Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme.

CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2-74.2%) and 46.5% (95%CI 37.6-57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1-44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3-75.8) and 55.3% (95%CI 43.6-70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival.

Practice guideline: Preparation for CAR T-cell therapy in children and young adults with B-acute lymphoblastic leukaemia.

The objective of this guideline, prepared by the ALL subgroup of the Advanced Cell Therapy Sub-Committee of BSBMTCT (British Society of Blood and Marrow Transplantation), is to provide healthcare professionals with practical guidance on the preparation of children and young adults with B-acute lymphoblastic leukaemia from the point of referral to that of admission for CAR T-cell treatment. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate the levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org.

Management of ALL in adults: 2024 ELN recommendations from a European expert panel.

ABSTRACT: Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups.

Paediatric syndromic scoliosis: proceedings of the half-day course at the 57th annual meeting of the Scoliosis Research Society.

There are some syndromes that present with unique manifestations pertaining to the spinal column. A good working understanding of these common syndromes is useful for the spinal deformity surgeons and related healthcare providers. This review attempts to encompass these unique features and discuss them in three broad groups: hypermobility syndromes, muscle pathology-related syndromes, and syndromes related to poor bone quality. This review explores the features of these syndromes underpinning the aspects of surgical and medical management. This review represents the proceedings of the Paediatric Half-Day Course at the 57th Annual Meeting of the Scoliosis Research Society.

Diagnosis, prognostic factors, and assessment of ALL in adults: 2024 ELN recommendations from a European expert panel.

ABSTRACT: Working groups of the European LeukemiaNet have published several important consensus guidelines. Acute lymphoblastic leukemia (ALL) has many different clinical and biological subgroups and the knowledge on disease biology and therapeutic options is increasing exponentially. The European Working Group for Adult ALL has therefore summarized the current state of the art and provided comprehensive consensus recommendations for diagnostic approaches, biologic and clinical characterization, prognostic factors, and risk stratification as well as definitions of endpoints and outcomes. Aspects of treatment, management of subgroups and specific situations, aftercare, and supportive care are covered in a separate publication. The present recommendation intends to provide guidance for the initial management of adult patients with ALL and to define principles as a basis for future collaborative research.

Does intervertebral disc degeneration in adolescent idiopathic scoliosis correlate with patient-reported pain scores? A review of 968 cases.

PURPOSE: Report the rate and severity of degenerative disc disease (DDD) in non-surgical adolescent idiopathic scoliosis (AIS) patients and correlate these findings with patient-reported symptomatology scores. Additionally, to quantify the rate of concurrent pathological radiological findings in this group. METHODS: This was a retrospective chart review study at a single tertiary centre. AIS patients aged 10-16 who had received a whole spine MRI between September 2007 and January 2019 and who had not received surgical intervention to their spine were included. MRI scan reports were screened to extract those who had evidence of DDD. These were then reviewed by a blinded second reviewer who graded every disc using the Pfirrmann grading system. SRS-22 scores were extracted for patients when available. RESULTS: In total, 968 participants were included in the study. Of these, 93 (9.6%) had evidence of DDD, which was Pfirrmann grade ≥ 3 in 28 (2.9%). The most commonly affected level was L5/S1 (59.1% of DDD cases). A total of 55 patients (5.7%) had evidence of syringomyelia, 41 (3.4%) had evidence of spondylolisthesis (all L5/S1), 14 (1.4%) had bilateral L5 pars defects, and 5 (0.5%) had facet joint degeneration. Spondylolisthesis and bilateral pars defects were more common in patients with DDD identified on MRI scan (p < 0.001 and p = 0.04, respectively). Function (p = 0.048) and pain (p = 0.046) scores were worse in patients with DDD. CONCLUSION: We present a baseline for the rate and severity of DDD in the non-operative AIS cohort. This should assist in decision-making and counselling of patients prior to surgery. LEVEL OF EVIDENCE: III.

Homeostasis Theory of Well-being.

The Homeostasis Theory of Well-being proposes a homeostatic modular system for the creation of human well-being. This article aims to: (i) provide a proof-of-concept demonstration of the feasibility of the theory in its biopsychosocial context; (ii) indicate prima facie empirical support for the homeostatic nature of the 16 proposed modules; (iii) discuss the similarities to and differences from other homeostasis theories of well-being. Following the Central Limit Theorem, any homeostatic system with multiple inputs produces outputs with a Gaussian distribution. The data-base of studies contains approximately 2000 publications reporting U- or inverse U-shaped curves for the 16 homeostatic domains specified in the theory. The Homeostasis Theory of Well-being remains speculative and requires controlled longitudinal study to determine the scientific validity of the causal network proposed by the theory. The theory has implications for our understanding of humans' drive for balance, equilibrium and stability in this increasingly uncertain world.

