Diffuse Large B Cell Lymphoma: A Single Centre Study.

BACKGROUND : Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphoma with variation in patient survival. Information regarding clinical presentation, staging, prognostic determinant (biological [GCB, non-GCB] and clinical[IPI]), and response to chemotherapy (CHOP and Rituximab CHOP) in exclusively nodal cases of DLBCL is limited. AIMS AND OBJECTIVES: To analyse the response to chemotherapy (CHOP and Rituximab CHOP) and to access the prognostic significance of IPI and biological subgrouping of nodal DLBCL cases in our institution. METHODS : All patients with nodal DLBCL cases who underwent treatment with minimum six months follow up in the Department of Haematology between January 2006 and April 2010 and whose slides and blocks could be retrieved from Department of Pathology were included in the study. RESULTS: Of the 106 patients, 71(67%) male and 78(73.6%) patients were <60 years of age. 72(67.9%) presented with B-symptoms, 62(58.5%) had stage III/IV, and 80(75.5%) had high LDH at diagnosis. 22(20.8%) had one or more extra-nodal disease and 21(19.8%) had bulk disease. Out of 106 patients 66(62.2%) were in low IPI risk (0,1,2) and 40(37.7%) were in high IPI risk(3,4,5). Based on immune-histochemistry(Hanset.al) we classified 43(40.5%)patients as GCB DLBCL and 63(59.4%) as non-GCB DLBCL. The clinical characteristics of patients in sub groups were similar.The CR+CRu was 88% in Rituximab vs 70.9%% in non-Rituximab treated patients at the end of six cycles of chemotherapy (p=0.082). After a median follow up of 36 months (range:6-44months in RCHOP and 6-42 months in CHOP),the three year cumulative relapse free survival(RFS) and overall survival(OS) was 56.4% and 74.5% respectively in those who received CHOP chemotherapy. The addition of Rituximab improved the cumulative RFS and OS to 86.3% and 76.5% respectively, though the difference was not significant. Addition of Rituximab in high IPI risk group patients, improve EFS and OS at 24 months to 74.9% and 83.3% vs 19.8% and 41.5% in CHOP group(p=0.002). Rituximab treated patients in either GCB or non-GCB subgroup had similar EFS and cumulative RFS at median follow up of 24 months in comparison to non-Rituximab patients. In GCB group of patients the Rituximab significantly improves the OS (89.1%vs50.3%) at median follow up of 24 months (p=0.02). Neutropenia with or without fever was the most common chemotherapy related complication and was significantly more in RCHOP patients 68.6% vs 47.3% (p=0.032). CONCLUSION : This is the largest series of patients with DLBCL comprehensively evaluated and analyzed for outcome after treatment with CHOP and RCHOP. Patients were classified into low and high IPI risk group as well GCB and non-GCB origin of their disease. Addition of Rituximab has significant advantage in GCB and high IPI risk subgroups. In non-GCB and IPI low risk sub group, Rituximab increases relapse free survival but not the overall survival. Further analysis needs to be done with more number of patients and longer follow-up to truly understand the trend observed in this study for patients in India

Markers of cognitive function in individuals with metabolic disease: Morquio Syndrome and Tyrosinemia Type III

We characterized cognitive function in two metabolic diseases. MPS–IVa (mucopolysaccharidosis IVa, Morquio) and tyrosinemia type III individuals were assessed using tasks of attention, language and oculomotor function. MPS–IVa individuals were slower in visual search, but the display size effects were normal, and slowing was not due to long reaction times (ruling out slow item processing or distraction). Maintaining gaze in an oculomotor task was difficult. Results implicated sustained attention and task initiation or response processing. Shifting attention, accumulating evidence and selecting targets were unaffected. Visual search was also slowed in tyrosinemia type III, and patterns in visual search and fixation tasks pointed to sustained attention impairments, although there were differences from MPS–IVa. Language was impaired in tyrosinemia type III but not MPS–IVa. Metabolic diseases produced selective cognitive effects. Our results, incorporating new methods for developmental data and model selection, illustrate how cognitive data can contribute to understanding function in biochemical brain systems

An observational, prospective, multicenter, natural history study of patients with mucopolysaccharidosis type IIIA

Mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome) is a rare genetic lysosomal storage disease characterized by early and progressive neurodegeneration resulting in a rapid decline in cognitive function affecting speech and language, adaptive behavior, and motor skills. We carried out a prospective observational study to assess the natural history of patients with MPS IIIA, using both standardized tests and patientcentric measures to determine the course of disease progression over a 2-year period. A cohort of 23 patients (7 girls, 16 boys; mean age 28–105 months at baseline) with a confirmed diagnosis of MPS IIIA were assessed and followed up at intervals of 3–6 months; cognitive function was measured using Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III) to derive cognitive development quotients (DQ). Daily living, speech/ language development and motor skills were measured using the Vineland Adaptive Behavior Scale (VABS-II). Sleep–wake patterns, behavior and quality-of-life questionnaires were also reported at each visit using parent/ caregiver reported outcome tools. All patients had early onset severe MPS IIIA, were diagnosed before 74 months of age, and had cognitive scores below normal developmental levels at baseline. Patients less than 40 months of age at baseline were more likely to continue developing new skills over the first 6–12 months of follow-up. There was a high variability in cognitive developmental age (DA) in patients between 40 and 70 months of age; twothirds of these patients already had profound cognitive decline, with a DA ≤10 months. The highest cognitive DA achieved in the full study cohort was 34 months. Post hoc, patients were divided into two groups based on baseline cognitive DQ (DQ ≥50 or <50). Cognitive DQ decreased linearly over time, with a decrease from baseline of 30.1 and 9.0 points in patients with cognitive DQ ≥50 at baseline and cognitive DQ <50 at baseline, respectively. Over the 2-year study, VABS-II language scores declined progressively. Motor skills, including walking, declined over time, although significantly later than cognitive decline. No clear pattern of sleep disturbance was observed, but night waking was common in younger patients. Pain scores, as measured on the quality-of-life questionnaire, increased over the study period. The findings of this study strengthen the natural history data on cognitive decline in MPS IIIA and importantly provide additional data on endpoints, validated by the patient community as important to treat, that may form the basis of a multidomain endpoint capturing the disease complexity

MR spectroscopy-based brain metabolite profiling in propionic acidaemia: metabolic changes in the basal ganglia during acute decompensation and effect of liver transplantation

Background: Propionic acidaemia (PA) results from deficiency of Propionyl CoA carboxylase, the commonest form presenting in the neonatal period. Despite best current management, PA is associated with severe neurological sequelae, in particular movement disorders resulting from basal ganglia infarction, although the pathogenesis remains poorly understood. The role of liver transplantation remains controversial but may confer some neuro-protection. The present study utilises quantitative magnetic resonance spectroscopy (MRS) to investigate brain metabolite alterations in propionic acidaemia during metabolic stability and acute encephalopathic episodes.Methods: Quantitative MRS was used to evaluate brain metabolites in eight children with neonatal onset propionic acidaemia, with six elective studies acquired during metabolic stability and five studies during acute encephalopathic episodes. MRS studies were acquired concurrently with clinically indicated MR imaging studies at 1.5 Tesla. LCModel software was used to provide metabolite quantification. Comparison was made with a dataset of MRS metabolite concentrations from a cohort of children with normal appearing MR imaging.Results: MRI findings confirm the vulnerability of basal ganglia to infarction during acute encephalopathy. We identified statistically significant decreases in basal ganglia glutamate+glutamine and N-Acetylaspartate, and increase in lactate, during encephalopathic episodes. In white matter lactate was significantly elevated but other metabolites not significantly altered. Metabolite data from two children who had received liver transplantation were not significantly different from the comparator group.Conclusions: The metabolite alterations seen in propionic acidaemia in the basal ganglia during acute encephalopathy reflect loss of viable neurons, and a switch to anaerobic respiration. The decrease in glutamine + glutamate supports the hypothesis that they are consumed to replenish a compromised Krebs cycle and that this is a marker of compromised aerobic respiration within brain tissue. Thus there is a need for improved brain protective strategies during acute metabolic decompensations. MRS provides a non-invasive tool for which could be employed to evaluate novel treatments aimed at restoring basal ganglia homeostasis. The results from the liver transplantation sub-group supports the hypothesis that liver transplantation provides systemic metabolic stability by providing a hepatic pool of functional propionyl CoA carboxylase, thus preventing further acute decompensations which are associated with the risk of brain infarction

In-depth phenotyping for clinical stratification of Gaucher disease.

