Present Time Research Articles

Acute Abdominal and Pelvic Complications in Patients with Non-Promyelocytic Acute Myeloid Leukaemia Undergoing Intensive Induction Chemotherapy Are Associated with Favorable Prognosis

Acute abdominal abnormalities are relatively uncommon during the treatment of acute leukaemia but, historically, have been associated with high mortality rates (Hawkins JA, Mower WR, Nelson EW. Acute abdominal conditions in patients with leukaemia. Am J Surgery 1985;150:739-742). Given the improvement in diagnostic and supportive measures for patients with acute myeloid leukaemia (AML) over time, we aimed to determine the rate and outcomes of acute abdominal and pelvic complications in a cohort of AML patients at our hospital. We retrospectively reviewed the medical records, radiology reports and laboratory test results of 70 consecutive newly diagnosed, non-promyelocytic AML patients undergoing intensive induction chemotherapy between January 2012 and December 2019. Seventeen patients developed 22 episodes of acute abdominal or pelvic pathology and were investigated by radiology (abdominal X ray, CT scan and/or MRI). Table 1 summarises the underlying causes for these complications, as well as neutrophil count and platelet count at time of presentation. Colitis was the most common complication, occurring 6 times. The neutrophil count was <1x10 9/L in 15 of the 22 episodes. Platelet count <20x10 9/L occurred in 8 of the episodes, including the 2 cases of ureteric obstruction by clot. All complications resolved completely with conservative management, except for 1 patient who required surgical drainage of an intraperitoneal and psoas muscle abscess in addition to intravenous broad spectrum antibiotics. In conclusion, acute abdominal and pelvic complications were relatively rare in our cohort of patients. All but 1 of these episodes resolved with conservative management alone. These results suggest that, with current diagnostic and therapeutic measures, the prognosis for non-promyelocytic AML patients who develop such complications is favorable.

Physician Treatment Preferences in Relapsed/Refractory Follicular Lymphoma: A Discrete Choice Experiment

Introduction: Follicular lymphoma (FL) is an indolent form of non-Hodgkin lymphoma with limited treatment options at disease progression. Novel treatments, like bispecific antibodies and chimeric antigen receptor T-cell therapy, have recently emerged, each with novel safety and management profiles. Yet, contemporary research evaluating treatment preferences among physicians treating relapsed or refractory (r/r) FL is lacking. The objective of this study was to identify key treatment attributes that influence physicians' treatment decisions when treating patients with r/r FL. Methods: We fielded a multi-country survey of physicians from the United States (US), United Kingdom (UK), Brazil, Japan, Germany and France, with up to 50 participants in each country. Data collected as of June 13, 2023 are reported with the remaining data from all countries expected by July 31st. Physicians were recruited through a healthcare research panel for an online, cross-sectional survey that included two discrete choice experiment (DCE) exercises: one for 2 nd line (2L) and one for 3 rd line (3L) therapy. The DCEs prompted physicians to choose between 2 treatment profiles that varied on 7 attributes associated with treatment for r/r FL: progression-free survival (PFS), overall survival (OS), serious adverse events (AE), cytokine release syndrome (CRS) events, neurological events, fatigue and administration/impact on functioning. Attributes and levels of interest were informed by a targeted literature review, clinical data on r/r FL treatments and clinical input. Sociodemographic and practice characteristics were summarized using descriptive statistics. We generated attribute level preference weights using hierarchical Bayesian modeling. Relative attribute importance (RI) was computed based on differences in preference weights between the most and least favorable level of each attribute. Bivariate statistics were used to evaluate differences between physicians. Interim results from the UK and US are reported with plans to include additional countries at time of presentation. Results: This analysis included 98 physicians (49 US; 49 UK) who averaged 13.7 years treating patients with FL. Most physicians specialized in medical oncology or hematology oncology (US: 100.0%; UK: 83.7%). Overall, 55.1% of physicians practiced in academic settings whereas 44.9% practiced in community settings; the proportion of academic-based physicians was higher in the UK vs the US (79.6% vs 30.6%; p<0.001). Roughly 60% of patients managed by physicians were >50 years of age. The mean number of FL patients treated over the past six months among physicians from the UK was greater than physicians from the US [65.0 vs 43.0, respectively]. Yet, the mean proportion of patients receiving 2L and 3L therapy over the past six months was roughly equal between physicians from the US and UK [2L: 27.2% vs 26.1%; 3L: 15.9% vs 15.6%]. In the context of 2L (Figure 1) and 3L (Figure 2) therapy, improved PFS was selected as most important (2L RI=20.4%; 3L RI=27.5%) whereas reducing the risk of serious AEs was least important (2L=5.6%; 3L RI=6.7%). In 2L, reducing the risk of neurological events was the second most important attribute (RI=19.1%) followed by increasing OS (RI=16.2%). Conversely, in 3L therapy, increasing OS was the second most important attribute (RI=18.9%) followed by reducing the risk of neurological events (RI=14.3%). Reducing the risk of neurological events and the risk of CRS were relatively more important to physicians in the 2L vs 3L setting. In general, physicians from the US and UK assigned similar levels of importance to each attribute evaluated, regardless of treatment line. However, the RI of fatigue was higher among physicians from the UK compared to those from the US (13.5% vs. 10.0%; p=0.047). Conclusion: Assessing physician treatment preference facilitates alignment between what matters most to patients and physicians' treatment decisions in r/r FL, particularly amidst an evolving treatment landscape. PFS was the most important attribute influencing physicians' treatment decisions for patients in 2L and 3L settings, which suggests that preserving a longer treatment-free period is important to physicians at both lines of therapy. Future treatments for r/r FL may need to demonstrate PFS benefits to influence physicians' willingness to make trade-offs between efficacy and side effects in earlier treatment lines.

