Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function.

The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.

A single bout of vigorous intensity exercise enhances the efficacy of rituximab against human chronic lymphocytic leukaemia B-cells ex vivo.

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal proliferation and accumulation of mature B-cells and is often treated with rituximab, an anti-CD20 monoclonal antibody immunotherapy. Rituximab often fails to induce stringent disease eradication, due in part to failure of antibody-dependent cellular cytotoxicity (ADCC) which relies on natural killer (NK)-cells binding to rituximab-bound CD20 on B-cells. CLL cells are diffusely spread across lymphoid and other bodily tissues, and ADCC resistance in survival niches may be due to several factors including low NK-cell frequency and a suppressive stromal environment that promotes CLL cell survival. It is well established that exercise bouts induce a transient relocation of NK-cells and B-cells into peripheral blood, which could be harnessed to enhance the efficacy of rituximab in CLL by relocating both target and effector cells together with rituximab in blood. In this pilot study, n = 20 patients with treatment-naïve CLL completed a bout of cycling 15 % above anaerobic threshold for âˆ¼ 30-minutes, with blood samples collected pre-, immediately post-, and 1-hour post-exercise. Flow cytometry revealed that exercise evoked a 254 % increase in effector (CD3-CD56+CD16+) NK-cells in blood, and a 67 % increase in CD5+CD19+CD20+ CLL cells in blood (all p < 0.005). NK-cells were isolated from blood samples pre-, and immediately post-exercise and incubated with primary isolated CLL cells with or without the presence of rituximab to determine specific lysis using a calcein-release assay. Rituximab-mediated cell lysis increased by 129 % following exercise (p < 0.001). Direct NK-cell lysis of CLL cells - independent of rituximab - was unchanged following exercise (p = 0.25). We conclude that exercise improved the efficacy of rituximab-mediated ADCC against autologous CLL cells ex vivo and propose that exercise should be explored as a means of enhancing clinical responses in patients receiving anti-CD20 immunotherapy.

National advisory panels for childhood cancer in the United Kingdom: An evaluation of current practice and a best practice statement for the future.

BACKGROUND: National advisory panels (NAPs) have been established for the care of children and young people (CYP) with cancer in the United Kingdom since 2011, with an increase in panel number in recent years. Their practice has not previously been reviewed; therefore, we sought to evaluate the role, practice and impact of six selected NAPs offering expertise in ependymoma, histiocytosis, leukaemia, neuroblastoma, renal tumours and sarcoma. PROCEDURE: This service evaluation used mixed methodology, including review of NAP documentation, semi-structured interviews with the NAP chairs and an analysis of the cases referred for discussion. RESULTS: Total 1110 referrals were analysed. Results demonstrated the significant scope and amount of work undertaken by the NAPs, largely testament to the commitment of the panel members. Specific roles fulfilled have been highlighted, and NAP recommendations have been shown to influence clinical decision-making and be implemented in the majority of cases. Despite widespread good practice, areas to address have been identified; these include clarity regarding NAP membership, consistency in recommendations, the consideration of holistic information to promote personalised management and the exploration of wider multidisciplinary team roles. CONCLUSIONS: In the context of increasing demand and the escalating number of NAPs, it is timely to consider how service improvement can be facilitated. Best practice guidelines have been formulated as a product of this study, to promote a sustainable and effective model for NAPs. Review and benchmarking national panel performance against these guidelines will drive high standards of care going forward and they should be embedded as standard practice.

Tri-Lineage Differentiation Potential of Osteosarcoma Cell Lines and Human Bone Marrow Stromal Cells from Different Anatomical Locations.

The bone cancer osteosarcoma, found mainly in adolescents, routinely forms around the growth plate/metaphysis of long bones. Bone marrow composition changes with age, shifting from a more hematopoietic to an adipocyte-rich tissue. This conversion occurs in the metaphysis during adolescence, implicating a link between bone marrow conversion and osteosarcoma initiation. To assess this, the tri-lineage differentiation potential of human bone marrow stromal cells (HBMSCs) isolated from the femoral diaphysis/metaphysis (FD) and epiphysis (FE) was characterized and compared to two osteosarcoma cell lines, Saos-2 and MG63. Compared to FE-cells, FD-cells showed an increase in tri-lineage differentiation. Additionally, differences were found between the Saos-2 cells exhibiting higher levels of osteogenic differentiation, lower adipogenic differentiation, and a more developed chondrogenic phenotype than MG63, with the Saos-2 being more comparable to FD-derived HBMSCs. The differences found between the FD and FE derived cells are consistent with the FD region containing more hematopoietic tissue compared to the FE. This may be related to the similarities between FD-derived cells and Saos-2 cells during osteogenic and chondrogenic differentiation. These studies reveal distinct differences in the tri-lineage differentiations of 'hematopoietic' and 'adipocyte rich' bone marrow, which correlate with specific characteristics of the two osteosarcoma cell lines.

