mNUTRIC Score in ICU Mortality Prediction: An Emerging Frontier or Yet Another Transient Trend?

How to cite this article: Arunachala S, Kumar J. mNUTRIC Score in ICU Mortality Prediction: An Emerging Frontier or Yet Another Transient Trend? Indian J Crit Care Med 2024;28(5):422-423.

Daratumumab in Indian patients with relapsed and refractory multiple myeloma: a prospective, multicenter, phase IV study.

Aim: To assess the safety and effectiveness of daratumumab monotherapy in Indian patients with relapsed/refractory multiple myeloma. Methods: In this prospective, multicenter, phase IV study, patients (aged ≥18 years) received intravenous daratumumab (16 mg/kg) in six cycles. Safety was the primary end point. Results: Of the 139 patients included, 121 (87.1%) experienced ≥1 treatment-emergent adverse events (TEAEs; 53 [38.1%] drug-related), 32 (23%) had ≥1 serious TEAEs (five [3.6%] drug-related) and 16 (11.5%) deaths were reported (one death [0.7%] was drug-related). Overall response rate was 26.3%; 62.7% of patients had stable disease. Median time to first response and median progression-free survival were 5.2 and 5.9 months, respectively. Functional status and well-being were improved. Conclusion: Daratumumab showed an acceptable and expected safety profile with consistent efficacy, providing a novel therapeutic option for relapsed/refractory multiple myeloma management in India.

Daratumumab is a monoclonal antibody approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). This study evaluated the outcome of daratumumab single therapy in Indian patients who were not cured with other drugs used for the same disease. 139 adult patients were included in this study from 15 institutes across India. Daratumumab (16 mg/kg) was diluted with 500 or 1000 ml of saline solution and given slowly through the intravenous route 16-times within 6 months. The study examined whether the safety profile and benefits of daratumumab reported in Indian patients were similar to those reported in the RRMM populations of other countries. The study found that most of the adverse events were not severe and could be easily treated by the study physician. 16 patients died (one might have been due to daratumumab treatment). Daratumumab treatment provided life support and recovery benefits to many patients. Daratumumab single therapy provides an appropriate and acceptable safety profile with no new adverse events and consistent benefits in RRMM patients. Clinical Trial Registration: NCT03768960 (ClinicalTrials.gov), CTRI/2019/06/019546.

De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.

The contribution of de novo variants as a cause of intellectual disability (ID) is well established in several cohorts reported from the developed world. However, the genetic landscape as well as the appropriate testing strategies for identification of de novo variants of these disorders remain largely unknown in low-and middle-income countries like India. In this study, we delineate the clinical and genotypic spectrum of 54 families (55 individuals) with syndromic ID harboring rare de novo variants. We also emphasize on the effectiveness of singleton exome sequencing as a valuable tool for diagnosing these disorders in resource limited settings. Overall, 46 distinct disorders were identified encompassing 46 genes with 51 single-nucleotide variants and/or indels and two copy-number variants. Pathogenic variants were identified in CREBBP, TSC2, KMT2D, MECP2, IDS, NIPBL, NSD1, RIT1, SOX10, BRWD3, FOXG1, BCL11A, KDM6B, KDM5C, SETD5, QRICH1, DCX, SMARCD1, ASXL1, ASXL3, AKT3, FBN2, TCF12, WASF1, BRAF, SMARCA4, SMARCA2, TUBG1, KMT2A, CTNNB1, DLG4, MEIS2, GATAD2B, FBXW7, ANKRD11, ARID1B, DYNC1H1, HIVEP2, NEXMIF, ZBTB18, SETD1B, DYRK1A, SRCAP, CASK, L1CAM, and KRAS. Twenty-four of these monogenic disorders have not been previously reported in the Indian population. Notably, 39 out of 53 (74%) disease-causing variants are novel. These variants were identified in the genes mainly encoding transcriptional and chromatin regulators, serine threonine kinases, lysosomal enzymes, molecular motors, synaptic proteins, neuronal migration machinery, adhesion molecules, structural proteins and signaling molecules.

