6-Mercaptopurine-associated Sinusoidal Obstructive Syndrome During Interim Maintenance I: A Case Report.

Thiopurine-methyltransferase (TPMT) and nudix-hydrolase-15 (NUDT15) are enzymes relevant to the metabolism of thiopurine medications, used to treat immunologic disorders and malignancies. Standard dosing administered in the setting of TPMT/NUDT15 dysfunction can cause excessive cytotoxic metabolites and life-threatening complications. We describe an adolescent with high-risk B-cell acute lymphoblastic leukemia (ALL) whose TPMT/NUDT15 status was unknown due to lack of insurance approval for genetic testing. He subsequently developed myelosuppression and severe veno-occlusive disease (VOD) after receiving 6-mercaptopurine (6-MP). Our patient provides an example of a very rare 6-MP-related toxicity and the potential benefit of TPMT/NUDT15 screening before initiating thiopurine therapy.

Sequences at gene segment termini inclusive of untranslated regions and partial open reading frames play a critical role in mammalian orthoreovirus S gene packaging.

Mammalian orthoreovirus (MRV) is a prototypic member of the Spinareoviridae family and has ten double-stranded RNA segments. One copy of each segment must be faithfully packaged into the mature virion, and prior literature suggests that nucleotides (nts) at the terminal ends of each gene likely facilitate their packaging. However, little is known about the precise packaging sequences required or how the packaging process is coordinated. Using a novel approach, we have determined that 200 nts at each terminus, inclusive of untranslated regions (UTR) and parts of the open reading frame (ORF), are sufficient for packaging S gene segments (S1-S4) individually and together into replicating virus. Further, we mapped the minimal sequences required for packaging the S1 gene segment into a replicating virus to 25 5' nts and 50 3' nts. The S1 UTRs, while not sufficient, were necessary for efficient packaging, as mutations of the 5' or 3' UTRs led to a complete loss of virus recovery. Using a second novel assay, we determined that 50 5' nts and 50 3' nts of S1 are sufficient to package a non-viral gene segment into MRV. The 5' and 3' termini of the S1 gene are predicted to form a panhandle structure and specific mutations within the stem of the predicted panhandle region led to a significant decrease in viral recovery. Additionally, mutation of six nts that are conserved across the three major serotypes of MRV that are predicted to form an unpaired loop in the S1 3' UTR, led to a complete loss of viral recovery. Overall, our data provide strong experimental proof that MRV packaging signals lie at the terminal ends of the S gene segments and offer support that the sequence requirements for efficient packaging of the S1 segment include a predicted panhandle structure and specific sequences within an unpaired loop in the 3' UTR.

A Midwest Stakeholder Evaluation of an Adolescent and Young Adult Cancer Survivor Needs Assessment Survey.

Purpose: Over 87,000 adolescents and young adults (AYAs) are diagnosed with cancer in the United States each year. Improvement in outcomes in the AYA population has lagged that of both younger and older patients. This decrement may be attributable to several factors, including insufficient supportive care services. Our team modified the Needs Assessment & Service Bridge (NA-SB) tool, utilizing an iterative approach with patient and clinician stakeholders to meet the needs of the AYA population at a large Midwestern Cancer Center. Methods: We recruited a 10-member AYA Advisory Board (AB) from our Cancer Center patients, and met five times over 9 months to discuss supportive care and the NA-SB. We recruited a multidisciplinary group of oncology clinicians to assess content validity and conducted interviews with nine clinician stakeholders to discuss implementation. Results: The AB generated a 59-item-modified NA-SB, retaining most of the original NA-SB items and adding several more. Five items with concerns for relevance and/or clarity were revised to create the final 58-item-modified NA-SB. Priorities for implementation were identified by AB and clinician stakeholders. Conclusions: The modified NA-SB thoroughly reflects supportive care needs of our Midwestern AYA cancer survivors. When implemented, the tool may facilitate patient-care team communication and provide data to prioritize development of new supportive care resources. AYA cancer survivors have unique supportive care needs that are insufficiently addressed by current care models; using the modified NA-SB may help address those needs, leading to improved AYA outcomes.

Creation and characterization of a recombinant mammalian orthoreovirus expressing σ1 fusion proteins encoding human epidermal growth factor receptor 2 peptides.

Mammalian orthoreovirus (MRV) is an oncolytic virus that has been tested in over 30 clinical trials. Increased clinical success has been achieved when MRV is used in combination with other onco-immunotherapies. This has led the field to explore the creation of recombinant MRVs which incorporate immunotherapeutic sequences into the virus genome. This work focuses on creation and characterization of a recombinant MRV, S1/HER2nhd, which encodes a truncated σ1 protein fused in frame with three human epidermal growth factor receptor 2 (HER2) peptides (E75, AE36, and GP2) known to induce HER2 specific CD8+ and CD4+ T cells. We show S1/HER2nhd expresses the σ1 fusion protein containing HER2 peptides in infected cells and on the virion, and infects, replicates in, and reduces survival of HER2+ breast cancer cells. The oncolytic properties of MRV combined with HER2 peptide expression holds potential as a vaccine to prevent recurrences of HER2 expressing cancers.

