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Management of Intraocular Retinoblastoma: ICMR Consensus Guidelines
No full textRetinoblastoma (RB) is the most common childhood intraocular malignancy. Delayed presentation due to a lack of awareness and advanced intraocular tumors are a common scenario in low-middle income countries (LMICs). Remarkable treatment advances have been made in the past few decades allowing globe salvage in advanced intraocular RB (IORB) including systemic chemotherapy with focal consolidation and targeted treatments like intraarterial chemotherapy and intravitreal chemotherapy. However, a lack of availability and affordability limits the use of such advances in LMICs. External beam radiotherapy, despite risk of second cancers in RB with germline mutations, still remains useful for recalcitrant RB not responding to any other treatment. When choosing conservative treatment for advanced IORB, the cost and long duration of treatment, morbidity from multiple evaluation under anesthesias (EUAs), side effects of treatment and risk of treatment failure need to be taken into account and discussed with the parents. In this article, the authors discuss the ICMR consensus guidelines on the management of IORB
Helical superstructures from the hierarchical self-assembly of coil–coil block copolymer guided by side chain amyloid-β(17–19) lvf peptide.
No full textThe rational design of precisely controlled hierarchical chiral nanostructures from synthetic polymers garnered inspiration from sophisticated biological materials. Since chiral peptide motifs induce helix formation in macromolecules, herein we report the synthesis of a novel type of hybrid polymer consisting of a β-sheet forming a LVF [L = leucine, V = valine, and F = phenylalanine] tripeptide pendant polymethacrylate block and a poly[poly(ethylene glycol) methyl ether methacrylate] (PPEGMA) block. The designed block copolymer self-organized into helical superstructures with a left-handed twisting sense, as visualized by field emission scanning electron microscopy, transmission electron microscopy, and atomic force microscopy. This intriguing hierarchical self-assembly is driven by the minimalistic peptide motif that itself has a high propensity to adopt an antiparallel β-sheet conformation. We also report the generation of a diverse array of nanostructures, including spherical micelles, spindle micelles, rod-like micelles, vesicles, helical supramolecular fibers, and helical toroids via self-assembly of the designed block copolymer in tetrahydrofuran/water mixed solvents. To realize the observable helical superstructure, a twisted two-dimensional core–shell tape is proposed as a structure model in which the peptide segments form an antiparallel β-sheet with a polymer shell. The findings contribute to the advancement of a helical polymer or the superhelical self-assembly of polymers, paving the way for diverse applications in materials science and related fields
Coassembly of charged copolymer amphiphiles featuring ph-regulated antifouling properties.
No full textUnderstanding the formation of highly ordered structures through self-assembly is crucial for developing various biologically relevant systems. A significant expansion in the development of self-assembly chemistry features stable coassembly formation using a mixture of two oppositely charged polymers. This study provides insightful findings on the coassembly of hydrophobic coumarin-integrated cationic (P1–P3) and anionic (P1′–P3′) copolymers toward the formation of vesicles in aqueous medium at pH 7.4, with a hydrodynamic diameter (Dh) of 160 ± 10 nm and electrically neutral zwitterionic surfaces, confirmed by dynamic light scattering. Upon varying the solution pH, an intriguing charge switchable behavior (+ve → 0 → −ve) and a drastic morphological transition to spherical aggregates of the vesicles were noticed. At pH 7.4, these coassembled vesicles possess a neutral surface charge, empowering them to resist nonspecific protein (pepsin and lysozyme) adsorption via electrostatic repulsion, as evidenced by size evolution and protein binding measurements. Additionally, the bilayer membrane allows for the encapsulation of hydrophilic and hydrophobic guest molecules and their sustained release in the presence of 10 mM esterase; thus, this study demonstrates potential applications of coassembly to serve as a drug delivery vehicle
Immunophenotypic characterization of leukemic stem cells in acute myeloid leukemia using single tube 10‐colour panel by multiparametric flow cytometry: Deciphering the spectrum, complexity and immunophenotypic heterogeneity
No full textIntroduction
Despite extensive research, comprehensive characterization of leukaemic stem cells (LSC) and information on their immunophenotypic differences from normal haematopoietic stem cells (HSC) is lacking. Herein, we attempted to unravel the immunophenotypic (IPT) characteristics and heterogeneity of LSC using multiparametric flow cytometry (MFC) and single-cell sequencing.