First case report of Cyclosporiasis from eastern India: Incidence of Cyclospora cayetanensis in a patient with unusual diarrheal symptoms.

Cyclospora cayetanensis, a recently described coccidian parasite causes severe gastroenteric disease worldwide. Limited studies are found on the incidence of C. cayetanensis infection from India; hence remains largely unknown. To date, no case of cyclosporiasis from eastern India has been reported. In this study, we described an incidental case of C. cayetanensis in a 30 years old Bengali female patient with no travel history from eastern India. In June 2022, the patient presented with a history of diarrhoea persisting for more than two months with continuous passage foul smelling stools for which she took multiple antibiotics that were ineffective. There were no Salmonella, Shigella, or Vibrio-like organisms in the patient's faecal sample, and Toxin A/B of Clostridium difficile was also not detected by ELISA. The patient was HIV-negative. Finally, UV autofluorescence and DNA-based diagnosis confirmed the presence of C. cayetanensis, and the treatment with a combination of appropriate antibiotics was successful. This case report could raise awareness about C. cayetanensis associated diarrhoeal cases in India.

Hematopoietic stem-cell transplantation in a zoo of multidrug-resistant organisms: Data from a cancer center in eastern India.

BACKGROUND: Infections by multidrug-resistant organisms (MDRO) are a major hurdle in hematopoietic stem-cell transplants (HSCTs). Conditioning regimens lead to mucosal barrier injury, which in-turn leads to transmigration of gut bacteria and sepsis. Pre-transplant stool and throat surveillance cultures can guide empirical antibiotic policy during the neutropenic period. In this paper, we document colonization with MDRO in pre-transplant surveillance cultures and the correlation with bloodstream infections in HSCT patients and analyze transplant outcomes with respect to these infections. METHODS: A single-center, retrospective study on HSCT was performed between January 2021 and December 2021. The incidence of bacterial infections, percentage of MDROs, correlation with pre-transplant stool/throat surveillance cultures, and their impact on overall 100-day and post-100-day to 6-month post-transplant survival were analyzed. RESULTS: Sixty-four patients were included in the study. Pre-transplant stool surveillance cultures were positive for MDRO in 85.9% of patients. Almost half (48.5%) of the isolates were positive for carbapenemase-producing genes (mainly New Delhi metallo-beta-lactamase-1 [NDM-1] and oxacillinase-48 [OXA-48]). Eighteen patients (18/64, 28%) had a positive blood culture for MDRO in the peri-engraftment neutropenic period. Correlation between surveillance and blood cultures was seen in 61% (11/18) of patients. All-cause mortality was 14.1% (9/64) and 25% (16/64) in patients at 100 days and 6 months post-HSCT, respectively. The 100-day and post-100-day all-cause mortality rates were higher in patients with Gram-negative MDRO bloodstream infections (p < .012 and <.008, respectively). CONCLUSION: MDRO infections can adversely affect HSCT outcomes. Pre-transplant stool and throat surveillance cultures may guide empirical antibiotic policy and lead to favorable transplant outcomes.

Design, synthesis and biological evaluation of novel pyrazolo-pyrimidin-amines as potent and selective BTK inhibitors.

To discover the best-in-class Bruton's Tyrosine Kinase (BTK) inhibitors, for th treatment of autoimmune disorders like cancer (B-Cell Lymphoma (BCL)) and rheumatoid arthritis (RA), in the present investigation, novel structural optimizations were carried out. Introduction of novel bicyclic amine linkers and aromatic backbone led to series of compounds 9a-h and 14a-u. Compound 14b was found to be potent, orally bioavailable, selective and irreversible BTK inhibitor. In vitro, 14b showed IC50 of 1.0 nM and 0.8 nM, in BTK and TMD8 assays, respectively. In vivo,14b displayed robust efficacy in collagen-induced arthritis (CIA) and TMD8 xenograft models, which could be correlated with its improved oral bioavailability. In the repeated dose acute toxicity study, 14b showed no adverse changes, indicating that the BTK inhibitor 14b could be viable therapeutic option for the treatment of autoimmune disorders.