BackgroundThe Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study.ResultsAt baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery.ConclusionGaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria

Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study

Ornithine transcarbamylase deficiency (OTCD) is an X-linked defect of ureagenesis and the most common urea cycle disorder. Patients present with hyperammonemia causing neurological symptoms, which can lead to coma and death. Liver transplantation (LT) is the only curative therapy, but has several limitations including organ shortage, significant morbidity and requirement of lifelong immunosuppression. This study aims to identify the characteristics and outcomes of patients who underwent LT for OTCD. // We conducted a retrospective study for OTCD patients from 5 UK centres receiving LT in 3 transplantation centres between 2010 and 2022. Patients' demographics, family history, initial presentation, age at LT, graft type and pre- and post-LT clinical, metabolic, and neurocognitive profile were collected from medical records.// A total of 20 OTCD patients (11 males, 9 females) were enrolled in this study. 6/20 had neonatal and 14/20 late-onset presentation. 2/20 patients had positive family history for OTCD and one of them was diagnosed antenatally and received prospective treatment. All patients were managed with standard of care based on protein-restricted diet, ammonia scavengers and supplementation with arginine and/or citrulline before LT. 15/20 patients had neurodevelopmental problems before LT. The indication for LT was presence (or family history) of recurrent metabolic decompensations occurring despite standard medical therapy leading to neurodisability and quality of life impairment. Median age at LT was 10.5 months (6–24) and 66 months (35–156) in neonatal and late onset patients, respectively. 15/20 patients had deceased donor LT (DDLT) and 5/20 had living related donor LT (LDLT). Overall survival was 95% with one patient dying 6 h after LT. 13/20 had complications after LT and 2/20 patients required re-transplantation. All patients discontinued dietary restriction and ammonia scavengers after LT and remained metabolically stable. Patients who had neurodevelopmental problems before LT persisted to have difficulties after LT. 1/5 patients who was reported to have normal neurodevelopment before LT developed behavioural problems after LT, while the remaining 4 maintained their abilities without any reported issues. // LT was found to be effective in correcting the metabolic defect, eliminates the risk of hyperammonemia and prolongs patients' survival

Management of B-cell lineage acute lymphoblastic leukemia: expert opinion from an Indian panel via Delphi consensus method

IntroductionCurrently, there are no guidelines for the management of B-cell lineage acute lymphoblastic leukemia (B-ALL) from an Indian perspective. The diagnostic workup, monitoring, and treatment of B-ALL vary among different physicians and institutes.ObjectiveTo develop evidence-based practical consensus recommendations for the management of B-ALL in Indian settings.MethodsModified Delphi consensus methodology was considered to arrive at a consensus. An expert scientific committee of 15 experts from India constituted the panel. Clinically relevant questions belonging to three major domains were drafted for presentation and discussion: (i) diagnosis and risk assignment; (ii) frontline treatment; and (iii) choice of therapy (optimal vs. real-world practice) in relapsed/refractory (R/R) settings. The questionnaire was shared with the panel members through an online survey platform. The level of consensus was categorized into high (≥ 80%), moderate (60%–79%), and no consensus (&lt; 60%). The process involved 2 rounds of discussion and 3 rounds of Delphi survey. The questions that received near or no consensus were discussed during virtual meetings (Delphi rounds 1 and 2). The final draft of the consensus was emailed to the panel for final review.ResultsExperts recommended morphologic assessment of peripheral blood or bone marrow, flow cytometric immunophenotyping, and conventional cytogenetic analysis in the initial diagnostic workup. Berlin–Frankfurt–Münster (BFM)–based protocol is the preferred frontline therapy in pediatric and adolescent and young adult patients with B-ALL. BFM/German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia–based regimen is suggested in adult patients with B-ALL. Immunotherapy (blinatumomab or inotuzumab ozogamicin) followed by allogeneic hematopoietic cell transplantation (allo-HCT) is the optimal choice of therapy that would yield the best outcomes if offered in the first salvage in patients with R/R B-ALL. In patients with financial constraints or prior allo-HCT (real-world practice) at first relapse, standard-intensive chemotherapy followed by allo-HCT may be considered. For subsequent relapses, chimeric antigen receptor T-cell therapy or palliative care was suggested as the optimal choice of therapy.ConclusionThis expert consensus will offer guidance to oncologists/clinicians on the management of B-ALL in Indian settings