Prevalence of metachronous contralateral mature ovarian teratoma: A systematic review.

There is increasing recognition that contralateral metachronous tumor may occur following treatment of unilateral mature ovarian teratoma. We aimed to define this risk to guide appropriate surveillance strategies. We undertook a systematic review of three large medical databases (Ovid Medline, Embase, and Cochrane Controlled Trials Register) to April 2020 using a defined search strategy. From 1831 articles retrieved, 23 were included, reporting 1101 girls with unilateral mature ovarian teratomas. The intensity and duration of follow-up varied between studies, with only five reporting close surveillance. Overall prevalence of metachronous contralateral mature teratoma was 2.1%, with a prevalence per study of 0%-23% (median 0%). Prevalence was higher (7%) among studies with more robust surveillance. These data suggest a small but real risk of metachronous contralateral tumors. Surveillance ultrasonography is proportionate and indicated alongside further prospective data collection to record the natural history and impact of surveillance in greater detail.

Thirteen-Valent Pneumococcal Conjugate Vaccine in Children With Acute Lymphoblastic Leukemia: Protective Immunity Can Be Achieved on Completion of Treatment.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) are at increased risk of developing invasive pneumococcal disease. This study describes the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) during and after chemotherapy. METHODS: Children with ALL were allocated to study groups and received a single dose of PCV13: group 1, maintenance chemotherapy; group 2, end of chemotherapy; group 3, 6 months after chemotherapy. A protective vaccine response was defined as at least 10 of 12 serotypes (or >83% of serotypes with data) achieving postvaccination serotype-specific immunoglobulin G ≥0.35 µg/mL and ≥4-fold rise, compared to prevaccination at 1 and 12 months. RESULTS: One hundred eighteen children were recruited. Only 12.8% (5/39; 95% confidence interval [CI], 4.3%-27.4%) of patients vaccinated during maintenance (group 1) achieved a protective response at 1 month postvaccination and none had a protective response at 12 months. For group 2 patients, 59.5% (22/37; 95% CI, 42.1%-75.3%) achieved a response at 1 month and 37.9% (11/29; 95% CI, 20.7%-57.7%) maintained immunity at 12 months. For group 3 patients, 56.8% (21/37; 95% CI, 39.5%-72.9%) achieved a protective response at 1 month and 43.3% (13/30; 95% CI, 25.5%-62.6%) maintained immunity at 12 months. CONCLUSIONS: This study demonstrated that the earliest time point at which protective immunity can be achieved in children with ALL is on completion of chemotherapy. This is earlier than current recommendations and may improve protection during a period when children are most susceptible to infection. CLINICAL TRIALS REGISTRATION: EudraCT 2009-011587-11.

The Role of Pre-Clinical 3-Dimensional Models of Osteosarcoma.

Treatment for osteosarcoma (OS) has been largely unchanged for several decades, with typical therapies being a mixture of chemotherapy and surgery. Although therapeutic targets and products against cancer are being continually developed, only a limited number have proved therapeutically active in OS. Thus, the understanding of the OS microenvironment and its interactions are becoming more important in developing new therapies. Three-dimensional (3D) models are important tools in increasing our understanding of complex mechanisms and interactions, such as in OS. In this review, in vivo animal models, in vitro 3D models and in ovo chorioallantoic membrane (CAM) models, are evaluated and discussed as to their contribution in understanding the progressive nature of OS, and cancer research. We aim to provide insight and prospective future directions into the potential translation of 3D models in OS.

Hypercalcaemia secondary to ectopic parathyroid hormone expression in an adolescent with metastatic alveolar rhabdomyosarcoma.

We report the case of a 14-year-old male with metastatic alveolar rhabdomyosarcoma, presenting with hypercalcaemia (3.89 mmol/l) and elevated parathyroid hormone (PTH) level (10.2 pmol/l). Imaging demonstrated extensive bony lytic damage, with "floating teeth" in the mandible. Normalisation of calcium levels and bony reformation of the mandible occurred following chemotherapy; PTH levels decreased initially but remained above normal levels. Imaging did not demonstrate any evidence of parathyroid abnormality. Tumour ectopic PTH secretion is a very rare cause of hypercalcaemia of malignancy in children. Hypercalcaemia with an elevated PTH, in the absence of parathyroid-related cause, should prompt investigation for underlying malignancy.