CNS Involvement in Pediatric Hodgkin Lymphoma: A Comprehensive Retrospective Analysis from the Staging, Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL) Group

Introduction Hodgkin lymphoma (HL) accounts for approximately 7% of childhood cancer, most frequent in adolescents and young adults. In contrast to non-Hodgkin lymphoma (NHL), central nervous system (CNS) involvement at the time of diagnosis with HL is rare and poorly understood. Information regarding the clinical presentation, management, response to treatment and outcome of patients who exhibit this finding is limited to case reports or small series. We sought to describe CNS involvement at the time of diagnosis with pediatric HL by performing a retrospective analysis of 3 large international clinical trials. Methods Patients with CNS involvement were identified from the imaging databases of the COG trial AHOD1331 (NCT02166463) and EuroNet trials PHL-C1 (NCT00433459, EudraCT 2006-000995-33) and PHL-C2 (NCT02684708, EudraCT 2012-004053-88). Imaging was reviewed collaboratively by COG and Euronet radiologists and nuclear medicine physicians with expertise in HL, with input from radiation oncologists and pediatric oncologists. All identified cases of CNS involvement had morphologic (CT) and metabolic (FDG-PET) imaging prior to initiation of therapy, as well as disease response assessment after 2 cycles of therapy. Variables evaluated included: age, sex, Ann Arbor stage, histology, symptoms at the time of presentation (pain, neurologic symptoms), corticosteroid administration prior to FDG-PET scan, number and location of CNS lesions, tissue of origin of the CNS lesion, anatomic description of the involvement of the CNS lesion, number and location of E-lesions, whether emergency irradiation or an operative procedure were performed at diagnosis, FDG tracer uptake at the time of initial staging, response of the CNS lesions after 2 cycles of chemotherapy, whether relapse occurred and in which location. CNS involvement was defined in 2 ways: (1) lesions originating within the CNS parenchyma and (2) lesions extending into the CNS. Results 45 patients with 55 CNS lesions were identified from a combined cohort of 5569 patients with a new diagnosis of HL. 9 patients presented with pain and 4 with neurologic symptoms, however information regarding clinical symptoms was not available for 34/45 patients. Symptoms corresponded to the location of the CNS lesion. All identified lesions extended into the CNS from surrounding tissue, none originated within the CNS parenchyma. 82.2% of patients had a single lesion extending into the CNS, most commonly through the neural foramina into the thoracic spine (45.5%), sacrum (23.6%) or lumbar spine (21.8%). Lesions originated from adjacent bone (45%) or soft tissue (40%). 89% of patients with CNS lesions had stage IV HL, and 68.8% had extranodal (non-CNS) disease. 54.8% of lesions displaced the spinal cord, but none infiltrated the spinal cord itself. After 2 cycles of chemotherapy, 67.3% of CNS lesions had a >75% reduction in size or complete resolution, and 32.7% of CNS lesions decreased in volume by 50-75%. A residual mass was present for 74% of lesions involving the neural foramina after 2 cycles of chemotherapy. 89.1% of lesions were PET negative at interim response assessment (IRA). 2 CNS lesions were associated with relapse at the CNS site, these were PET negative at IRA. 13 lesions received irradiation, none of these were sites of subsequent relapse. Conclusions This large, combined cohort of intermediate- and high-risk pediatric patients enrolled on clinical trials from 2007 to 2021 confirms the rarity of CNS involvement at the time of diagnosis with HL, with an overall incidence of 0.8%. Importantly, CNS lesions extended from adjacent tissue and did not originate within the CNS itself. These lesions never directly infiltrated the brain parenchyma or spinal cord. They were highly metabolically active at diagnosis, and demonstrated an excellent metabolic and morphologic response to the first 2 cycles of chemotherapy. Patients with CNS involvement had a 2-fold greater incidence of extranodal disease than previously reported cohorts. In summary, this retrospective study provides key information about CNS involvement in pediatric HL at the time of diagnosis, contributing to our understanding of this rare, yet important, clinical presentation.

Identification of a Novel AML Patient Subset Sensitive to Venetoclax Using Matched Proteomics and Diverse Ex Vivo Models

AML is one of the most common and deadly hematopoietic malignancies. The molecular and biological heterogeneity of AML poses significant challenges to the identification of novel agents to treat it and the optimal triage of patients for the most effective therapeutic regimens. Ex vivo models for drug sensitivity using cell lines and/or primary AML samples have been a fruitful resource for the exploration and discovery of novel compounds in the treatment of AML, and investigators have coupled genomic and transcriptomic profiling with ex vivo models in the hope to further enhance the reliability and accuracy of results. However, primary AML blasts are molecularly complex and fastidious, relying on extracellular matrix (ECM) and signals for optimal survival, making their use for large, high-throughput drug screens impractical. Available AML cell lines are more robust and less dependent upon the ECM but often harbor strong driver alterations (e.g., KMT2A rearrangements, TP53 mutations) that occur in only a small subpopulation of AML cases. Thus, current AML cell lines may not accurately predict agent sensitivity for most patients. Here, we report the results of a novel approach coupling cutting-edge proteomics with ex vivo drug sensitivity models to develop and describe a more diverse and representative set of patient-derived cell models for drug discovery and therapeutic positioning. Initial studies focused on proteomic biomarker signatures and cell lines to predict drug sensitivity for Venetoclax, which has become a stable component for treatment of older and unfit patients with AML. To identify a proteomic biosignature associated with Venetoclax sensitivity, we examined the Beat AML dataset of 210 patient proteomics coupled to ex vivo sensitivity assays. Beat AML patients clustered by unbiased proteomics which resulted in a cluster with a patient population significantly enriched in sensitivity to Venetoclax. A partial least squares discriminant analysis (PLSDA) was used to discover proteins driving the differentiation of Venetoclax sensitive and insensitive clusters. The resulting significant proteins describe a mechanism of altered DNA double stranded break repair and Interleukin-8 (IL-8)-CXCR2 signaling separating patients. These mechanisms were partially comprised of high-quality targets with differential analysis results shown in Fig. 1A. The identities of the targets will be revealed at the time of presentation as they are currently moving forward in preclinical studies. To examine the potential predictive power of the Venetoclax sensitivity biosignature a set of novel ex vivo cell models were derived from a diverse independent population of patients obtained from FHCC/UW Myeloid Disease Repository. This population was not enriched for KMT2A or TP53 mutations. The proteomes of 90 diagnostic AML samples were examined and measured via a tandem mass tag protocol coupled with liquid chromatography with tandem mass spectrometry (TMT-LC-MS/MS). In addition, a proprietary set of novel ex vivo AML cell lines (n=17) representing the diverse genomic phenotype were generated from this same cohort of patients using proprietary media and pyrimidoindole derivative agonists of hematopoietic stem cell self-renewal. As with the primary samples, TMT-LC-MS/MS was utilized to quantify the proteome within the proprietary AML cell lines and 16 commercially available lines. Viability assays with Venetoclax were performed for all ex vivo cell models. Ex vivo cell models were then grouped based on the Venetoclax biosignature. The correlation between the proteomic biosignature for Venetoclax the measured sensitivity to Venetoclax was then examined for the ex vivo cell models (Fig. 1B). The results showed a strong correlation between the biosignature and actual ex vivo sensitivity to Venetoclax in proprietary cell models, but not in the 16 currently available cell models. Genetic drift of cell models from the primary AML patients was examined using differential proteomic analysis and no significant drift was found. The results indicated that the primary AML specimens harbored the Venetoclax sensitivity signature. Our findings reveal that the integration of unbiased patient proteomics with optimized ex vivo cell cultures can be used to identify sensitive patient subsets and exclude non-responders for novel therapeutics, as well as expanding patient access for currently approved therapies.