Bortezomib-based induction therapy followed by autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients: A single-center experience and review of Indian literature.

INTRODUCTION: High-dose chemotherapy with melphalan, followed by autologous hematopoietic stem cell transplantation (AHCT) remains the standard of care for consolidation therapy of fit patients with newly diagnosed multiple myeloma (NDMM), for more than 20 years now. MATERIAL AND METHODS: This is a retrospective study of NDMM patients who underwent AHCT at our center from 2011 to 2018. Data was undertaken using the hospital electronic medical records (EMR). RESULTS: Among transplant eligible patients (which were 764), 78 patients (10.2%) underwent AHCT. The predominant stage in the study cohort was International Scoring System (ISS)-III (55%), and IgG-kappa (44%) was the commonest subtype of multiple myeloma (MM). Light chain myeloma was found in 23.5% of patients. Pretransplant, 42%, 48%, and 10% patients were in more than very good partial response (>VGPR), very good partial response (VGPR), and partial response (PR), respectively. The median duration of follow-up was 57.2 months (range: 12.1-120.2 months). The entire cohort's 5-year overall survival (OS) and progression-free survival (PFS) were 89.1% and 41.8%, respectively. CONCLUSION: Bortezomib based triplet induction regimens were effective and well tolerated in this retrospective analysis of Indian patients. We observed that AHCT effectively achieves deep and durable remission in MM.

Conference report: Introducing oncology to undergraduate medical and allied health sciences students: reflections from 2nd ecancer TMC Oncology Congress 2023 at Kolkata, India.

Despite the high cancer burden in low-middle-income-countries, medical students often have inadequate exposure to oncology. This may contribute to reduced interest in pursuing training in the field. The second ecancer TMC Oncology Congress at Kolkata on 30th September and 1st October 2023 was planned primarily to introduce undergraduate medical and allied health science students to oncology. There were separate sessions on breast cancer, thyroid cancer, myeloma and research methods so that students get exposure to a wide range of topics. Multi-disciplinary case-based discussions on common clinical presentations helped the students grasp the way a modern cancer hospital functions. Eighty-two percent (131/159, 82%) of the pre-registered delegates attended the congress alongside 44 national and international faculty from surgical oncology, radiation oncology, medical oncology, nuclear medicine, radiology, histopathology, psychiatry and palliative medicine. Of those who offered written anonymous feedback, 76% (70/91, 76%) rated the congress to be excellent. Broadly the following themes emerged from the qualitative feedback a) Delegates positively viewed the opportunity to 'interact and learn from some of the best of minds in the field of medicine' b) Suggestions included 'more interactive sessions through case histories, demonstrations of techniques, videos, quizzes, etc.' to make the learning experience more engaging. c) Considerable appreciation was expressed for learning about 'scientific writing' d) A few delegates were also inspired by the 'style' of some of the presentations and felt that this would help to design their presentations in the future. Introducing oncology early during their career may inspire undergraduate students to explore the option of pursuing a career in oncology and allied specialties. A video summarising the event is available at https://ecancer.org/en/video/11672-introducing-oncology-to-undergraduate-medical-and-allied-health-sciences-students. All the talks presented during the conference are available at https://ecancer.org/en/conference/1505-2nd-ecancer-tmc-kolkata-oncology-congress.

Should we adopt an automated de-centralized model of chimeric antigen receptor- T cells manufacturing for low-and middle-income countries? A real world perspective.

Autologous chimeric antigen receptor-T (CAR-T) cell therapy has proven itself as an effective therapeutic modality for cancers, especially hematological malignancies and is emerging as a potential candidate for solid organ cancers as well. However, the accessibility to treatment has been limited due to complexities and costs associated with manufacturing a genetically modified autologous product. The centralized model of CAR-T manufacturing which has emerged as the dominant model in developed nations does not seem well-suited to the needs and realities of the developing economies. In this context, we explore the relative advantages and disadvantages of the two models from a developing nation's perspective.