Materials and Methods
Bone marrow aspirate samples from patients with acute myeloid leukaemia (AML) were evaluated using MFC at diagnostic and post induction time points using a single tube-10-colour-panel containing LSC-associated antibodies CD123, CD45RA, CD44, CD33 and COMPOSITE (CLL-1, TIM-3, CD25, CD11b, CD22, CD7, CD56) with backbone markers that is, CD45, CD34, CD38, CD117, sCD3. Single-cell sequencing of the whole transcriptome was also done in a bone marrow sample.
Results
LSCs and HSCs were identified in 225/255 (88.2%) and 183/255 (71.6%) samples, respectively. Significantly higher expression was noted for COMPOSITE, CD45RA, CD123, CD33, and CD44 in LSCs than HSCs (p < 0.0001). On comparing the LSC specific antigen expressions between CD34+ (n = 184) and CD34- LSCs (n = 41), no difference was observed between the groups. More than one sub-population of LSC was demonstrated in 4.4% of cases, which further revealed high concordance between MFC and single cell transcriptomic analysis in one of the cases displaying three LSC subpopulations by both methods.
Conclusion
A single tube-10-colour MFC panel is proposed as an easy and reproducible tool to identify and discriminate LSCs from HSCs. LSCs display both inter- and intra-sample heterogeneity in terms of antigen expressions, which opens the facets for single cell molecular analysis to elucidate the role of subpopulations of LSCs in AML progression
Baseline and Post-NACT Imaging in Retinoblastoma With Optic Nerve Involvement: Can MRI Predict Prognosis?
No full textPurpose:To describe a staging system for optic nerve invasion using magnetic resonance imaging (MRI) and report any correlation with survival outcome.
Methods:This was a ambispective study. Twenty-one patients with retinoblastoma who had optic nerve involvement on MRI were staged at baseline based on contrast enhancement and/or thickening and length of involvement. Response to neoadjuvant chemotherapy (NACT) was noted according to proposed response evaluation criteria and results were correlated with survival outcome.
Results:Baseline MRI staging was able to predict event-free survival (EFS) (P = .0015) using the log-rank test for trends. Patients with optic nerve enhancement alone showed 100% survival prognosis. Optic nerve thickening cases with complete or partial response to NACT showed better EFS (P > .90) than those with stable disease according to response evaluation criteria.
Conclusions:The modified staging system for optic nerve invasion used in the current study significantly predicted EFS. The study also showed that response to NACT may be affected by baseline staging. The authors recommend that cases with optic nerve enhancement only, irrespective of the length of involvement (stage 0), may be treated with upfront enucleation. Cases with optic nerve thickening may be staged to evaluate the correlation with survival outcome in a larger cohort in future studies
Machine learning algorithm-based prediction of acute graft-versus-host-disease at engraftment through immune and cytokine profile
No full textIntroduction: Acute Graft-versus-Host-Disease (aGVHD) is a major immune complication following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), initiated by conditioning regimen-associated tissue damage. It involves the complex interplay of immune cells and cytokines. Our study aims to leverage machine learning (ML) algorithms on the immune and cytokine profile of Allo-HSCT recipients to develop biomarker-based classification models to predict the onset of aGVHD at the time of engraftment.
