mass is normal in children born who were born preterm. Twenty-five preterm-born children were matched to a term-born child. Lumbar spine bone mass was measured using dual-energy X-ray absorptiometry. The BV and BMAD were calculated. Z-scores based on age and height were calculated. The preterm group had reduced absolute height, weight, BMC, BV, and BMAD, and reduced height, weight, and BMC for their age. The BMC was appropriate for height. The BV was appropriate for age. The BMAD was reduced for age but appropriate for height. In preterm children, the major abnormality at the lumbar spine is a decrease in volumetric density; however, this decrease is proportional with their reduced stature, and we speculate that there is no reduction in the strength of the lumbar spine.

Gene discovery in Carcinus maenas and Homarus americanus via expressed sequence tags.

Expressed sequence tags (ESTs) were produced for normalized cDNA libraries prepared from several tissues of 2 marine crustaceans, the green shore crab Carcinus maenas and the American lobster Homarus americanus. Tissues represented in the Carcinus library were anterior and posterior gills, hypodermis, heart, hepatopancreas, antennal gland, brain, testis, and skeletal muscle, obtained from animals acclimated to 35 and 10‰ salinity. Tissues represented in the Homarus library were gill, epipodite, branchiostegite, heart, ovary, testis, antennal gland, skeletal muscle, hepatopancreas, and brain, obtained from intermolt and post-molt animals. Directional libraries from oligo-dT-primed cDNA were constructed in the pCMVsport6.1 vector and normalized by self-subtraction at 2 different Cot values. Randomly picked clones were single-pass sequenced from the 5' end. Raw sequence data were trimmed and prepared for submission to dbEST using phred, cross-match, and blastx protocols embedded within trace2dbest software. A total of 4604 Homarus and 12 401 Carcinus ESTs produced 540 and 2651 clusters, respectively, as determined by TIGR Gene Index Clustering software. Gene Ontology analysis with reference to a Drosophila melanogaster database using GOblet revealed 187 positive hits (35%) with the Homarus clusters and 1037 positive hits (39%) with the Carcinus clusters. Combining the number of assembled sequences with the number of singlets obtained after cluster analysis suggested that transcripts representing as much as 25% of the total number of genes in Carcinus have been isolated.