Changes in supportive care needs over time from diagnosis up to two years after treatment in head and neck cancer patients:A prospective cohort study

Objectives: To investigate changes in supportive care needs (SCNs) over time from diagnosis up to 2 years after treatment among head and neck cancer (HNC) patients, in relation to demographic, personal, clinical, psychological, physical, social, lifestyle, and cancer-related quality of life factors.Materials and methods: Data of the longitudinal NETherlands QUality of Life and Biomedical Cohort study (NET-QUBIC) was used. SCNs were measured using the Supportive Care Needs Survey (SCNS-SF34) and HNC-specific module (SCNS–HNC) before treatment, three, six, 12 and 24 months after treatment. Linear mixed model analyses were used to study SCNs on the physical &amp; daily living (PDL), psychological (PSY), sexuality (SEX), health system, information and patient support (HSIPS), HNC-functioning (HNC-Function), and lifestyle (HNC-Lifestyle) domain, in relation to demographic, personal, clinical, psychological, physical, social, lifestyle, and cancer-related symptoms as measured at baseline.Results: In total, 563 patients were included. SCNs changed significantly over time. At baseline, 65% had ≥1 moderate/high SCN, versus 42.8% at 24 months. Changes in PDL needs were associated with gender, tumor location, smoking, fear of cancer recurrence, oral pain, and appetite loss, changes in PSY with tumor location, fear of recurrence, social support, emotional functioning, physical functioning, coughing, and use of painkillers, changes in SEX with treatment, changes in HSIPS with muscle strength, changes in HNC-Function with tumor stage, location, social support, physical functioning, fatigue, nausea and vomiting, and speech problems, and changes in HNC-Lifestyle with smoking and alcohol use.Conclusion: SCNs diminish over time, but remain prevalent in HNC patients.</p

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. As novel and improved immunotherapies may fill this need, we dissected the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 25 tumors (10 pre- and 15 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas were infiltrated by NK, T and B cells, and immunosuppressive myeloid populations. NK cells showed reduced cytotoxicity and T cells had a dysfunctional profile. Interaction analysis revealed a vast immunoregulatory network and identified NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduced neuroblastoma growth, with complete responses in vivo. Moreover, addition of TIGIT blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model significantly improved survival. Concluding, our integrative analysis of neuroblastoma’s vast immunoregulatory network provides novel targets and a rationale for immunotherapeutic combination strategies

Changes in supportive care needs over time from diagnosis up to two years after treatment in head and neck cancer patients:A prospective cohort study

Objectives: To investigate changes in supportive care needs (SCNs) over time from diagnosis up to 2 years after treatment among head and neck cancer (HNC) patients, in relation to demographic, personal, clinical, psychological, physical, social, lifestyle, and cancer-related quality of life factors.Materials and methods: Data of the longitudinal NETherlands QUality of Life and Biomedical Cohort study (NET-QUBIC) was used. SCNs were measured using the Supportive Care Needs Survey (SCNS-SF34) and HNC-specific module (SCNS–HNC) before treatment, three, six, 12 and 24 months after treatment. Linear mixed model analyses were used to study SCNs on the physical &amp; daily living (PDL), psychological (PSY), sexuality (SEX), health system, information and patient support (HSIPS), HNC-functioning (HNC-Function), and lifestyle (HNC-Lifestyle) domain, in relation to demographic, personal, clinical, psychological, physical, social, lifestyle, and cancer-related symptoms as measured at baseline.Results: In total, 563 patients were included. SCNs changed significantly over time. At baseline, 65% had ≥1 moderate/high SCN, versus 42.8% at 24 months. Changes in PDL needs were associated with gender, tumor location, smoking, fear of cancer recurrence, oral pain, and appetite loss, changes in PSY with tumor location, fear of recurrence, social support, emotional functioning, physical functioning, coughing, and use of painkillers, changes in SEX with treatment, changes in HSIPS with muscle strength, changes in HNC-Function with tumor stage, location, social support, physical functioning, fatigue, nausea and vomiting, and speech problems, and changes in HNC-Lifestyle with smoking and alcohol use.Conclusion: SCNs diminish over time, but remain prevalent in HNC patients.</p

The number of DE genes between liver and kidney at a cutoff p-value < 10⁻⁴ for different normalization methods.