Methods: Seventy patients diagnosed with hematological disorders who had undergone Ist Allo-HSCT were recruited from All India Institute of Medical Sciences, New Delhi, India. Peripheral blood was collected from the patients at the time of engraftment, and the immune cell subtypes and cytokine profiles were analyzed using flow cytometry and ELISA respectively. The individual cell counts were then processed using basic ML models, including support vector classifier with RBF kernel, Decision Tree, and Random Forest, chosen for their mathematical simplicity and feature importance advantage of Decision Trees and Random Forests. Various data settings were utilized in the study: combined immune and cytokine counts, only immune cell counts, only cytokine counts, only T-cell counts, both T- and NK-cell counts, only dendritic cell counts, and only B-cell counts. These configurations were selected to investigate how different data sets impact the prediction of aGVHD before its onset.
Results:
At the engraftment flow cytometric analysis of reconstituted lymphocytes in patients who developed acute GVHD revealed that there was a remarkable increase in the decrease in the ratio of CD4+/CD8+ T-cell (p: ≤0.0001), Tregs (p: ≤0.0001) with an increase in the cytotoxic regulatory NK-cell (p: ≤0.0001), dendritic cells (p: ≤0.0001) and B-cell (p: ≤0.0001). The levels of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β, MIP-1α, IL-17α), and Th17- and Th1-cells were elevated with consequent decline of the levels of anti-inflammatory cytokine IL-10, and Th2-, Th9-, and Th22-cells.
Machine learning based on 40 parameters [all immune cell subsets n=34 and all cytokines (n=6)]. The correlation heat map shows a higher correlation of aGVHD with the cytokine profile with or without immune cells (accuracy: 1), T-cell with or without NK-cell (accuracy: 1) than for any other individual cell [NK cell (accuracy 0.93), dendritic cell (accuracy: 0.86), and B cell (accuracy: 0.86)]
Conclusion:
The current models classify perfectly, indicating the potential for a machine learning (ML) algorithm in predicting the onset of aGVHD. However, a study with a larger sample size is required to validate these classification models and mitigate the risk of overfitting observed due to the consistently high performance.
The study also highlights the potential of cytokine profiles as a viable alternative to T-cell counts, as evidenced by the correlation heat map and classifier models. These findings provide valuable insights into dataset requirements and future directions for integrating ML models into aGVHD prediction
Unique Challenges in the Management of Retinoblastoma in India – Need for Country-Specific Guidelines
No full textThe management of retinoblastoma in the Indian subcontinent is riddled with unique challenges. Compared to Western countries, a significant proportion of children with retinoblastoma in India present with an advanced disease, and consequently, there is a relatively lower proportion of globe salvage and cure rates achieved. The international guidelines for the management of retinoblastoma are often not suited for addressing the varying stages of presentation of retinoblastoma in India and its specific socio-cultural context. The need for a comprehensive country-specific guideline, which incorporates updated recommendations as per latest available evidence, along with additional aspects specific for implementation in India, was felt. The recently published guidelines, developed by an expert committee constituted by Indian Council of Medical Research (ICMR), was a necessary step to address that need [1,2,3]. The guidelines were developed by robust review of literature, along with expert-consensus statements, wherever the available literature was unclear. The guidelines have applicability both in international as well as local context, especially for entire South East Asia and other low-middle income settings.
Singh et al. succinctly summarized the differing epidemiology of retinoblastoma in India [1]. The article clearly brings out the delayed age of presentation in India compared to high-income countries, which in turn perhaps contributes to more advanced stage of presentation. Children in India often face multiple barriers to achieve diagnosis of malignancy and initiation of appropriate treatment [4]. The delay is often multi-factorial and may be linked to difficult healthcare resource access, inadequate available infrastructure as well as poor compliance to treatment. Sex-based disparity in favor of boys also contributes to treatment abandonment and consequently, inferior outcomes across childhood cancers in India [5]. Hence, ensuring socio-economic support and compliance during treatment forms an integral component of management of retinoblastoma in India.