Rational design of oral drugs targeting mucosa delivery with gut organoid platforms.

Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads (i.e., immunogens) against gastric damage. In this study, hollowed nanocarriers (NCs: silica nanospheres and gold nanocages) with poly-l-lysine (PLL) coating and mammalian orthoreovirus cell attachment protein σ1 functionalization (NC-PLL-σ1) were explored as functional oral drug delivery vehicles (ODDVs). The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells (M-cells) mediated transcytosis (via σ1-α2-3-linked sialic acids adherence) across gastrointestinal epithelia. PLL coating provided protection and slow-release of rhodamine 6 G (R6G), a model payload. The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro. When compared with other experimental groups, the fully functionalized ODDV system (with PLL-σ1) demonstrated two significant advantages: a significantly higher transport efficiency (198% over blank control at 48 h); and protection of payloads which led to both better transport efficiency and extended-release of payloads (61% over uncoated carriers at 48 h). In addition, it was shown that the M cell presence in intestinal organoid monolayers (modulated by Rank L stimulation) was a determining factor on the transport efficiency of the ODDVs: more M-cells (induced by higher Rank L) in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload (R6G). The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.

Adolescent and Young Adult (AYA) Oncology, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

Sequences at gene segment termini inclusive of untranslated regions and partial open reading frames play a critical role in mammalian orthoreovirus S gene packaging.

Mammalian orthoreovirus (MRV) is a prototypic member of the Spinareoviridae family and has ten double-stranded RNA segments. One copy of each segment must be faithfully packaged into the mature virion, and prior literature suggests that nucleotides (nts) at the terminal ends of each gene likely facilitate their packaging. However, little is known about the precise packaging sequences required or how the packaging process is coordinated. Using a novel approach, we have determined that 200 nts at each terminus, inclusive of untranslated regions (UTR) and parts of the open reading frame (ORF), are sufficient for packaging each S gene segment (S1-S4) individually and together into replicating virus. Further, we mapped the minimal sequences required for packaging the S1 gene segment to 25 5' nts and 50 3' nts. The S1 UTRs alone are not sufficient, but are necessary for packaging, as mutations of the 5' or 3' UTRs led to a complete loss of virus recovery. Using a second novel assay, we determined that 50 5'nts and 50 3' nts of S1 are sufficient to package a non-viral gene segment into MRV. The 5' and 3' termini of the S1 gene are predicted to form a panhandle structure and specific mutations within the predicted stem of the panhandle region led to a significant decrease in viral recovery. Additionally, mutation of six nts that are conserved in the three major serotypes of MRV and are predicted to form an unpaired loop in the S1 3'UTR, led to a complete loss of viral recovery. Overall, our data provide strong experimental proof that MRV packaging signals lie at the terminal ends of the S gene segments and offer support that the sequence requirements for efficient packaging of the S1 segment include a predicted panhandle structure and specific sequences within an unpaired loop in the 3' UTR.

Mammalian orthoreovirus infection in human epidermal growth factor receptor 2 positive (HER2+) breast cancer cells.

Mammalian orthoreovirus (MRV) is a clinically benign oncolytic virus which has been investigated for use in multiple cancer types, including breast cancer (BC). In human clinical trials, MRV has been shown to be safe, and multiple BC patients have shown partial responses to intratumoral and intravenous virus delivery. Combination therapies inclusive of MRV and current FDA approved BC chemotherapies are being investigated to target metastatic, early BC, and triple negative BC. Though MRV is being tested clinically, we still do not fully understand the highly variable patient responses to MRV therapy. One of the most aggressive BC subtypes is HER2+ BC, in which human epidermal growth factor receptor 2 (HER2) is dysregulated, resulting in increased growth, survival, and metastasis of cancer cells. FDA approved therapies, trastuzumab and pertuzumab, target HER2 to prevent signaling of the phosphoinositide 3-kinase (PI3K) pathway. However, recent findings show that accumulation of hypoxia inducible factor-1 alpha (HIF-1α) in HER2+ BC cells contributes to trastuzumab resistance. In this work, we provide evidence that MRV infects, replicates in, and kills HER2 overexpressing cells. MRV infection is also found to have variable effects on signaling pathways that activate or are activated by HER2 expression. Finally, we show that MRV reduces HIF-1α accumulation in all the cell lines tested, including a HER2+ BC cell line. These studies provide further evidence that MRV holds promise for use in conjunction with trastuzumab to treat HER2+ BC patients.