The perception of non-economics and business major students towards the compulsory entrepreneurship course: Have the learning outcomes of the course been achieved?

Entrepreneurship contributes to economic growth, making it an important factor in advancing society and the economy in the present time. The significance of innovation and entrepreneurship in the current era necessitates that the younger generation understands the subject. This understanding can be achieved through entrepreneurship courses offered in higher education. Based on this, several universities have implemented policies that make entrepreneurship courses mandatory for all students. This research aims to explore in-depth the perception of students, specifically those not majoring in economics, management, business, or social sciences, regarding the entrepreneurship course and the university policy regarding the requirement to take it. The study adopts a qualitative approach using focus group discussion (FGD). The researcher, along with five students from the same university, discusses the learning outcomes of the Innovation and Entrepreneurship course and the university policy regarding the mandatory nature of the course. The FGD generates several points related to the learning outcomes of the course. These include students' ability to comprehend the concepts and principles of entrepreneurship, their ability to generate ideas for business creation, their capacity to develop innovative business plans, and the appropriateness of making the Innovation and Entrepreneurship course mandatory as it benefits all students, including those not majoring in economics, management, business, or social sciences.

A Novel, Probe-Based and Instrument-Free Method for Improved Ultrahigh-Throughput Single-Cell Gene Expression Analysis of Peripheral Blood Mononuclear Cells

Single-cell gene expression assays are critical tools for identifying functional subtypes of immune cells, as well as changes within cells resulting from pathology or treatment. However, most current methods are expensive, low in sample throughput, rely on reverse transcription and lack the sensitivity to consistently measure low expressed genes from single cells - preventing measurements of many key immune biomarkers and molecular pathways. Another problem with existing single-cell sequencing methods is that many of the cell-associated reads either fail to map to transcripts or map to uninformative ribosomal and mitochondrial genes. Some methods also require the use of live cells, which means the single-cell assay has to be carried out at the specific time of treatment or when culture is terminated. The aforementioned limitations have contributed to most single-cell sequencing studies being restricted to small numbers of samples and have prevented their wider scale adoption in biopharma, clinical, translational and applied applications. Here we report on the development and performance of a novel combinatorial split-pool-based workflow, TempO-LINC™, that adds cell-identifying molecular barcodes onto high-sensitivity gene expression probes within fixed cells. Cells can be fixed at the end of a treatment, or when obtained from a patient and stably stored for months until they are ready to be processed with other samples through the TempO-LINC assay. All probes within the same fixed cell receive an identical barcode, enabling the reconstruction of single-cell gene expression profiles across as few as several hundred cells and up to 100,000 cells per run. TempO-LINC simultaneously processes up to 96 fixed cell samples per run, has a simple workflow that is amenable to automation and as we will show, has a higher gene detection rate than existing single-cell platforms. We will also show that TempO-LINC has an observed doublet rate of less than 0.5% for 12,500 cells analyzed. Critically, TempO-LINC reduces sample sequencing costs and although we show the assay accurately profiles the whole transcriptome (23,000 transcripts), it can also be targeted to measure only genes/pathways of interest - dramatically reducing sequencing costs yet further. We applied TempO-LINC to assay PBMCs and a human hepatocyte model for toxicology and demonstrated the ability to correctly identify unique cell states and molecular pathways from these populations. We will also present time course and dose response data from compound treatment of cells. All of these features position TempO-LINC as a potential disruptive technology that hematology researchers, clinicians and drug developers can use for new large-scale applications/studies using single-cell sequencing across thousands of samples while obtaining improved data quality.

Fluorescence polarization immunoassay for the determination and screening of medicines.

Modern clinical medicine with its achievements has helped a person to get rid of many infectious and non-communicable diseases, restore health, preserve and improve the quality of life of people with chronic dis- eases. Tens of thousands of medicines are used in medical practice. However, paradoxical as it sounds, having created medicines for almost all diseases, humanity has not become healthier and the need for medicines is only growing every year. More than 20 % of people receiving medications during therapy have various complications. Therefore, the search for medicines does not stop, but only increases at the present time. Another important problem is the detecting drugs in environmental objects and food products. Most drugs that get into wastewater from pharmaceutical factories and farms, even after treatment at wastewater treatment plants, are still diagnosed in the water. The method of fluorescence polarization is extremely widespread in clinical and biomedical fields. Thanks to the introduction into laboratory diagnostics of devices capable of measuring the signal of fluorescence polarization on microplates, polarization fluorescent analysis is used not only in the traditional format: the detection of drugs in human physiological fluids, environmental objects and food, but also in high-tech screening of drugs, significantly speeding up and facilitating the process of identifying new drugs.