For management of intraocular retinoblastoma, in high-income settings, the emphasis is often more on intra-arterial therapy. However, the availability of expertise in intra-arterial therapy and its affordability is still limited across the country. Hence, intravenous chemotherapy with focal therapy has been emphasized as a reasonable and even preferable option for the management of intraocular retinoblastoma [3]. Similarly, the management of advanced and extra-ocular retinoblastoma has been elaborated in details in these guidelines, as they are commonly encountered in routine clinical practice in India, unlike that in Western countries, where familiarity and expertise in advanced retinoblastoma remains limited [2]. Children with advanced retinoblastoma where cure is not attainable, especially for those with central nervous system involvement, should be managed with palliative intent. These guidelines have judiciously suggested the use of oral metronomic therapies instead of intensive chemotherapy in such palliative settings, where the predominant aim is to improve the quality of life and reduce adverse effects. Quality of life should be accorded paramount importance for evaluating or selecting any therapy, especially in non-curative settings.
The guidelines have also briefly touched upon the aspect of retinoblastoma survivorship and follow-up evaluation. The follow-up of retinoblastoma survivors need multi-disciplinary collaboration among oculoplastic surgeons, oncologists, psychologists, and pediatricians. A previous study on quality of life in retinoblastoma survivors has demonstrated impaired quality of life, especially in emotional domain [6]. This suggests that comprehensive psychological evaluation and quality of life assessment should also form a part of survivorship care in retinoblastoma.
The guidelines also put forward multiple unanswered questions in the management of retinoblastoma. The role of high dose carboplatin to improve globe salvage in intraocular retinoblastoma was recently evaluated in a randomized controlled trial and it did not show any significant improvement in the proportion of globe salvage with the use of higher dose of carboplatin [7]. Yet, the trial was underpowered and hence, the current place of high-dose carboplatin in the management paradigm of retinoblastoma continues to be controversial. Similarly, the role of low-intensity therapies like metronomic therapies or alternative strategies like intrathecal therapies in intracranial involvement needs to be systematically studied with collaborative studies in India, where the burden of metastatic disease continues to remain high. The development of Indian Pediatric Oncology Group (InPOG) for spearheading collaborative research in various disease groups is a step in the right direction [8].
The guidelines did not address the potential areas of research and incorporation of traditional or alternative medications in the management of retinoblastoma. Traditional systems of medicine often have phytochemicals of significant anti-cancer properties, which warrant systematic study. There was a significant impetus for the clinical study of traditional medications during COVID-19 pandemic [9]. Recently, a screen of Chinese herbal medicines has identified xanthatin as an active agent, which specifically targets retinoblastoma cell lines and has also shown activity in in-vivo models [10]. Similarly, the Indian systems of medicine also have multiple herbal or other traditional compounds and encouraging their systematic evaluation may spearhead new drug development in the management of retinoblastoma.
The recently published comprehensive guidelines on the management of retinoblastoma were a necessary step in the development of country-specific guidelines to address unique needs suited for India. It will form a valuable resource for practicing clinicians as well as for healthcare trainees. Similar guidelines for other malignancies which are pragmatic and incorporate practical needs of clinicians in the country should be envisaged and developed
Early stoppage of empirical antibiotic therapy at clinical improvement in paediatric leukaemia patients with high-risk febrile neutropenia (ESAT-HR-FN study): Study protocol of a single centre investigator initiated randomised open label non-inferiority trial
No full textBackground and rationale
Febrile neutropenia (FN) is one of the major causes of early mortality among children undergoing induction chemotherapy for haematological malignancies. FN occurs in up to 80 % of the children undergoing intensive chemotherapy and FN specific mortality is as high as 10 %. The management of high-risk FN (HR-FN) is by early initiation of broad-spectrum empirical antibiotic therapy (EAT) which is continued till blood count recovery. Adverse effects of prolonged EAT among children without proven infective focus have questioned the rationale behind the duration of EAT. The non inferiority of early stoppage of EAT in patients with low-risk FN (LR-FN) when afebrile for 48 h, irrespective of marrow recovery, is proven among adults and children. However, there is paucity of data regarding the same in children with HR-FN. This study aims to determine whether early discontinuation of EAT in children with HR-FN without proven infective focus who become afebrile and awaiting marrow recovery, would reduce antibiotic duration and their adverse effects without any negative consequences for patients.