<p>The number of DE genes between liver and kidney at a cutoff p-value < 10⁻⁴ for different normalization methods.</p

Neuroblastoma and DIPG Organoid Coculture System for Personalized Assessment of Novel Anticancer Immunotherapies

Cancer immunotherapy has transformed the landscape of adult cancer treatment and holds a great promise to treat paediatric malignancies. However, in vitro test coculture systems to evaluate the efficacy of immunotherapies on representative paediatric tumour models are lacking. Here, we describe a detailed procedure for the establishment of an ex vivo test coculture system of paediatric tumour organoids and immune cells that enables assessment of different immunotherapy approaches in paediatric tumour organoids. We provide a step-by-step protocol for an efficient generation of patient-derived diffuse intrinsic pontine glioma (DIPG) and neuroblastoma organoids stably expressing eGFP-ffLuc transgenes using defined serum-free medium. In contrast to the chromium-release assay, the new platform allows for visualization, monitoring and robust quantification of tumour organoid cell cytotoxicity using a non-radioactive assay in real-time. To evaluate the utility of this system for drug testing in the paediatric immuno-oncology field, we tested our in vitro assay using a clinically used immunotherapy strategy for children with high-risk neuroblastoma, dinutuximab (anti-GD2 monoclonal antibody), on GD2 proficient and deficient patient-derived neuroblastoma organoids. We demonstrated the feasibility and sensitivity of our ex vivo coculture system using human immune cells and paediatric tumour organoids as ex vivo tumour models. Our study provides a novel platform for personalized testing of potential anticancer immunotherapies for aggressive paediatric cancers such as neuroblastoma and DIPG

Neuroblastoma and DIPG Organoid Coculture System for Personalized Assessment of Novel Anticancer Immunotherapies

Cancer immunotherapy has transformed the landscape of adult cancer treatment and holds a great promise to treat paediatric malignancies. However, in vitro test coculture systems to evaluate the efficacy of immunotherapies on representative paediatric tumour models are lacking. Here, we describe a detailed procedure for the establishment of an ex vivo test coculture system of paediatric tumour organoids and immune cells that enables assessment of different immunotherapy approaches in paediatric tumour organoids. We provide a step-by-step protocol for an efficient generation of patient-derived diffuse intrinsic pontine glioma (DIPG) and neuroblastoma organoids stably expressing eGFP-ffLuc transgenes using defined serum-free medium. In contrast to the chromium-release assay, the new platform allows for visualization, monitoring and robust quantification of tumour organoid cell cytotoxicity using a non-radioactive assay in real-time. To evaluate the utility of this system for drug testing in the paediatric immuno-oncology field, we tested our in vitro assay using a clinically used immunotherapy strategy for children with high-risk neuroblastoma, dinutuximab (anti-GD2 monoclonal antibody), on GD2 proficient and deficient patient-derived neuroblastoma organoids. We demonstrated the feasibility and sensitivity of our ex vivo coculture system using human immune cells and paediatric tumour organoids as ex vivo tumour models. Our study provides a novel platform for personalized testing of potential anticancer immunotherapies for aggressive paediatric cancers such as neuroblastoma and DIPG

Neuroblastoma and DIPG Organoid Coculture System for Personalized Assessment of Novel Anticancer Immunotherapies

Cancer immunotherapy has transformed the landscape of adult cancer treatment and holds a great promise to treat paediatric malignancies. However, in vitro test coculture systems to evaluate the efficacy of immunotherapies on representative paediatric tumour models are lacking. Here, we describe a detailed procedure for the establishment of an ex vivo test coculture system of paediatric tumour organoids and immune cells that enables assessment of different immunotherapy approaches in paediatric tumour organoids. We provide a step-by-step protocol for an efficient generation of patient-derived diffuse intrinsic pontine glioma (DIPG) and neuroblastoma organoids stably expressing eGFP-ffLuc transgenes using defined serum-free medium. In contrast to the chromium-release assay, the new platform allows for visualization, monitoring and robust quantification of tumour organoid cell cytotoxicity using a non-radioactive assay in real-time. To evaluate the utility of this system for drug testing in the paediatric immuno-oncology field, we tested our in vitro assay using a clinically used immunotherapy strategy for children with high-risk neuroblastoma, dinutuximab (anti-GD2 monoclonal antibody), on GD2 proficient and deficient patient-derived neuroblastoma organoids. We demonstrated the feasibility and sensitivity of our ex vivo coculture system using human immune cells and paediatric tumour organoids as ex vivo tumour models. Our study provides a novel platform for personalized testing of potential anticancer immunotherapies for aggressive paediatric cancers such as neuroblastoma and DIPG

Association of obesity with 3-month mortality in kidney failure patients with COVID-19.