Considering the benefits of egg consumption for older people at risk of sarcopenia.

Sarcopenia is an important health issue for older people. It is closely linked with frailty and malnutrition and can significantly reduce both health and quality of life for those affected. Sarcopenic decline in muscle mass can start as early as the fourth and fifth decade of life, so the maintenance of muscle mass throughout adulthood, through regular physical activity and a balanced diet, should be an important consideration in reducing the risk of sarcopenia in older age. Maintaining regular exercise throughout older age remains key to the treatment of sarcopenia, as does an adequate intake of nutrients, including high-quality protein and vitamin D. A significant proportion of older people fail to meet the recommended requirements for protein; it has also been suggested that the requirements in existing recommendations could be higher. Evidence is emerging that an adequate intake of protein at each meal may be required to optimise muscle synthesis in older people. Eggs are an inexpensive, widely available and easily digestible source of high-quality protein and contain a significant proportion of leucine, an amino acid that is important for muscle synthesis, as well as many other nutrients of significance for older people, including vitamin D and omega-3 fatty acids. For many older people, eggs are a familiar and acceptable protein food at breakfast and other meals. Encouraging both those approaching older age and older people to include eggs more frequently, as part of a healthy, balanced diet and in addition to physical activity, could help them maintain their muscle strength and function, thereby preserving their functional capacity and reducing morbidity, mortality and healthcare costs associated with sarcopenia.

Tumor-targeted and immune-targeted monoclonal antibodies: Going from passive to active immunotherapy.

Monoclonal antibodies (mAbs) have inaugurated the concepts of tumor-targeted therapy and personalized medicine. A new family of mAbs is currently emerging in the clinic, which target immune cells rather than cancer cells. These immune-targeted therapies have recently demonstrated long-term tumor responses in adults with refractory/relapsing metastatic solid tumors. Pediatric cancers are different from their adult counterparts in terms of histological features and immune infiltrates. However, the same immune checkpoint targets can be expressed within the microenvironment of pediatric tumors. The benefits of immune checkpoint blockade in pediatric cancers are currently under evaluation in early phase clinical trials.

Development of immunomonitoring of antibody­dependent cellular cytotoxicity against neuroblastoma cells using whole blood.

Neuroblastoma, a childhood tumour of neuroectodermal origin, accounts for 15 % of paediatric cancer deaths, which is often metastatic at diagnosis and despite aggressive therapies, it has poor long-term prognosis with high risk of recurrence. Monoclonal antibody (mAb) therapy targeting GD2, a disialoganglioside expressed on neuroblastoma, has shown promise in recent trials with natural killer cell (NK)-mediated antibody-dependent cellular cytotoxicity (ADCC) thought to be central to efficacy, although other immune effectors may be important. To further enhance therapy, immunomonitoring of patients is essential to elucidate the in vivo mechanisms of action and provides surrogate end points of efficacy for future clinical trials. Our aim was to establish a 'real-time' ex vivo wholeblood (WB) immunomonitoring strategy to perform within the logistical constraints such as limited sample volumes, anticoagulant effects, sample stability and shipping time. A fluorescent dye release assay measuring target cell lysis was coupled with flow cytometry to monitor specific effector response. Significant target cell lysis with anti-GD2 antibody (p < 0.05) was abrogated following NK depletion. NK up-regulation of CD107a and CD69 positively correlated with target cell lysis (r > 0.6). The ADCC activity of WB correlated with peripheral blood mononuclear cells (r > 0.95), although WB showed overall greater target cell lysis attributed to the combination of NK-mediated ADCC, CD16+ granulocyte degranulation and complement- dependent cytotoxicity. Response was maintained in heparinised samples stored for 24 h at room temperature, but not 4 °C. Critically, the assay showed good reproducibility (mean % CV < 6.4) and was successfully applied to primary neuroblastoma samples. As such, WB provides a resourceful analysis of multiple mechanisms for efficient end point monitoring to correlate immune modulation with clinical outcome.

Patient and parent perspectives on paediatric cancer multidisciplinary team working and national advisory panels in the UK: a qualitative research study.