Benefit of Interdisciplinary Care in Resource Identification in an Adolescent and Young Adult Oncology Care Model.

Purpose: There are limited data to identify the best care model to support the vulnerable adolescent and young adult (AYA) oncology population. We sought to compare the impact of AYA physician visits versus interdisciplinary team (IDT) care on AYA-specific resource identification and utilization, as well as to provide a model of AYA oncology care implementation. Methods: We identified AYA-aged patients 15-39 years with a current or prior history of cancer seen by the University of Wisconsin Carbone Cancer Center (UWCCC) AYA Oncology Program between January 21, 2021 and May 27, 2021. Patients in this program have a one-on-one clinic visit with an AYA oncologist followed 4 days later by presentation at an AYA IDT meeting. We conducted retrospective chart review to quantify AYA-specific resource utilization before the AYA program visit, as well as novel resources identified by the AYA physician visit and the IDT meeting, and conducted a descriptive statistical analysis of the data. Results: We identified 35 patients seen by the UWCCC AYA Oncology Program. Before their AYA clinic visit, patients used an average of 2.51 AYA-specific services. An average of 4.45 novel resources was identified by the AYA Oncology Program per patient. This included an average of 2.54 and 1.91 additional resources identified per patient through the AYA physician visit and IDT meeting, respectively. The most common resource needs identified overall fell into the "other" category, consisting of a wide variety of resource domains (26/35) and peer support (27/35). Conclusions: Our data support increased resource identification through an AYA-specific care model. These objective data support the critical importance of AYA interdisciplinary care, as well as the use of an AYA IDT meeting model as a method to include interdisciplinary care in AYA programs despite possible resource constraints.

Pre-Treatment Left Ventricular Ejection Fraction Assessment and Long-Term Cardiovascular Outcomes in Adolescent and Young Adult Lymphoma Survivors.

Purpose: Anthracyclines can cause long-term cardiovascular (CV) morbidity, especially in long-term Adolescent and Young Adult (AYA) lymphoma survivors. Pre-treatment left ventricular ejection fraction (LVEF) evaluation is recommended, although its utility in AYA is not established. We sought to determine the pre-treatment LVEF assessment practices in AYA lymphoma survivors treated with anthracyclines and factors associated with long-term cardiotoxicity. Methods: Through an electronic health records review, we retrospectively identified AYA lymphoma survivors with ≥5 years of follow-up postanthracycline treatment. Pre-treatment and follow-up data were abstracted. CV health conditions were defined as risk factors for CV disease and confirmed CV diagnoses. Survivors who had new CV health conditions at follow-up were compared to those who were not using descriptive statistics and logistic regression. Results: One hundred fifteen AYA lymphoma survivors met the study criteria. Pre-treatment LVEF assessment did not affect chemotherapy decisions. Survivors with pre-treatment CV evaluation had mean follow-up since diagnosis of 8 ± 3.3 years, while survivors without it had 10.3 ± 4.2 years, p < 0.05. Survivors with pre-treatment LVEF assessment received lower cumulative anthracycline dose (240.4 mg/m2 vs. 280.1 mg/m2, p < 0.05) and fewer cycles of chemotherapy (4.8 ± 1.5 vs. 5.6 ± 1.2, p < 0.05). Body mass index (BMI) category at diagnosis and follow-up, in addition to age were associated with development of new CV health conditions, pre-treatment LVEF evaluation was not. Conclusion: Pre-treatment LVEF assessment for AYA lymphoma survivors does not impact oncologic treatment decisions or development of CV health conditions. It may be more valuable to assess and modify CV risk factors such as BMI for CV disease prevention.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas include recommendations for the diagnosis and management of pediatric patients with primary mediastinal large B-cell lymphoma (PMBL) and sporadic variants of Burkitt lymphoma and diffuse large B-cell lymphoma. PMBL is now considered as a distinct entity arising from mature thymic B-cells accounting for 2% of mature B-cell lymphomas in children and adolescents. This discussion section includes the recommendations outlined in the NCCN Guidelines for the diagnosis and management of pediatric patients with PMBL.

Disparities in Treatment Satisfaction and Supportive Care Receipt for Young Adult Oncology Patients on the Basis of Residential Location.