BackgroundIn the general population with coronavirus disease 2019 (COVID-19), obesity is associated with an increased risk of mortality. Given the typically observed obesity paradox among patients on kidney function replacement therapy (KFRT), especially dialysis patients, we examined the association of obesity with mortality among dialysis patients or living with a kidney transplant with COVID-19.MethodsData from the European Renal Association COVID-19 Database (ERACODA) were used. KFRT patients diagnosed with COVID-19 between 1 February 2020 and 31 January 2021 were included. The association of Quetelet's body mass index (BMI) (kg/m2), divided into: &lt;18.5&nbsp;(lean), 18.5-24.9 (normal weight), 25-29.9 (overweight), 30-34.9 (obese I) and&nbsp;≥35 (obese II/III), with 3-month mortality was investigated using Cox proportional-hazards regression analyses.ResultsIn 3160 patients on KFRT (mean age: 65 years, male: 61%), 99 patients were lean, 1151 normal weight (reference), 1160 overweight, 525 obese I and 225 obese II/III. During follow-up of 3 months, 28, 20, 21, 23 and 27% of patients died in these categories, respectively. In the fully adjusted model, the hazard ratios (HRs) for 3-month mortality were 1.65 [95% confidence interval (CI): 1.10, 2.47], 1 (ref.), 1.07 (95% CI: 0.89, 1.28), 1.17 (95% CI: 0.93, 1.46) and 1.71 (95% CI: 1.27, 2.30), respectively. Results were similar among dialysis patients (N&nbsp;=&nbsp;2343) and among those living with a kidney transplant (N&nbsp;=&nbsp;817) (Pinteraction&nbsp;=&nbsp;0.99), but differed by sex (Pinteraction&nbsp;=&nbsp;0.019). In males, the HRs for the association of aforementioned BMI categories with 3-month mortality were 2.07 (95% CI: 1.22, 3.52), 1 (ref.), 0.97 (95% CI: 0.78. 1.21), 0.99 (95% CI: 0.74, 1.33) and 1.22 (95% CI: 0.78, 1.91), respectively, and in females corresponding HRs were 1.34 (95% CI: 0.70, 2.57), 1 (ref.), 1.31 (95% CI: 0.94, 1.85), 1.54 (95% CI: 1.05, 2.26) and 2.49 (95% CI: 1.62, 3.84), respectively.ConclusionIn KFRT patients with COVID-19, on dialysis or a kidney transplant, obesity is associated with an increased risk of mortality at 3 months. This is in contrast to the obesity paradox generally observed in dialysis patients. Additional studies are required to corroborate the sex difference in the association of obesity with mortality

Epigenetic modulation of neuroblastoma enhances T cell and NK cell immunogenicity by inducing a tumor-cell lineage switch

Background Immunotherapy in high-risk neuroblastoma (HR-NBL) does not live up to its full potential due to inadequate (adaptive) immune engagement caused by the extensive immunomodulatory capacity of HR-NBL. We aimed to tackle one of the most notable immunomodulatory processes in neuroblastoma (NBL), absence of major histocompatibility complex class I (MHC-I) surface expression, a process greatly limiting cytotoxic T cell engagement. We and others have previously shown that MHC-I expression can be induced by cytokine-driven immune modulation. Here, we aimed to identify tolerable pharmacological repurposing strategies to upregulate MHC-I expression and therewith enhance T cell immunogenicity in NBL.Methods Drug repurposing libraries were screened to identify compounds enhancing MHC-I surface expression in NBL cells using high-throughput flow cytometry analyses optimized for adherent cells. The effect of positive hits was confirmed in a panel of NBL cell lines and patient-derived organoids. Compound-treated NBL cell lines and organoids were cocultured with preferentially expressed antigen of melanoma (PRAME)-reactive tumor-specific T cells and healthy-donor natural killer (NK) cells to determine the in vitro effect on T cell and NK cell cytotoxicity. Additional immunomodulatory effects of histone deacetylase inhibitors (HDACi) were identified by transcriptome and translatome analysis of treated organoids.Results Drug library screening revealed MHC-I upregulation by inhibitor of apoptosis inhibitor (IAPi)- and HDACi drug classes. The effect of IAPi was limited due to repression of nuclear factor kappa B (NFκB) pathway activity in NBL, while the MHC-I-modulating effect of HDACi was widely translatable to a panel of NBL cell lines and patient-derived organoids. Pretreatment of NBL cells with the HDACi entinostat enhanced the cytotoxic capacity of tumor-specific T cells against NBL in vitro, which coincided with increased expression of additional players regulating T cell cytotoxicity (eg, TAP1/2 and immunoproteasome subunits). Moreover, MICA and MICB, important in NK cell cytotoxicity, were also increased by entinostat exposure. Intriguingly, this increase in immunogenicity was accompanied by a shift toward a more mesenchymal NBL cell lineage.Conclusions This study indicates the potential of combining (immuno)therapy with HDACi to enhance both T cell-driven and NKcell-driven immune responses in patients with HR-NBL

Association of obesity with 3-month mortality in kidney failure patients with COVID-19

In the general population with coronavirus disease 2019 (COVID-19), obesity is associated with an increased risk of mortality. Given the typically observed obesity paradox among patients on kidney function replacement therapy (KFRT), especially dialysis patients, we examined the association of obesity with mortality among dialysis patients or living with a kidney transplant with COVID-1