OBJECTIVE: The concept of patient-centred care is central to the role of cancer multidisciplinary teams (MDTs) and particularly pertinent with the recent rise in number of virtual national advisory panels (NAPs) for childhood cancer in the UK. We sought to explore patient and caregiver views regarding MDT working and NAPs. METHODS: Three focus groups were undertaken between March 2019 and January 2020. RESULTS: Sixteen participants attended. All regarded MDTs and NAPs highly, while highlighting patient involvement in decision-making should not be diluted by this process. The importance of personalised consultations was stressed, acknowledging that information-sharing preferences may change with circumstance and time. Most participants felt they had not been actively involved in decisions, including those made following MDT or NAP discussions. Group suggestions to improve patient-centred care included a clinician knowing them presenting their case, referral proformas to include family-related factors and an advocate attending meetings to represent the patient/family view. CONCLUSION: Several changes have been driven forward by this work, including the modification of NAP referral proformas to include additional information. Patient and parent perspectives are now embedded into a best practice model for the NAPs to promote personalised recommendations at national level.

The use of routinely collected electronic prescribing data to benchmark intravenous antibiotic use between two tertiary paediatric haematology-oncology inpatient units: a retrospective study.

Background: High-quality systematic data on antimicrobial use in UK inpatient paediatric haematology-oncology services are lacking, despite this population being at high risk from antimicrobial exposure and resistance. Objectives: We conducted a retrospective study to demonstrate how routinely collected electronic prescribing data can address this issue. Patients and methods: This retrospective study describes and compares IV antibiotic consumption between two UK paediatric haematology-oncology inpatient units, between 2018 and 2022. Both sites provide similar services and receive proactive antimicrobial stewardship input. Data were extracted from each site's antimicrobial surveillance system, which report monthly days of therapy (DOT) per 100 patient-days (PD). Consumption was reported for specific and total antibiotics. Trends were modelled using linear regression and autoregressive moving average models. Results: Total IV antibiotic consumption at each site was similar. Median monthly DOT per 100 PD were 25.9 (IQR: 22.1-34.0) and 29.4 (24.2-34.9). Total antibiotic use declined at both sites, with estimated annual yearly reductions of 3.52 DOT per 100 PD (95% CI: 0.46-6.59) and 2.57 (1.30-3.85). Absolute consumption was similar for carbapenems, piperacillin/tazobactam and aminoglycosides, whilst ceftriaxone and teicoplanin demonstrated approximately 3-fold relative differences in median monthly consumption. Meropenem, piperacillin/tazobactam, teicoplanin, vancomycin and gentamicin all demonstrated statistically significant reductions in use over time at either one or both sites, although this was most marked for piperacillin/tazobactam and vancomycin. Conclusions: Routinely collected electronic prescribing data can aid benchmarking of antibiotic use in paediatric haematology-oncology inpatients, highlighting areas to target stewardship strategies, and evaluating their impact. This approach should be rolled out nationally, and to other high-risk groups.

Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy.

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations. NK cells show reduced cytotoxicity and T cells have a dysfunctional profile. Interaction analysis reveals a vast immunoregulatory network and identifies NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduces neuroblastoma growth, with complete responses (CR) in vivo. Moreover, addition of TIGIT+PD-L1 blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.

Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial.

PURPOSE: Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). MATERIALS AND METHODS: Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. RESULTS: One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). CONCLUSION: The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Variation in the effects of three different breakfast meals on subjective satiety and subsequent intake of energy at lunch and evening meal.

PURPOSE: To determine the relative impact of three iso-caloric breakfast meals, of variable composition, on satiety, hunger and subsequent intake of energy. METHODS: In a three-way, crossover design, 30 healthy men (age of 21.7 ± 1.2 years; BMI, 23.1 ± 2.7 kg/m²) were randomised to one of three test breakfasts, on three separate occasions, separated by 1 week. The breakfasts consisted of eggs on toast, cereal (cornflakes) with milk and toast, or a croissant and orange juice. Subjective ratings of satiety, hunger, fullness and desire to eat were recorded at 30-min intervals by electronic visual analogue scales (VAS). Energy intake was assessed by weighed food intake at an ad libitum lunch and evening meal. RESULTS: Participants showed increased satiety, less hunger and a lower desire to eat after the breakfast containing eggs relative to the cereal (p < 0.02), and croissant-based meals (p < 0.0001). The egg breakfast was also accompanied by a significantly lower intake of energy relative to the croissant- and cereal-based breakfasts at the buffet lunch and evening meal, respectively, 1,284 ± 464 (egg) versus 1,442 ± 426 kcal (croissant), p = 0.03, 1,407 ± 379 (cereal) at lunch and 1,899 ± 729 (egg) versus 2,214 ± 620 kcal (cereal), p = 0.02, 2,047 ± 712 (croissant) at evening meal. The breakfast meal with the greatest effect on satiety and subsequent intake of energy was distinct in having the highest protein and lowest carbohydrate content relative to the other two breakfasts. CONCLUSION: These findings provide evidence to support the importance of food choice at breakfast as a means of increasing satiety in the morning and reducing energy intake at lunch.