A Case Report of a Patient with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan Who Underwent Major Surgery

Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterized by intravascular hemolysis, thrombosis and bone marrow failure. The appearance of the anti-C5 monoclonal antibody eculizumab revolutionized the treatment of PNH, controlling hemolysis and the incidence of thrombosis. However, some patients persist with anemia, due in part to extravascular C3-mediated hemolysis. More recently, the anti-C3 monoclonal antibody pegcetacoplan, which blocks the most proximal part of the complement cascade, has been marketed in Europe, achieving improvements in anemia in these patients. However, intercurrent infectious episodes or surgical interventions can trigger a hemolytic flare, so dose adjustments are necessary to prevent their occurrence. There is hardly any published information or established consensus on how to treat these patients. We present this case as an example of a successful treatment of a patient diagnosed with PNH under treatment with pegcetacoplan who has undergone major surgery. A 67 year-old man was diagnosed with aplastic anemia in 1997 and treated with immunosuppression (cyclosporine and oxytosone). In 2000, he presented his first intravascular hemolytic crisis with HPN clone detection. He presented several intravascular hemolytic crises for which he was treated with erythropoiesis-stimulating agents, corticosteroids and transfusions. In 2010, due to deterioration of renal function because of acute hemolysis episode, he started treatment with eculizumab. A reduction in the number of hemolytic crises was observed. However, he required an increase in the dose and frequency of administration of eculizumab due to pharmacokinetic breakthrough hemolysis. After one month of treatment, a positive direct coombs test appeared and presented anemia due to extravascular hemolysis, for which he again required treatment with corticosteroids on specific occasions. For this reason, in December 2022, he started treatment with pegcetacoplan at the usual dose of 1080 mg twice a week subcutaneously (sc). Prior to the start of pegcetacoplan, the patient had hemoglobin levels of 10.3 g/dL, hyperbilirubinemia of 3.2 mg/dL (indirect 2.6 mg/dL), consumed haptoglobin, elevated lactate dehydrogenase (LDH) of 281 U/L and reticulocytosis of 5-6%. Subsequently, since the beginning of pegcetacoplan, he presented clinical improvement, stable hemoglobin (12-13 g/dL) and normalization of reticulocytes, LDH and bilirubin levels. The haptoglobin has remained low until the present time. In June 2023, the patient underwent major surgery consisting of radical prostatectomy due to a benign prostatic hypertrophy. Suspecting that it might provoke a hemolytic crisis due to surgical stress, the dose of pegcetacoplan was increased as recommended by clinical experts to a dose of 1080 mg every 72 hours sc from one week prior to surgery until one week after. The procedure was carried out without incident and without an increase in hemolysis parameters. This is the first case report of a patient with PNH treated with pegcetacoplan undergoing major surgery in Spain. In this patient, the perioperative dose increase was successful in preventing the development of a hemolytic crisis.

Evaluating Multidisciplinary Bone Marrow Failure Care (EMBRACE) - a Hybrid Implementation-Effectiveness Study

The bone marrow failure syndromes (BMFS) are clinically diverse, with both inherited and acquired etiologies. Patients with BMFS may present unique, complex management issues and frequently experience poor outcomes due to multiple factors, including the rarity of the individual conditions. The Evaluating Multidisciplinary Bone maRrow fAilure CarE (EMBRACE) study is a multi-stage hybrid implementation-effectiveness study that aims to address these challenges by understanding the nature and scale of issues faced by these patients and their physicians, and then developing, implementing, and evaluating a comprehensive 10-component model of care (MoC10). Herein we report the results of the first stage of the EMBRACE study of issue identification and MoC10 development. To identify barriers to optimal care, we performed structured interviews with patients with BMFS and patient advocate groups, followed by a nation-wide physician survey. Thematic analysis of interviews (n = 9) revealed multiple challenges with patient care, including (i) a lack of access to genomic testing to provide a definitive diagnosis, (ii) widespread difficulty in accessing genetic counselling and fertility advice, (iii) a lack of disease-specific patient information at the time of diagnosis, and (iv) perceived failings in care when transitioning from pediatric to adult services. Patients also described anxiety resulting from frequent encounters with health professionals unfamiliar with their disease, leading to significant anxiety and demonstrating a clear need for education both at the time of initial presentation, in considering whether an underlying inherited condition could be present and also following diagnosis, permitting relevant disease specific surveillance and care. As part of this patient-facing analysis, there was a desire on behalf of patients and patient advocates for the opportunity to participate in research and clinical trials. A nation-wide physician survey was then performed targeting clinicians that treat patients with BMFS which received 74 responses across hematologists, oncologists, pediatricians and geneticists who cared for 267 patients with BMFS. The median number of patients cared for per physician was 2 (range 0 - 25), demonstrating a wide range of subspecialty experience and non-centralized care. Responses indicated a desire for affordable access to genomic testing, assistance with result interpretation and genetic counselling/cascade testing of extended kindred, a forum for complex case discussion and advice regarding patient management strategies. Responses from patients, patient advocates and physicians, along with existing evidence-based and best-practice guidelines, were then used to develop a MoC. The MoC10 (Figure 1) incorporates 10 pillars directed at optimising care for patients with BMFS including funded access to genomic testing, access to expert genetic and fertility counselling, standardized hematological and solid organ cancer surveillance, and opportunity for multidisciplinary case discussion including expert opinion regarding allogeneic stem cell transplant. In addition, uncertain and novel germline variants are presented alongside de-identified case presentations at a national forum attended by physicians, scientists, and researchers to promote education, collaboration and information sharing with treating teams. After institutional approval, the MoC10 has been implemented and is undergoing structured evaluation to determine patient and physician acceptability and adherence. Embracing the well-known ‘Plan, Do, Study, Act’ cycle, our implementation approach facilitates iterative learning for continuous improvement. In summary, after extensive stakeholder engagement, we have developed an evidence based comprehensive MoC addressing the current challenges facing patients with BMFS and their care teams. This comprehensive care program continues to undergo evaluation and audit consistent with the principles of an implementation-effectiveness study to determine both patient and physician satisfaction with the model, and iterative refinement in order to provide optimum care.