Defining and 'diagnosing' aphantasia: Condition or individual difference?

Research into the newly-coined 'condition' of 'aphantasia', an individual difference involving the self-reported absence of voluntary visual imagery, has taken off in recent years, and more and more people are 'self-diagnosing' as aphantasic. Yet, there is no consensus on whether aphantasia should really be described as a 'condition', and there is no battery of psychometric instruments to detect or 'diagnose' aphantasia. Instead, researchers currently rely on the Vividness of Visual Imagery Questionnaire (VVIQ) to 'diagnose' aphantasia. We review here fundamental and methodological problems affecting aphantasia research stemming from an inadequate focus on how we should define aphantasia, whether aphantasia is a pathological condition, and the extensive use of VVIQ as a 'diagnostic test' for aphantasia. Firstly, we draw attention to 'literature blindness' for visual imagery research from the 1960s-1990s concerning individual differences in visual imagery vividness. Secondly, despite aphantasia being defined as a 'condition' where voluntary visual imagery is absent as indicated by the lowest score on the VVIQ, aphantasia studies inconsistently employ samples comprised of a mixture of participants with no visual imagery and low visual imagery, and we argue that this hinders the uncovering of the underlying cause of aphantasia. Thirdly, the scores used to designate the boundary between aphantasia and non-aphantasia are arbitrary and differ between studies, compromising the possibility for cross-study comparison of results. Fourthly, the problems of 'diagnosing' aphantasia are not limited to the academic sphere, as one can 'self-diagnose' online, for example by using the variant-VVIQ on the Aphantasia Network website. However, the variant-VVIQ departs from the original in ways likely to impact validity and accuracy, which could lead people to falsely believe they have been 'diagnosed' with aphantasia by a scientifically-validated measure. Fifthly, we discuss the hypothesis that people who believe they have been 'diagnosed' with aphantasia might be vulnerable to health anxiety, distress, and stigma. We conclude with a discussion about some fundamental aspects of how to classify a disorder, and suggest the need for a new psychometric measure of aphantasia.

Phenomenological Studies of Visual Mental Imagery: A Review and Synthesis of Historical Datasets.

This article reviews historically significant phenomenological studies of visual mental imagery (VMI), starting with Fechner in 1860 and continuing to the present. This synthesis of diverse VMI phenomenological studies in healthy adults serves as a unique resource for investigators of individual differences, cognitive development and clinical and neurological conditions. The review focuses on two kinds of VMI, "memory imagery" and "eidetic imagery". Ten primary studies are drawn from three periods of the scholarly literature: early (1860-1929), middle (1930-1999) and recent (2000-2023). It is concluded that memory and eidetic imagery are two forms of constructive imagery, varying along a continuum of intensity or vividness. Vividness is a combination of clarity, colourfulness and liveliness, where clarity is defined by brightness and sharpness, colourfulness by image saturation and liveliness by vivacity, animation, feeling, solidity, projection and metamorphosis. The findings are integrated in a template that specifies, as a tree-like structure, the 16 properties of VMI vividness in healthy adult humans. The template takes into account the weight of evidence drawn from the accounts and reveals an extraordinary degree of consistency in reported VMI characteristics, revealed by specialized studies of healthy adult humans across time, space and culture.

Younger Matched Unrelated Donors Confer Decreased Relapse Risk Compared to Older Sibling Donors in Older Patients with B Cell Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