PURPOSE: Adolescent and young adult oncology programs are critical but exist primarily in academic centers, prompting potential disparities in care on the basis of patient residence. We studied the impact of residential location on supportive care receipt and treatment satisfaction in young adults (YAs) with cancer age 19-39 years treated at the University of Wisconsin Carbone Cancer Center (UWCCC). METHODS: YA patients with cancer age 19-39 years seen at UWCCC from March 30, 2019, to March 29, 2020, were sent a survey assessing supportive care receipt and satisfaction. Survey results were compared with retrospective chart review of YAs seen at UWCCC between April 1, 2011, and April 1, 2021. Data were categorized on the basis of residential location using distance from UWCCC and 2013 Rural-Urban Continuum Code (RUCC). RESULTS: Survey results were obtained for 145 YAs, including 29 from nonmetro RUCC (20.0%) and 81 living > 20 miles from UWCCC (55.9%). YAs from nonmetro locations had lower satisfaction with available treatments (79.3% v 91.4%, P = .005), and distant YAs living > 20 miles from UWCCC more frequently identified location as a barrier to supportive care receipt (35.6% v 15.8%, P = .02). Metro YAs more frequently listed fertility consultations as unavailable (38.0% v 16.0%, P = .04) in the survey despite chart review data showing higher rates of sexual health assessments (48.2% v 20.4%, P = .002) and fertility visits (29.6% v 18.5%, P = .18). CONCLUSION: We identified differences in both supportive care receipt and treatment satisfaction on the basis of residential location. These findings support the need for measures to successfully meet treatment and supportive care needs regardless of residential location.

Disparities Between Provider Assessment and Documentation of Care Needs in the Care of Adolescent and Young Adult Patients With Sarcoma.

PURPOSE: Given the occurrence of cancer during a complex developmental time, adolescent and young adult (AYA) patients have unique psychosocial needs that necessitate supportive care, which is optimally provided using National Comprehensive Cancer Network (NCCN) AYA guidelines. We sought to explore compliance with NCCN AYA guidelines and compare with oncology providers' perceptions of AYA care needs. METHODS: Retrospective chart reviews of AYA patients (15-39 years at time of cancer diagnosis) with sarcoma seen at least once in 2019 at the University of Wisconsin identified documentation of discussions deemed critical per NCCN AYA guidelines. As per the ASCO Quality Oncology Practice Initiative certification, we considered a threshold of these factors being discussed 75% of the time or higher to be compliant. Compliance was compared with an electronic survey of University of Wisconsin oncology providers regarding AYA patient needs, with items determined to have adequate resources if noted sufficient by at least 75% of providers. RESULTS: We identified 43 AYA patients with sarcoma. Less than 75% of patients had documentation of discussion of contraception, sexual health, fertility, finances, genetics, social work referral, and clinical trials indicating noncompliance with NCCN guidelines. Surveys, completed by 38 oncology providers, showed significant discordance between providers' perceptions of AYAs' access to resources and providers' documented discussions of supportive care resources. CONCLUSION: Disparities between oncology provider assessment of AYA care needs and documentation of critical components of AYA patient care demonstrate the need for novel tools to evaluate AYA care needs beyond provider assessments.

Inhibition of HIF-1α accumulation in prostate cancer cells is initiated during early stages of mammalian orthoreovirus infection.

Mammalian orthoreovirus (MRV) is a safe and effective cancer killing virus that has completed Phase I-III clinical trials against numerous cancer types. While many patients experience benefit from MRV therapy, pre-defined set points necessary for FDA approval have not been reached. Therefore, additional research into MRV biology and the effect of viral therapy on different tumor genetic subtypes and microenvironments is necessary to identify tumors most amenable to MRV virotherapy. In this work we analyzed the stage of viral infection necessary to inhibit HIF-1α, an aggressive cancer activator induced by hypoxia. We demonstrated that two viral capsid proteins were not necessary and that a step parallel with virus core movement across the endosomal membrane was required for this inhibition. Altogether, this work clarifies the mechanisms of MRV-induced HIF-1α inhibition and provides biological relevance for using MRV to inhibit the devastating effects of tumor hypoxia.

Embedding changes in legislation for organ and tissue donation across England and Jersey.

Cathy Miller, Louise Hubner (louise.hubner@nhsbt.nhs.uk), Sonya Paterson, Bobbee Cotter, Phil Walton, Helen Bentley, and Claire Roberts, of NHS Blood and Transplant.

Reovirus and the Host Integrated Stress Response: On the Frontlines of the Battle to Survive.

Cells are continually exposed to stressful events, which are overcome by the activation of a number of genetic pathways. The integrated stress response (ISR) is a large component of the overall cellular response to stress, which ultimately functions through the phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2α) to inhibit the energy-taxing process of translation. This response is instrumental in the inhibition of viral infection and contributes to evolution in viruses. Mammalian orthoreovirus (MRV), an oncolytic virus that has shown promise in over 30 phase I-III clinical trials, has been shown to induce multiple arms within the ISR pathway, but it successfully evades, modulates, or subverts each cellular attempt to inhibit viral translation. MRV has not yet received Food and Drug Administration (FDA) approval for general use in the clinic; therefore, researchers continue to study virus interactions with host cells to identify circumstances where MRV effectiveness in tumor killing can be improved. In this review, we will discuss the ISR, MRV modulation of the ISR, and discuss ways in which MRV interaction with the ISR may increase the effectiveness of cancer therapeutics whose modes of action are altered by the ISR.