Prephase Cyclophosphamide: An Advantageous Bridge to Definitive Therapy

Background Classic Hodgkin lymphoma (cHL) and aggressive non-Hodgkin lymphoma (NHL) account for an estimated 0.5% and 4.1% of all new cancer diagnosis in the US in 2023, respectively. At time of diagnosis, approximately 43% of cHL and 53% of NHL are staged as advanced disease (stage III-IV). While these diseases are considered curable, standard treatments involve intensive combination chemotherapy that may preclude certain patients from receiving optimal therapy. One option to minimize risks is to use prephase cyclophosphamide (pCy) as an initial treatment in aggressive lymphomas. There is however limited data on the utility, adverse effects, and outcomes of this approach. Here we present data on our institutional experience of employing pCy for patients ineligible for intensive chemotherapy. Methods We performed a single institution, retrospective chart review of patients with history of cHL and NHL that received cyclophosphamide (Cy) as an initial chemotherapy during hospitalization. Lymphoma subtype, medical history, baseline bloodwork at time of treatment initiation, outcomes including transplant, relapse data and overall survival were collected. Fifty patients received pCy at 200 mg/m2 with the remaining four receiving 100 mg/m2, 150 mg/m2, or 300 mg/m2 based on provider preference. Corticosteroids, including prednisone, dexamethasone or methylprednisolone, were administered simultaneously with varying duration and dosage. We analyzed hepatic and kidney injury at the time of diagnosis, after initiation of pCy and time to recovery. Acute kidney injury (AKI) was defined as an increase in creatine more than 30% from baseline and hepatic injury was defined based on Common Terminology Criteria for Adverse Events (CTCEA) version 5. Charlson scores for all patients were collected. Results Fifty-four patients received pCy as a bridge to possible definitive therapy. The most common diagnosis was diffuse large B-cell lymphoma (DLBCL) and cHL, with 29 (53.7%) and seven (13%) patients, respectively (Figure 1). The median age was 56 years (18-84) with 21 (39%) patients >65 years. Advanced stage was observed in 49 (90.7%) patients. Four patients required treatment for tumor lysis syndrome (TLS) prior to initiation of pCy. Nineteen (35%) patients had AKI and 15 (28%) patients had hepatic injury at the time of initial presentation. Five patients experienced AKI from pCy with an average time to recovery of 11.2 days. Six patients, with only two having concurrent AKI, had hepatic injury from pCy with an average time to recovery of 8.5 days. PCy allowed 42 (78%) patients to undergo definitive treatment in respect to their lymphoma subtype. Eight (14.8%) patients went on to receive a consolidative autologous transplantation (HSCT) after reaching a remission from definitive therapy. At the time of our analysis, 30 (55%) patients are deceased which includes four patients that underwent HSCT. Of the 30 deceased, 10 patients were transitioned to comfort care during the admission after receiving pCy. Median overall survival is 370.5 days. Conclusion Based on our institutional experience, pCy is a reliable method to salvage patients with aggressive lymphomas that are not candidates for intensive chemotherapy. In our analysis, pCy allowed 78% of patients to receive definitive therapy for their respective lymphoma. In general, patients receiving pCy required hospitalization related to disease burden and pCy represents an effective and cost-efficient bridging strategy to outpatient treatment. Cyclophosphamide has a broad indication across hematologic malignancies and is a well-tolerated chemotherapy with a limited side effect profile. The modest dosing in combination with corticosteroids allows initial disease control and provides the ability to start definitive therapy in a timely manner. Additionally, we feel that pCy should be considered when designing clinical trials in an effort to promote enrollment of the “real-world” patient.

High Titer ANA at Pediatric ITP Presentation Associated with Progression to Systemic Lupus Erythematosus