Although allogeneic hematopoietic cell transplantation (alloHCT) offers cure for older patients with acute lymphoblastic leukemia (ALL), disease relapse remains a major issue. Whether matched sibling donors (MSDs) are still the preferred donor choice compared to younger matched unrelated donors (MUDs) in the contemporary era of improved transplantation practices remains unknown. This retrospective cohort registry study queried the Center for International Blood and Marrow Transplant Research (CIBMTR) database in patients with B cell ALL (B-ALL) age ≥ 50 years undergoing alloHCT from older MSDs (age ≥ 50 years) or younger MUDs (age ≤ 35 years) between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft-versus-host disease (GVHD) prophylaxis strategies. The primary outcome was relapse risk, and secondary outcomes included nonrelapse mortality (NRM), GVHD, leukemia-free survival (LFS), and overall survival (OS). Among 925 eligible patients in the study cohort, 386 underwent alloHCT with an older MSD (median donor age, 58 years) and 539 underwent alloHCT from a younger MUD (median donor age, 25 year). In multivariable analysis, younger MUDs conferred a significantly decreased risk of relapse (hazard ratio [HR], .68; P = .002) compared with older MSDs. The adjusted cumulative incidence of relapse at 5 years was significantly lower with younger MUDs than with older MSDs (26% versus 37%; P = .001). Younger MUDs were associated with a greater risk of chronic GVHD compared to older MSDs (HR, 1.33; 95% confidence interval [CI], 1.10 to 1.61; P = .003). Compared to older MSDs, younger MUDs conferred an increased NRM (HR, 1.38; P = .02) and higher adjusted cumulative incidence of NRM at 5 years (31% versus 22%; P = .006). There were no differences in post-alloHCT OS or LFS rates between younger MUDs and older MSDs (OS: HR, 1.09; [P = .37]; LFS: HR, .95 [P = .57]). The use of younger MUDs could be considered as a possible way to prevent relapse after alloHCT in older adults with ALL. Combining the use of younger MUDs with improved strategies to reduce GVHD merits further exploration to improve outcomes.

ALL-RIC trial protocol: a comparison of reduced dose total body irradiation (TBI) and cyclophosphamide with fludarabine and melphalan reduced intensity conditioning in adults with acute lymphoblastic leukaemia (ALL) in complete remission.

INTRODUCTION: The usage of a T-cell depleted, reduced intensity conditioning (RIC) approach to haematopoietic cell transplantation (HCT) in adult patients with acute lymphoblastic leukaemia (ALL) over 40 years of age and in first complete remission (CR) has resulted in encouraging rates of event-free and overall survival in a population of adults with high risk disease. However, relapse rates remain high-with disease progression being the major cause of treatment failure. Using different, more powerful conditioning approaches is the logical next step in examining the role of RIC allogeneic HCT in adult ALL. METHODS AND ANALYSIS: The ALL-RIC trial is a two-arm, phase II, multicentre, randomised clinical trial in adult patients with ALL in first or second CR, who are undergoing allogeneic HCT. Comparison of a novel RIC transplant conditioning regimen using reduced-dose total body irradiation (TBI), cyclophosphamide and alemtuzumab, is made against a standardised RIC approach using fludarabine, melphalan and alemtuzumab. The primary outcome of the study is disease-free survival at 3 years, defined as time from randomisation to the first of either relapse or death from any cause. Patients who are still alive and progression-free at the end of the trial will be censored at their last date known to be alive. Secondary outcomes include overall survival and non-relapse mortality. ETHICS AND DISSEMINATION: The protocol was approved by the East Midlands-Leicester Central Research Ethics committee (18/EM/0112). Initial approval was received on 12 June 2018. Current protocol version (V.6.0) approval obtained on 18 November 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: EudraCT Number: 2017-004800-23.ISRCTN99927695.

A simple prognostic system in patients with myelofibrosis undergoing allogeneic stem cell transplantation: a CIBMTR/EBMT analysis.

To develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.

Systematic Review and Meta-analysis: Does Anterior-Posterior Spinal Fusion Still have a Role in Severe Thoracic Adolescent Idiopathic Scoliosis?

Background: Debate exists as to whether anterior-posterior spinal fusion (APSF), rather than posterior-only spinal fusion (PSF), provides benefit for treating severe thoracic adolescent idiopathic scoliosis (AIS). This systematic review and meta-analysis compare (1) Cobb angle correction, (2) complication and reoperation rate, (3) pulmonary function, (4) number of fused segments, and 5) patient-reported outcome measures (PROMs) in both groups. Methods: Electronic databases were searched to identify studies that met the following inclusion criteria: comparative studies (level 3 or above), severe thoracic curves (≥ 70°), age ≤ 16, AIS aetiology, Lenke 1-4 curves and follow-up ≥ 1 year for ≥ 95% of patient population. Literature was graded for quality and bias using GRADE and MINORS criteria. Results: Eight studies were included, defined by GRADE as low or moderate level evidence. Three studies showed superior curve correction in the APSF group; however, the meta-analysis showed no significant difference in curve correction between groups (95% CI - 3.45-12.96, P = 0.26). There were more complications in the APSF group, without statistical significance (95% CI 0.53-3.39, P = 0.54; I 2 = 0%, P = 0.78). There were no re-operations in either group. Two studies reported pulmonary function; one showed better function in the APSF group, the other better function in the PSF group. One study showed fewer fused segments in the APSF group, however, no significance was observed in the meta-analysis (95%CI - 1.65-0.31, P = 0.18). Three studies reported PROMs with no differences reported between groups. Conclusions: APSF and PSF have been found to have comparable results. The present evidence cannot support recommendations for guidelines on future practice with regards to effect on curve correction, complications, re-operations, pulmonary function or PROMs. Level of evidence: Level III, Systematic review of Level-III studies.