The E262K mutation in Lamin A links nuclear proteostasis imbalance to laminopathy-associated premature aging.

Deleterious, mostly de novo, mutations in the lamin A (LMNA) gene cause spatio-functional nuclear abnormalities that result in several laminopathy-associated progeroid conditions. In this study, exome sequencing in a sixteen-year-old male with manifestations of premature aging led to the identification of a mutation, c.784G>A, in LMNA, resulting in a missense protein variant, p.Glu262Lys (E262K), that aggregates in nucleoplasm. While bioinformatic analyses reveal the instability and pathogenicity of LMNAE262K , local unfolding of the mutation-harboring helical region drives the structural collapse of LMNAE262K into aggregates. The E262K mutation also disrupts SUMOylation of lysine residues by preventing UBE2I binding to LMNAE262K , thereby reducing LMNAE262K degradation, aggregated LMNAE262K sequesters nuclear chaperones, proteasomal proteins, and DNA repair proteins. Consequently, aggregates of LMNAE262K disrupt nuclear proteostasis and DNA repair response. Thus, we report a structure-function association of mutant LMNAE262K with toxicity, which is consistent with the concept that loss of nuclear proteostasis causes early aging in laminopathies.

Analysis of trimodal pattern of mortality among hospitalized COVID-19 patients- Lessons from tertiary care hospital.

Background and Aims: Many patients with COVID-19 become critically ill and requireICU admission. Risk factors associated with mortality have been studied, but this study provides insight regarding disease progression and hence help to plan rescue strategies to improve patient outcome. Material and Methods: This retrospective, observational study included all patients with diagnosis of COVID-19 from March1 to June30,2021 who died in hospital. Results: During the study period, 1600 patients were admitted, with 1138 (71%) needing ICU care. There were 346 (21.6%) deaths, distributed as 15.8%(n = 55) within 48h of admission, 46.2%(n = 160) in next 10 days, and 37.8%(n = 131) thereafter. This trimodal mortality pattern of distribution was similar to polytrauma patients. Patients were divided into categories according to time duration from admission to death. In our cohort, 235 (14.7%) patients required mechanical ventilation, with a mortality of 85.4%(n = 201). Tachypnea was significantly (P < 0.001) associated with death at all times; however, hypotension was associated with early death and low oxygen saturation with poor outcome upto 10 days (P < 0.001). Refractory hypoxia was cause of death in all three groups, while other causes in group II were AKI (28%), sepsis (18%), and MODS (10%). Group III patients had different causes of mortality, including barotrauma (9%), pulmonary thromboembolism (8%), refractory hypercarbia (12%), MODS (13%), AKI (10%), sepsis (7%), and cardiac events (6%). Conclusion: While physiological dearrangements are associated with rapid progression and early death, complications related to hyper-coagulable state, lung injury, and organ failure lead to death later. Providing quality care to a high volume of patients is a challenge for all, but posthoc analysis such as air crash investigation can help find out potential areas of improvement and contribute to better outcomes and mortality reduction.

Optimisation of momelotinib with improved potency and efficacy as pan-JAK inhibitor.

Dysregulated JAK-STAT signaling has been proven to be involved in several immune-mediated diseases. Several janus kinase (JAK) inhibitors have been approved for the treatment of various inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD). Here, we report the design, optimisation, synthesis and biological evaluation of momelotinib analogues (a pyrimidine based JAK inhibitor), to get pan-JAK inhibitors. Systematic structure activity relationship studies led to the discovery of compound 32, which potently inhibited JAK1, JAK2 and JAK3. The in vivo investigation indicated that compound 32 possessed favourable pharmacokinetic properties and displayed superior anti-inflammatory efficacy than momelotinib 1. Accordingly, compound 32 was advanced into preclinical development.

A Systematic Cytogenetic Strategy to Identify Masked Hypodiploidy in Precursor B Acute Lymphoblastic Leukemia in Low Resource Settings.