Introduction: Immune thrombocytopenia (ITP) is a feature of systemic lupus erythematosus (SLE) in 5-20% of cases. ITP may present at the time of SLE presentation or may precede SLE diagnosis by up to nearly a decade. Even in the absence of an SLE diagnosis, ITP patients may have a positive ANA in ~20% of cases. Some studies suggest that a positive ANA in ITP may herald chronic and more refractory disease, while other studies have not demonstrated a link between ANA+ ITP and progression to SLE. The natural history of ANA+ pediatric ITP patients remains unclear. With the concept that hydroxychloroquine may modulate progression to systemic autoimmunity, European hematologists report using hydroxychloroquine in ANA+ pediatric ITP patients with titers as low as 1:160. However, whether ANA+ ITP patients represent a distinct cohort clinically and should receive different therapies is not well established. The goals of this study were to evaluate the significance and degree of a positive ANA titer at presentation in a cohort of pediatric ITP patients. Methods: Data from a retrospective cohort of 711 ITP patients treated at Texas Children's Hospital from 2012-2022 were reviewed. Patients were defined as SLE if diagnosed as such by rheumatology. To focus on the prognostic value of an ANA upfront, the cohort was refined to include only ITP patients with ANA testing within the newly diagnosed period (0-3 months). Individuals who received IVIG prior to ANA testing were coded as having a missing ANA result given the possibility of false positive results. Being diagnosed concurrently with SLE and ITP was defined as diagnoses within 1 month of each other. Fisher's exact tests were used to compare nonparametric data with a P <0.05 defined as statistically significant. P values were corrected for multiple testing. Results: One hundred sixty-one ITP patients were included for analysis. The cohort was an average of 11.9 years-of-age with a slight female predominance (58.4%). Most of the population self-identified as White and non-Hispanic (84.7%, 45.5%). Nearly 80% had primary ITP and 66.7% were ultimately diagnosed with chronic ITP (cITP). The mean follow-up time for the cohort was 2.2 years (with a range from 0 to 12 years). Forty-seven of 161 (29.2%) individuals had a high titer ANA ³1:1280 at ITP presentation. (Figure 1) There was a statistically significant difference in ANA titer and presence of secondary ITP (P<0.001). Sixty-eight percent (n=23) of secondary ITP patients had a high titer (≥1:1280) ANA versus 20% (n=24) of the primary ITP patients. There was no difference between ANA titer and development of cITP vs. non-cITP. Of this cohort, 20 patients had an ANA tested at ITP presentation and were diagnosed with SLE by rheumatology. Most of these patients had an ANA titer ≥1:1280 (84.2%). The remaining 3 patients had titers of 1:320. Of this cohort, 9 patients had SLE and ITP diagnosed concurrently and 2 had SLE preceding ITP diagnosis by an average of 3.8 years. All 11 patients had an ANA ≥1:1280. Of the 9 who were not diagnosed with SLE at ITP presentation, 6 (66.6%) had an ANA ≥1:1280 and 3 had a titer of 1:320. The lead time to being diagnosed with SLE after presenting with ITP was 1.76 years. Discussion and Conclusions: In this cohort, high titer ANAs in newly diagnosed ITP patients were linked to development of secondary ITP and SLE. Lower titer ANAs were less common, even in those who went on to develop SLE. These findings suggest that specifically high titer ANA results may herald SLE development in pediatric ITP patients. To allow the onset of SLE to be identified earlier, individuals with a high titer ANA at ITP presentation may warrant closer follow-up to monitor for progression to systemic autoimmune disease. This subset of ITP patients could benefit from earlier institution of SLE-directed therapy, such as hydroxychloroquine. Further analysis is underway, including expansion of this analysis to multiple sites within the Pediatric ITP Consortium of North America, as well as surveying pediatric ITP treaters on their practice regarding ANA testing and management in ITP patients.

Clinicopathologic Features of CD23-Positive Nodal Marginal Zone Lymphomas

Abstract Objectives: To identify and describe the clinicopathologic features characterizing a set of patients with nodal marginal zone lymphoma (N-MZL) positive for expression of CD23 and to contrast findings against those of a cohort of patients with CD23-negative N-MZL. Methods: Cases of N-MZL diagnosed over a 20-year interval were identified from the medical record and allocated to two cohorts based on immunophenotypic expression of CD23. Clinical, morphologic, immunophenotypic and cytogenetic data were retrospectively reviewed. Results: Twenty-six cases with histological and immunophenotypic findings typical of N-MZL were identified, 12 of which expressed CD23 by flow cytometry or immunohistochemistry. In the CD23-positive N-MZL cohort, only 2/12 (17%) of patients demonstrated multicompartment lymphadenopathy and another 3/12 (25%) demonstrated bone marrow involvement, with an Ann Arbor disease stage IV. In the CD23-negative cohort, 8/14 (57%) patients presented with multicompartment lymphadenopathy and an additional 6/14 (43%) demonstrated bone marrow involvement, with an Ann Arbor disease stage IV. The average follow-up period for all patients (CD23-positive and CD23-negative cohorts) was 6.7 years (range: 1-17; IQR: 10). In the CD23-positive disease cohort, treatment and follow-up data were recorded for 10/12 (83%) patients. Three patients were followed without intervention, one of which transformed to an aggressive lymphoma. This patient was treated with a series of rituximab-based chemotherapies and remains well two years post stem cell transplant. One patient was surgically managed with adjuvant radiation and remains well with no evidence of disease. Six others were treated with various rituximab-based chemotherapy regimens. Two died secondary to sequalae related to progression of their disease. The others remain alive and well with no evidence of active disease. In the CD23-negative disease cohort, treatment and follow-up data were recorded for 13/14 (93%) patients. For seven patients in this cohort followed by observation only, five were alive and well at last follow-up. Two were deceased due to unrelated causes. For those otherwise treated, there was only a single fatality due to progression of disease. Comparing the two cohorts, those with CD23-positive disease were significantly more likely to present with a lower Ann Arbor stage (p=0.0155) and FLIPI score (p=0.0086). However, neither 5-year (p=0.6908) nor overall survival (p=0.5956) were significantly different between the two cohort medians. Conclusions: CD23 expression in our cohort of N-MZL patients correlated with greater likelihood of single versus multiple compartment lymphadenopathy, restriction of lymphadenopathy to the head and neck regions, lower Ann Arbor stage, and lower FLIPI score. The data here, while derived from a limited cohort, demonstrates that CD23 correlates with a lower-grade clinical assessment at time of disease presentation but is associated with a more rapid clinical decline given a lack of evidence for survival benefits in the long term.

Evaluation of Efficacy and Safety of Nivolumab in Treatment of Relapsed/Refractory Classical Hodgkin Lymphoma at King Abdulaziz Medical City-Jeddah/the Kingdom of Saudi Arabia Experience