The Action Cycle Theory of Perception and Mental Imagery.

The Action Cycle Theory (ACT) is an enactive theory of the perception and a mental imagery system that is comprised of six modules: Schemata, Objects, Actions, Affect, Goals and Others' Behavior. The evidence supporting these six connected modules is reviewed in light of research on mental imagery vividness. The six modules and their interconnections receive empirical support from a wide range of studies. All six modules of perception and mental imagery are influenced by individual differences in vividness. Real-world applications of ACT show interesting potential to improve human wellbeing in both healthy people and patients. Mental imagery can be applied in creative ways to make new collective goals and actions for change that are necessary to maximize the future prospects of the planet.

Converging Evidence of Similar Symptomatology of ME/CFS and PASC Indicating Multisystemic Dyshomeostasis.

The purpose of this article is to review the evidence of similar symptomatology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-acute sequelae of SARS-CoV-2 infection (PASC). Reanalysis of data from a study by Jason comparing symptom reports from two groups of ME/CFS and PASC patients shows a notably similar symptomatology. Symptom scores of the PASC group and the ME/CFS group correlated 0.902 (p < 0.0001) across items. The hypothesis is presented that ME/CFS and PASC are caused by a chronic state of multisystemic disequilibrium including endocrinological, immunological, and/or metabolic changes. The hypothesis holds that a changed set point persistently pushes the organism towards a pathological dysfunctional state which fails to reset. To use an analogy of a thermostat, if the 'off switch' of a thermostat intermittently stops working, for periods the house would become warmer and warmer without limit. The hypothesis draws on recent investigations of the Central Homeostasis Network showing multiple interconnections between the autonomic system, central nervous system, and brain stem. The hypothesis helps to explain the shared symptomatology of ME/CFS and PASC and the unpredictable, intermittent, and fluctuating pattern of symptoms of ME/CFS and PASC. The current theoretical approach remains speculative and requires in-depth investigation before any definite conclusions can be drawn.

Patient-specific 3D printing to replace components of a rib-to pelvis "Eiffel Tower" vertebral expanding prosthetic titanium rib system in an infant: a case report.

PURPOSE: To address the anatomical challenges facing complex and revision spinal surgery, patient-specific 3D-printed models (3D-PMs) have received growing attention worldwide, primarily in adults. We report the use of a 3D-PM in the treatment of a case of wound breakdown over a component of a VEPTR (Vertical Expandable Prosthetic Titanium Rib; DePuy-Synthes) system, requiring replacement of Dunn-McCarthy hook and sleeve with components contoured to a patient-specific 3D-PM of the spine. METHOD: A two-year-old born with myelomeningocele (MMC), repaired at birth, developed progressive MMC-associated kyphoscoliosis. Elective insertion of a rib-to-pelvis 'Eiffel Tower' bilateral VEPTR growing rods construct was performed without initial complication. Prominence of the right VEPTR sleeve and Dunn-McCarthy hook side-to-side connector resulted in breakdown of overlying poor-quality soft tissues, necessitating washout, partial implant removal, intravenous antibiotic therapy and delayed primary wound closure. A patient-specific 3D-PM, utilising pre-operative CT spine and pelvis 3D-reconstructions, allowed pre-operative formation of a contoured implant, which was inserted without need for further revision. RESULTS: The patient underwent further VEPTR lengthening without recurrent infection, wound breakdown or implant failure at 24-month follow-up. Satisfactory control of the deformity has been achieved with continued improvement in sitting height and radiographic indices. CONCLUSION: This case illustrates the possibility, in certain cases, of using 3D-PM to develop complex components of spinal implant systems pre-operatively, removing the time and difficulty of intra-operative contouring. Consequently, custom-contoured implants may be produced, sterilised and implanted. This technique may be an option, in infants, including MMC-associated kyphoscoliosis, where midline fixation is not possible.