Hypodiploidy with < 40 chromosomes is associated with poor prognosis in B cell precursor acute lymphoblastic leukemia. In some patients, the hypodiploid clone undergoes endoreduplication, resulting in doubling of the number of chromosomes and masquerades as a high hyperdiploid BCP-ALL. Karyotyping reveals metaphases with 50-79 chromosomes masking the hypodiploid clone. Identifying hypodiploidy in such cases requires awareness of non random alterations of chromosomal copy numbers found in hypodiploid BCP-ALL. We used a systematic strategy to identify masked hypodiploidy integrating targeted fluorescence in situ hybridization (FISH) analysis directed towards identifying monosomies of chromosomes 7, 15 and 17 and flow cytometry-based ploidy analysis (FCPA). Of 445 patients diagnosed as BCP ALL, 2.9% (13/445) were classified as hypodiploid including patients with masked hypodiploidy. Karyotype analysis showed hypodiploidy in 3 patients, near triploidy in 4 patients and normal karyotype in 6 patients. Four patients with near triploid clone on karyotype showed either bimodal peak (2 patients) or single low hypodiploid peak (1 patient) or only near triploid peak (1 patient) on FCPA. All 6 patients with normal karyotype revealed either bimodal peak (4 patients) or hypodiploid peak (2 patients) on FCPA. Targeted FISH analysis unmasked hypodiploid clone showing monosomies of chromosomes 7, 15 and 17 in all ten patients. Our algorithm successfully identified masked hypodiploidy in patients, including those with endoreduplication (4 patients) and normal karyotype (6 patients). Integrating FCPA with targeted FISH analysis provides a practical, sensitive and specific approach to identify masked hypodiploidy in low resource settings.

Outcomes of diffuse large B-cell lymphoma in elderly patients-real-world experience from a middle-income country setting.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the commonest subtype of lymphoma in the elderly and poses unique challenges in this group of patients. There is a need for more information on real-world outcomes across economic disparities. METHODS: Electronic Medical Record of 3,087 lymphomas (>18 years) were evaluated retrospectively, of which 842 (27%) patients were ≥65 years. Two hundred and twelve patients who were ≥65 years received first line treatment for DLBCL between May 2011 and Dec 2016. Demography, clinical features, associated co-morbidities, first line treatment outcomes and hospital costs were analysed. Patients were followed up till March 2020. RESULTS: The median age at presentation was 71 years. Gender ratio was 2.5:1. 38% patients presented with early-stage disease, 37% with low and low-intermediate International prognostic index, 49% with nodal disease. One or more co-morbidities were present in 58%. The commonest extra nodal site was gastro-intestinal (29%). Two-thirds of the patients presented with non-Germinal centre B subtype. The overall response (OR) to treatment was 72.5%. Patients who received anthracycline-based therapy (n = 124) and rituximab-based therapy (n = 159) had a median progression free survival (PFS), not reached and 47.0 months, respectively, versus 10 months and 7.9 months, respectively, for patients receiving non-anthracycline and non-rituximab therapies. At a median follow-up of 24 months, the 5-year overall survival and PFS are 44% and 41%, respectively, for the entire cohort. CONCLUSIONS: DLBCL is a curable lymphoma in elderly patients with standard anthracycline and rituximab-based therapies. Improvement in outcomes largely depends on social and financial support to complete the scheduled treatments.

Relapsed plasmablastic lymphoma in a HIV-negative patient: Pushing the envelope.

This case emphasizes that, with the availability of novel immunotherapy agents (Daratumumab), and repurposed use of bortezomib, a patient with HIV-negative relapsed PBL can be treated successfully and consolidated with an allogeneic haploidentical hematopoietic cell transplantation.

Discovery of a potent G-protein-coupled receptor 119 agonist for the treatment of type 2 diabetes.