Introduction: Hodgkin's lymphoma (HL) is one of the most common lymphoid cancers. Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. Nivolumab, an immune checkpoint inhibitor, which has shown great efficacy in relapsed/refractory cHL (R/R cHL) in multiple clinical trials. The aim of this study is to evaluate the efficacy and safety of Nivolumab in R/R cHL patients treated at King Abdulaziz Medical City in Jeddah-Kingdome of Saudi Arabia Methods: We conducted a retrospective analysis on all patients received nivolumab for R/R cHL at King Abdulaziz Medical City, Jeddah, Saudi Arabia. From introduction of nivolumab in our center till the present time, it was used in a total of 21 patients, all of them were included in our analysis. Data of these patients were entered into an Excel sheet, and analyzed using SPSS software version 25.0. Statistical significance was determined as (P<0.05). Results: Total of 21 patient were included in this analysis. The average age of the participants was 26 years, almost equal gender distribution, 63% were advanced stage, 72% were nodular sclerosis subtype. Patients had received a median of 5 prior regimens (range 4-7). 12 patients received Nivolumab as post-ASCT salvage and 9 patients did not undergo ASCT prior Nivolumab treatment. The number of treatment cycles with Nivolumab ranged between 3 and 121, with an average of 31 cycles. Overall response rate (ORR) was 84.2% includes 52.6% of patients has achieved complete response (CR). In the patients who received the Nivolumab as post-ASCT salvage, 40% had CR, 20% had PR, 10% had stable disease and 30% had disease progression. ORR was 60% and 40% of those patients had disease progression later. 28.6% of the patients studied were still on Nivolumab, and the main reason for stopping the Nivolumab was the disease progression. Nine patients still required treatment after Nivolumab. Our study showed that neutropenia and hypothyroidism were the most common adverse effects of Nivolumab therapy, 33.3%, and 19.0%, respectively, whereas fatigue, tachycardia, fever, itching, pneumonitis and cough were less common, 4.8% for each. Conclusion: Nivolumab is a safe drug and could be given to patients with HL. However, neutropenia and hypothyroidism were the most common adverse effects; therefore, routine complete blood count and thyroid function tests should be obtained. Regarding the efficacy of Nivolumab, our results revealed relatively low survival and response rates.

Phaeoviruses Present in Cultured and Natural Kelp Species, Saccharina latissima and Laminaria hyperborea (Phaeophyceae, Laminariales), in Norway.

Phaeoviruses (Phycodnaviridae) are large icosahedral viruses in the phylum Nucleocytoviricota with dsDNA genomes ranging from 160 to 560 kb, infecting multicellular brown algae (Phaeophyceae). The phaeoviral host range is broader than expected, not only infecting algae from the Ectocarpales but also from the Laminariales order. However, despite phaeoviral infections being reported globally, Norwegian kelp species have not been screened. A molecular analysis of cultured and wild samples of two economically important kelp species in Norway (Saccharina latissima and Laminaria hyperborea) revealed that phaeoviruses are recurrently present along the Norwegian coast. We found the viral prevalence in S. latissima to be significantly higher at the present time compared to four years ago. We also observed regional differences within older samples, in which infections were significantly lower in northern areas than in the south or the fjords. Moreover, up to three different viral sequences were found in the same algal individual, one of which does not belong to the Phaeovirus genus and has never been reported before. This master variant therefore represents a putative new member of an unclassified phycodnavirus genus.

Void probability function inside cosmic voids: evidence for hierarchical scaling of high-order correlations in real space

ABSTRACT We compare the reduced void probability function (VPF) inside and outside of cosmic voids in the TNG300-1 simulation, both in real and simulated redshift space. The VPF is a special case of the Counts-in-Cells approach for extracting information of high-order clustering that is crucial for a full understanding of the distribution of galaxies. Previous studies have validated the hierarchical scaling paradigm of galaxy clustering moments, in good agreement with the ‘negative binomial’ model, in redshift surveys but have also reported that this paradigm is not valid in real space. However, in this work, we find that hierarchical scaling can indeed be found in real space inside cosmic voids. This is well fitted by the negative binomial model. We find this result to be robust against changes in void identification, galaxy mass, random dilutions, and redshift. We also obtain that the VPF in real space at high redshift approaches the negative binomial model, and, therefore, it is similar to the VPF inside voids at the present time. This study points, for the first time, towards evidence of hierarchical scaling of high-order clustering of galaxies in real space inside voids, preserving the pristine structure formation processes of the Universe.

Stress corrosion and interaction behaviour of adjacent cracks in rock-like material under hydro-mechanical Coupling: An experimental and numerical study

Under long-term hydro-mechanical coupling, the propagation of adjacent cracks present obvious time effect, and have significant influence on the progressive failure mode of rock-like materials. The creep tests were carried out based on the cement mortar specimen containing adjacent cracks, and the low-field Nuclear Magnetic Resonance (NMR) technology were used to evaluate the evolution of crack structure in the specimen. Based on the numerical simulation, the influences of the interaction behaviour between cracks on the time-dependent propagation of cracks and failure of specimens is revealed. The results show that: The specimen presents a tension-shear failure mode, and the macro fracture on its surface is Z-shaped; Crack interaction has an important role in promoting the formation and connection of microcracks, which increases the number of seepage channels and promotes the formation of the macro fracture; The propagation of adjacent cracks show significant asymmetry and non-uniformity, due to the stress superposition effects in the rock bridge area; The interaction between cracks is manifested as the inhibition of wing crack propagation in the rock bridge area at the initiation stage and then promotion effect at the later stage.

PAUL LEUCKFELD (1859–1930) AND THE INDUCTIVE PHILOSOPHY OF WILLIAM WHEWELL (1794–1866)

This article presents a little-studied issue of critical analysis of the main provisions of the inductive philosophy of the English thinker William Whewell (1794–1866) within the framework of university philosophy, in particular in the publications of the famous Kharkiv professor Pavlo Emilievych Leuckfeld (1859–1930). In this context, the main stages of Pavlo (Paul) Leuckfeld's creative and scientific path are indicated at the beginning, in particular his studies at the 2nd Kharkiv Gymnasium (1871–1878) and at the Faculty of History and Philology of Kharkiv University (1878–1883). Further, attention is focused on his teaching activities at Kharkiv University (1884–1918), in particular on his fellowship since 1884, teaching the history of philosophy and logic as a private docent (since 1886), extraordinary professor (since 1893) and ordinary professor of philosophy (since 1899). His participation in international philosophical and psychological congresses, in particular in Munich (1896), Geneva (1904), Heidelberg (1908), and the peculiarities of his scientific fellowship at the University of Graz (Austria) with the authoritative professor Alexius Meinong are also indicated. In addition, attention is paid to the main features of Pavlo Leuckfeld's teaching and publications during his “Simferopol (Crimean) period”, when he was a professor of philosophy and psychology there. Pavlo Leuckfeld's publications were devoted to three main areas: 1) logic and the history of logic, 2) psychology and pedagogy, and 3) the history of philosophy. Among the publications of the first direction, two of his monographs were of great importance: “Various Trends in Logic and the Main Tasks of this Science” (1890) and “Logical Doctrine of Induction in the Main Historical Moments of Its Development” (1896). In these works, he analyzed the relevant positions of famous ancient and English philosophers (Aristotle, Francis Bacon, John Herschel, and John Stuart Mill). An important place in his analysis is occupied by the critical interpretation of the inductive philosophy of William Whewell, presented in particular in the third edition of the three-volume work “History of the Inductive Sciences, from the Earliest to the Present Time” (1857). In this sense, the features of this work of the English philosopher were first pointed out, and then the main theses of Paul Leuckfeld in presenting his understanding of the position of William Whewell.