Review: Targeting EZH2 in neuroblastoma.

Neuroblastoma is one of the commonest extra-cranial pediatric tumors, and accounts for over 15% of all childhood cancer mortality. Risk stratification for children with neuroblastoma is based on age, stage, histology, and tumor cytogenetics. The majority of patients are considered to have high-risk neuroblastoma, for which the long-term survival is less than 50%. Current treatments combine surgical resection, chemotherapy, stem cell transplantation, radiotherapy, anti-GD2 based immunotherapy as well as the differentiating agent isotretinoin. Despite the intensive multimodal therapies applied, there are high relapse rates, and recurrent disease is often resistant to further therapy. Enhancer of Zeste Homolog 2 (EZH2), a catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is a histone methyltransferase that represses transcription through trimethylation of lysine residue K27 on histone H3 (H3K27me3). It is responsible for epigenetic repression of transcription, making EZH2 an essential regulator for cell differentiation. Overexpression of EZH2 has been shown to promote tumorigenesis, cancer cell proliferation and prevent tumor cells from differentiating in a number of cancers. Therefore, research has been ongoing for the past decade, developing treatments that target EZH2 in neuroblastoma. This review summarises the role of EZH2 in neuroblastoma and evaluates the latest research findings on the therapeutic potential of targeting EZH2 in the treatment of neuroblastoma.

Integrated re-analysis of transcriptomic and proteomic datasets reveals potential mechanisms for Zika viral-based oncolytic therapy in neuroblastoma.

Background: Paediatric neuroblastoma and brain tumours account for a third of all childhood cancer-related mortality. High-risk neuroblastoma is highly aggressive and survival is poor despite intensive multi-modal therapies with significant toxicity. Novel therapies are desperately needed. The Zika virus (ZIKV) can access the nervous system and there is growing interest in employing ZIKV as a potential therapy against paediatric nervous system tumours, including neuroblastoma. Methods: Here, we perform extensive data mining, integration and re-analysis of ZIKV infection datasets to highlight molecular mechanisms that may govern the oncolytic response in neuroblastoma cells. We collate infection data of multiple neuroblastoma cell lines by different ZIKV strains from a body of published literature to inform the susceptibility of neuroblastoma to the ZIKV oncolytic response. Integrating published transcriptomics, interaction proteomics, dependency factor and compound datasets we propose the involvement of multiple host systems during ZIKV infection. Results: Through data mining of published literature, we observed most paediatric neuroblastoma cell lines to be highly susceptible to ZIKV infection and propose the PRVABC59 ZIKV strain to be the most promising candidate for neuroblastoma oncolytic virotherapy. ZIKV induces TNF signalling, lipid metabolism, the Unfolded Protein Response (UPR), and downregulates cell cycle and DNA replication processes. ZIKV infection is dependent on sterol regulatory element binding protein (SREBP)-regulated lipid metabolism and three protein complexes; V-ATPase, ER Membrane Protein Complex (EMC) and mammalian translocon. We propose ZIKV non-structural protein 4B (NS4B) as a likely mediator of ZIKVs interaction with IRE1-mediated UPR, lipid metabolism and mammalian translocon. Conclusions: Our work provides a significant understanding of ZIKV infection in neuroblastoma cells, which will facilitate the progression of ZIKV-based oncolytic virotherapy through pre-clinical research and clinical trials.

A Case of Prepubertal Ovarian Tissue Cryopreservation in Metachronous Bilateral Mature Ovarian Teratoma Requiring Bilateral Oophorectomy.

Mature ovarian teratoma has the potential to occur metachronously in the contralateral ovary. There are significant implications for fertility as bilateral oophorectomy may be indicated. In prepubertal girls, ovarian tissue cryopreservation (OTC) offers the only possibility of a future biological pregnancy but outcome data are limited. We present a case of prepubertal OTC in a 12-year-old girl undergoing a second oophorectomy for metachronous contralateral mature teratoma. We offer a discussion of the challenges that emerged regarding perioperative decision-making, balancing the need for safe oncological resection with the desire to preserve fertility.