Objective
To compare the rates of recurrent fever in paediatric patients (2–18 years) with HR-FN when EAT is continued till marrow recovery (control group) versus when stopped early at defervescence irrespective of marrow recovery (study group).
Methodology
This is the study protocol of a phase 3, single centre, randomized, open label, non-inferiority clinical trial. The primary outcome is the rate of fever recurrence among patients with HR-FN, when EAT is stopped early irrespective of marrow recovery (study group) and will be compared to the rate of fever recurrence on continuation of EAT till marrow recovery which is defined as an absolute neutrophil count (ANC) ≥ 500/mm3 (control group). Secondary outcomes include the comparison of duration of antibiotic use, mortality rates, hospital re-admission rates, requirement of multiple broad-spectrum antibiotics, therapeutic anti-fungal usage and need for organ support between the study and the control groups. A total of 280 children with acute leukaemia undergoing EAT for grade 3 or severe FN (ANC <500/μL) without clinico-laboratory evidence of infective foci are being randomized in the ratio of 1:1 between the study and the control group after defervescence for 48 h. The patients will be followed up for primary outcome (fever recurrence) till the end of induction period (day 35) or recovery of ANC ≥500/mm3 whichever is earlier.
Expected outcome
ESAT-HR FN study is the first large phase 3 randomised study to assess the impact of early stoppage of EAT irrespective of marrow recovery among a homogenous paediatric cohort of HR-FN in the setting of induction chemotherapy for acute leukaemia. This study will be seminal in addressing the duration of EAT in HR-FN among children without infective foci and if proven to be non-inferior this strategy will help to reduce the adverse effects from prolonged antibiotic use, the emergence of drug resistance, decrease hospital stay length and overall health care cost
A guideline to determine Faradaic efficiency in electrochemical CO<sub>2</sub> reduction
No full textThis article does not have an abstract
Transition metal phosphide-based oxygen electrocatalysts for aqueous zinc–air batteries
No full textElectrically rechargeable zinc–air batteries (ZABs) are emerging as promising energy storage devices in the post-lithium era, leveraging the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) at the air cathodes. Efficient bifunctional oxygen electrocatalysts, capable of catalyzing both the ORR and OER, are essential for the operation of rechargeable ZABs. Traditional Pt- and RuO2/IrO2-based catalysts are not ideal, as they lack sufficient bifunctional ORR and OER activity, exhibit limited long-term durability, require high overpotentials and are expensive. In contrast, non-precious metal-based catalysts, including transition metal phosphides (TMPs), have gained significant attention for their promising bifunctional catalytic properties, making them attractive candidates for ZABs. Despite encouraging lab-scale achievements, translating these advancements into market-ready applications remains challenging due to suboptimal energy performance. Rationally engineered bifunctional TMPs hold great potential for overcoming these challenges and meeting the requirements of rechargeable ZABs. This feature article reviews recent progress in the development of TMP-based catalysts for ZABs, providing a comprehensive overview of ZAB fundamentals and strategies for catalyst design, synthesis, and engineering. A particular emphasis is placed on widely studied bifunctional Fe, Co, and Ni phosphides, along with approaches to enhance their catalytic performance. Key performance metrics are critically evaluated, including the potential gap (ΔE) between the ORR and the OER, specific capacity, peak power density, and charge–discharge cycling stability. Finally, this feature article discusses the challenges faced in TMP-based ZABs, proposes strategies to address these issues, and explores future directions for improving their rechargeability to meet the demands of commercial-scale energy storage technologies