Disease Response Assessment Modalities in Chronic Myeloid Leukemia: Past, Present, and Future

AbstractChronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the BCR::ABL1 fusion gene, which results from a reciprocal translocation between chromosome 9 and 22 t(9;22)(q34;q11). The use of tyrosine kinase inhibitor (TKI) against the chimeric BCR::ABL1 fusion protein has led to a paradigm shift in CML patient outcomes. Despite generational advancements in TKI, a fraction of patients harbor residual disease or exhibit resistance to TKI. The importance of disease monitoring and detection of resistance mechanisms has gained prominence with increasing knowledge about disease evolution. In the past, cytogenetic techniques such as karyotyping and fluorescence in situ hybridization were widely utilized for monitoring disease and prognostication. These techniques had various challenges related to limited sensitivity in minimal residual disease (MRD) monitoring; however, their importance still holds in the detection of additional chromosomal aberrations and in cases with cryptic insertions, variants, and masked Philadelphia chromosome. Molecular genetics has evolved significantly from the past to the present times for MRD monitoring in CML patients. Qualitative reverse transcription polymerase chain reaction (RQ-PCR) can be performed at diagnosis to detect the BCR::ABL1 transcript, while quantitative RQ-PCR is the most widely used and well-standardized MRD monitoring method. The DNA-based assays demonstrated high sensitivity and specificity, with many efforts directed toward making the laborious step of BCR::ABL1 breakpoint characterization less tedious to increase the utility of DNA-based MRD approach in the future. Flow cytometric–based approaches for the detection of the BCR::ABL1 fusion protein have been under trial with a scope of becoming a more robust and convenient methodology for monitoring in the future. Upcoming techniques such as digital PCR and ultra-deep sequencing next-generation sequencing (UDS-NGS) have shown promising results in residual disease monitoring and detection of resistance mutations. Novel MRD monitoring systems that are independent of BCR::ABL1 fusion such as the detection of CD26+ leukemic stem cells and microRNA mutations are the future of residual disease monitoring, which can go up to the level of a single cell. In this review, we tried to discuss the evolution of most of the above-mentioned techniques encompassing the pros, cons, utility, and challenges for MRD monitoring and detection of TKI resistance mutations.

Frequency and Outcome of Pregnant Females Presenting With Thrombocytopenia at a Tertiary Care Hospital.

Platelet-related problems are more frequently discovered in women during pregnancy because screening is carried out as part of the initial clinic examination using automated blood counts. This study was done to find out the frequency and outcomes of pregnant females presenting with thrombocytopenia at a tertiary care hospital. This cross-sectional study was conducted at the Department of Obstetrics and Gynecology, Jinnah Hospital, Lahore, Pakistan, from April 2023 to September 2023. This study involved 280 pregnant women presenting in the third trimester. Blood examination was acquired, and a platelet count less than 150x109/L was labeled as thrombocytopenia. Outcome variables were frequency of thrombocytopenia, while post-delivery, frequency of placental abruption, preterm delivery, stillbirth, need for blood transfusion, and poor Apgar score were noted and compared among women with and without thrombocytopenia. In a total of 280 pregnant females, the mean age and gestational age at the time of presentation were 29.34±4.38 years and 31.30±2.87 weeks, respectively. The mean BMI of the females was 27.97±4.72 kg/m2. Thrombocytopenia was noted in 34 females (12.1%). Placental abruption, preterm delivery, need for blood transfusion, stillbirth, and poor Apgar score were observed in 1.4%, 4.3%, 8.2%, 1.1%, and 2.1% cases, respectively. Placental abruption (11.8% vs. 0.0%; p<0.001), preterm delivery (29.4% vs. 0.8%; p<0.001), need of blood transfusion (35.3% vs. 4.5%; p<0.001), stillbirth (8.8% vs. 0.0%; p<0.001), and poor Apgar score (17.6% vs. 0.0%; p<0.001) were all significantly higher among pregnant women with thrombocytopenia as compared to those with a normal platelet count. The frequency of thrombocytopenia was 12.1% among pregnant females. The frequency of placental abruption, preterm delivery, need for blood transfusion, stillbirth, and poor Apgar score were all significantly higher among pregnant women with thrombocytopenia as compared to those with a normal plateletcount, irrespective of the patient's age, parity, and BMI.

Oligo-Metastatic Disease in Oncology: Exploring the Limits and the Potential of Genetic Assessment.

Oligo-metastatic disease (OMD) in the field of oncology denotes a distinct subset of metastatic tumors characterized by less aggressive biological behavior and extended survival times in comparison to their widely metastatic counterparts. While there is a general consensus regarding the existence of OMD, there remains a lack of widely accepted criteria for its a priori identification at the time of presentation. This review delves into the concept of OMD, placing a particular emphasis on the significance of understanding the limitations and potential of genetic assessments. It explores how these aspects are crucial in advancing our comprehension of this phenomenon. In a rapidly advancing era of precision medicine, understanding the intricacies of OMD opens up exciting possibilities for tailored treatment approaches. By elucidating the genetic underpinnings and dynamic nature of this condition, we stand to improve patient outcomes and potentially shift the paradigm of metastatic cancer management.