Prospective multiparametric CMR characterization and MicroRNA profiling of anthracycline cardiotoxicity: A pilot translational study.

Background: Anthracycline cardiotoxicity is a significant clinical challenge. Biomarkers to improve risk stratification and identify early cardiac injury are required. Objectives: The purpose of this pilot study was to prospectively characterize anthracycline cardiotoxicity using cardiovascular magnetic resonance (CMR), echocardiography and MicroRNAs (MiRNAs), and identify baseline predictors of LVEF recovery. Methods: Twenty-four patients (age 56 range 18-75 years; 42 % female) with haematological malignancy scheduled to receive anthracycline chemotherapy (median dose 272 mg/m2 doxorubicin equivalent) were recruited and evaluated at three timepoints (baseline, completion of chemotherapy, and 6 months after completion of chemotherapy) with multiparametric 1.5 T CMR, echocardiography and circulating miRNAs sequencing. Results: Seventeen complete datasets were obtained. CMR left ventricular ejection fraction (LVEF) fell significantly between baseline and completion of chemotherapy (61 ± 3 vs 53 ± 3 %, p < 0.001), before recovering significantly at 6-month follow-up (55 ± 3 %, p = 0.018). Similar results were observed for 3D echocardiography-derived LVEF and CMR-derived longitudinal, circumferential and radial feature-tracking strain. Patients were divided into tertiles according to LVEF recovery (poor recovery, partial recovery, good recovery). CMR-derived mitral annular plane systolic excursion (MAPSE) was significantly different at baseline in patients exhibiting poor LVEF recovery (11.7 ± 1.5 mm) in comparison to partial recovery (13.7 ± 2.7 mm), and good recovery (15.7 ± 3.1 mm; p = 0.028). Furthermore, baseline miRNA-181-5p and miRNA-221-3p expression were significantly higher in this group. T2 mapping increased significantly on completion of chemotherapy compared to baseline (54.0 ± 4.6 to 57.8 ± 4.9 ms, p = 0.001), but was not predictive of LVEF recovery. No changes to LV mass, extracellular volume fraction, T1 mapping or late gadolinium enhancement were observed. Conclusions: Baseline CMR-derived MAPSE, circulating miRNA-181-5p, and miRNA-221-3p were associated with poor recovery of LVEF 6 months after completion of anthracycline chemotherapy, suggesting their potential predictive role in this context. T2 mapping increased significantly on completion of chemotherapy but was not predictive of LVEF recovery.

Culture media composition influences patient-derived organoid ability to predict therapeutic responses in gastrointestinal cancers.

BACKGROUNDA patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO's ability to predict clinical response to gastrointestinal (GI) cancers.METHODSWe generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments.RESULTSWe report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures.CONCLUSIONWhile we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.TRIAL REGISTRATIONNot applicable.FUNDINGThe Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research, GI Cancer program of the Mayo Clinic Cancer Center, Mayo Clinic SPORE in Pancreatic Cancer, Center of Individualized Medicine (Mayo Clinic), Department of Laboratory Medicine and Pathology (Mayo Clinic), Incyte Pharmaceuticals and Mayo Clinic Hepatobiliary SPORE, University of Minnesota-Mayo Clinic Partnership, and the Early Therapeutic program (Department of Oncology, Mayo Clinic).

Role of Intracellular Amyloid ß as Pathway Modulator, Biomarker, and Therapy Target.

The ß- and γ-secretase-driven cleavage of the amyloid precursor protein (APP) gives rise to the amyloid ß peptide, which is believed to be the main driver of neurodegeneration in Alzheimer's disease (AD). As it is prominently detectable in extracellular plaques in post-mortem AD brain samples, research in recent decades focused on the pathological role of extracellular amyloid ß aggregation, widely neglecting the potential meaning of very early generation of amyloid ß inside the cell. In the last few years, the importance of intracellular amyloid ß (iAß) as a strong player in neurodegeneration has been indicated by a rising number of studies. In this review, iAß is highlighted as a crucial APP cleavage fragment, able to manipulate intracellular pathways and foster neurodegeneration. We demonstrate its relevance as a pathological marker and shed light on initial studies aiming to modulate iAß through pharmacological treatment, which has been shown to have beneficial effects on cognitive properties in animal models. Finally, we display the relevance of viral infections on iAß generation and point out future directions urgently needed to manifest the potential relevance of iAß in Alzheimer's disease.