The ever-growing prevalence of Type-2 diabetes in the world has an urgent need for multiple orally effective agents that can regulate glucose homeostasis. G-Protein coupled receptor 119 (GPR 119) agonists have demonstrated the glucose-dependent insulin secretion and showed beneficial effects on glycemic control in humans and/or relevant animal models. Herein, we describe our efforts towards identification of a potent and oral GPR 119 agonist 13c (ZY-G19), which showed in vitro potency in the cell-based assay and in vivo efficacy without exerting any significant signs of toxicity in relevant animal models.

Relapsed Refractory Hodgkin Lymphoma and Brentuximab Vedotin-Bendamustine Combination Therapy as a Bridge to Transplantation: Real-World Evidence From a Middle-Income Setting and Literature Review.

INTRODUCTION: Despite high cure rates with standard treatment, 30% patients with Hodgkin lymphoma develop relapsed or refractory (R/R) disease. Salvage therapy followed by autologous hematopoietic cell transplantation (HCT) is considered standard of care. Brentuximab Vedotin (Bv) in combination with Bendamustine (B) has been tested in the salvage setting with promising results. MATERIALS AND METHODOLOGY: We conducted a single centre retrospective chart review of patients who received BBv salvage therapy to determine its activity and safety in patients with R/R classical Hodgkin lymphoma (HL). Between May 2011- December 2019, 179 patients were diagnosed with R/R HL. RESULTS: Thirty patients received BBv [median age: 30 (15-59) years, females (n=15)]. Primary refractory disease in 19 patients (63%), and 26 patients (87%) had advanced stage at treatment. Most patients received BBv after 2 prior lines of therapy [n=16 (53%)]. The median number of cycles of BBv were 3 (1-6). The number of BBv cycles delivered as outpatient was 63%. The most common Grade III/IV hematological adverse event was neutropenia [n=21, (70%)], while grade III/IV non-hematological toxicities included infections in 4 (13%), neuropathy in 4(13%), skin rash in 2 (7%), GI toxicities in 3 (10%) and liver dysfunction in 2 (7%) patients. The ORR and CR rates were 79% and 62%, respectively. Seventeen patients (57%) underwent an autologous HCT and 8 (26%) underwent an Allogeneic HCT (all haploidentical). The median follow up time from BBv administration was 12 months. Six patients died: 2 = disease progression, and 4 = non-relapse causes (Infection and sepsis = 2, GVHD=2). In addition to this, one patient progressed soon after HCT and another patient relapsed 22 months post HCT. Three year Overall survival (OS) and Event free survival (EFS) probability post-BBv treatment was 75% and 58%, respectively. OS and EFS analysis based on response (viz., CMR) to BBv demonstrated that patients in CMR had better survival probability [93% (p=0.0022) 3yr-OS and 72% (p=0.038) 3yr-EFS probability]. CONCLUSIONS: BBv is an active and well-tolerated salvage treatment for patients with R/R HL, even in refractory and advanced settings. In middle-income settings, cost constraints and access determine patient uptake of this regimen.

Impact of COVID-19 on peripheral stem cell collection and preservation at a hematopoietic cell transplant center in India: Experience 2020.

The prevailing corona virus disease 19 (COVID-19) pandemic has adversely affected the healthcare services globally. Hematopoietic cell transplantation (HCT) is considered as the preferred treatment option for several hematological malignancies, and HPC collection facilities have to function continuously along with implementing safety measures. Based on the national and international guidelines, we implemented additional measures and modifications to our standard operating procedure (SOP) to ensure secure HPC collection from patients as well as donors. Here, we report our experience with HPC collection and processing from 1st January, 2020 until 31st December, 2020. We collected 59 HPC products through apheresis and 41 cryopreservation procedures. Compared to 2019, there was a 33% decrease in the number of HPC transplants and 31% reduction in HPC collection procedures. However, we report an 86% (13 procedures) increase in the cryopreservation of HPC products from related donors, as several organizations recommend cryopreservation of HPC products. We report our institutional experience to better understand the impact of COVID-19 on HCT services in a tertiary care center in the developing world. It may also help in being prepared for any future waves of COVID-19 cases.