Comparison of Critical Illness Score in Patients Admitted to Intermediate Care Units of a Tertiary Care Hospital: A Comparative Cross-Sectional Study from Karachi, Pakistan.

Introduction: Intermediate care units (IMCUs) serve as step-up units for emergency department patients and as step-down units for critically ill patients transferred from intensive care units. This study compares four critical illness scores for assessment of acutely ill patients and their accuracy in predicting mortality in patients admitted to IMCU. Methods: A comparative cross-sectional study on patients aged ≥18 admitted to IMCU of Aga Khan University Hospital from 2017 to 2019. All patients admitted to IMCU from the emergency room were included in the study. Patient's record were reviewed for demographic data, physiological and laboratory parameters. Critical illness scores were calculated from these variables for each patient. Results: A total of 1192 patients were admitted to the IMCU, of which 923 (77.4%) medical records were finally analyzed. The mean (SD) age of participants was 62 years (± 16.5) and 469 (50.8%) were women. The overall hospital mortality rate of patients managed in IMCU was 6.4% (59/923 patients). The median scores of APACHE II, SOFA, SAPS II and MEWS were 16 (IQR 11-21), 4 (IQR 2-6), 36 (IQR 30-53) and 3 (IQR 2-4) points respectively. AUC for SAPS II was 0.763 (95% CI: 0.71-0.81), SOFA score was 0.735 (95% CI: 0.68-0.79) and MEWS score was 0.714 (95% CI: 0.66-0.77). The lowest ROC curve was 0.584 (95% CI: 0.52-0.64) for APACHE II. Conclusion: In conclusion, our study found that SAPS II, followed by SOFA and MEWS scores, provided better discrimination in stratifying critical illness in patients admitted to IMCU of a tertiary care hospital in Pakistan.

Therapeutic options for large B-cell lymphoma relapsing after CD19-directed CAR T-cell therapy.

In recent years, chimeric antigen receptor T-cell therapy (CAR T) has revolutionized the treatment landscape for large B cell lymphoma (LBCL), demonstrating remarkable efficacy and ushering a new era of therapeutic possibilities. However, a subset of patients may not achieve the desired response with CAR T. This review examines strategies aimed at optimizing outcomes for patients who relapse or progress after CAR T. Available data on utilization of CD19-directed monoclonal antibodies and antibody drug conjugates have shown limited efficacy in this setting. Moreover, bispecific antibodies have also emerged as an alternative therapy in relapsed and or refractory LBCL, but long-term follow up treated cases post-CAR T failure are lacking. Several observational studies have shown efficacy of allogeneic hematopoietic cell transplantation, but attainment of a complete remission prior to allografting is a prerequisite to achieve durable remissions. As we navigate the intricate landscape of treatment of post CAR T failure, it becomes evident that this represents a therapeutic challenge which necessitates a multifaceted approach.

Comparison of Efficacy of Topical Betamethasone Dipropionate and Topical Minoxidil in Patients With Alopecia Areata.

Background and objective Alopecia areata (AA) is a reiterative and nonscarring type of hair loss that can affect any hairy area of the body, particularly the scalp. It manifests as patchy or confluent hair loss with variations in demographics and ethnicity. There are numerous treatment options available, including topical and systemic steroids, topical minoxidil, dithranol, tacrolimus, psoralen and ultraviolet therapy (PUVA), contact immunotherapy, and oral immunosuppressive drugs. However, no previous contrast for efficacy is present between the topical betamethasone versus topical minoxidil alone in our population. This study aims to compare the efficacy of topical betamethasone dipropionate versus topical minoxidil in patients with AA. Methodology A nonrandomized controlled study was conducted at the Department of Dermatology, Jinnah Hospital Lahore, incorporating the data of patients between July 26, 2016, and January 26, 2017, after obtaining institutional ethical approval. One hundred patients with alopecia, either on the scalp or any other hairy part, from both genders, aged between 18 and 50 years, were included in the study. Two groups were created, and patients were assigned to these groups based on the clinician's choice. Group A patients were administered betamethasone dipropionate (0.05%) lotion twice daily on affected areas for 12 weeks. Group B patients were administered minoxidil (5%) solution twice daily on affected areas for 12 weeks. A four-week follow-up plan was followed. A five-point scale score system was used for alopecia grading. After 12 weeks, the hair regrowth score (RGS) was used to compare the efficacy of treatment between the two groups. Results A total of 100 patients with grades S1 to S3 AA of less than three months duration were enrolled. Two groups were created, with 50 patients in each group. The mean age in Group A was 29.08 ± 6.51 years, while in Group B, it was 29.38 ± 6.62 years. In Group A, there were 76% males and 24% females, while in Group B, there were 74% males and 26% females. Comparison of efficacy of topical betamethasone dipropionate versus topical minoxidil in patients with AA demonstrated a greater efficacy of 74% (Grade 3 and Grade 4 responses) in Group A, while in Group B, only 42% of patients showed efficacy. A statistically significant difference was found, with a P-value of 0.001. No serious side effects were noted. Conclusions Our study concluded that topical betamethasone dipropionate (0.05%) lotion has statistically significantly higher efficacy compared to topical minoxidil (5%) solution in patients with AA.

Tumor-informed ctDNA assessment as a valuable prognostic and predictive biomarker in diffuse large B-cell lymphoma.

Background: A novel approach for molecular residual disease (MRD) detection and treatment monitoring is needed in diffuse large B-cell lymphoma (DLBCL) to identify patients with a poor prognosis. We performed a retrospective evaluation of commercial ctDNA testing in patients with stage I-IV DLBCL to evaluate the prognostic and predictive role of tumor-informed ctDNA assessment. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for ctDNA detection and quantification. Results: In total, 50 patients (median age: 59 years; median follow-up: 12.68 months) were analyzed, of which 41 had pretreatment time points with ctDNA detected in 95% (39/41). Baseline ctDNA levels correlated with R-IPI scores and stage. ctDNA clearance during first-line therapy was predictive of improved therapy responses and outcomes (EFS, HR: 6.5, 95% CI: 1.9-22, p=0.003 and OS, HR: 22, 95% CI: 2.5-191, p=0.005). Furthermore, 48% (13/27) of patients cleared their ctDNA following the first cycle of treatment. Patients who cleared their ctDNA, irrespective of their R-IPI score, had superior outcomes compared to ctDNA-positive patients. ctDNA clearance outperformed other factors associated with EFS in multivariate analysis (HR: 49.76, 95% CI:1.1-2225.6, p=0.044). Finally, ctDNA clearance predicted complete response (CR)/no evidence of disease (NED) on average 97 days (range: 0-14.7 months) ahead of imaging/biopsy. Conclusion: ctDNA testing in patients with DLBCL is predictive of patient outcomes and may enable personalized surveillance, intervention, and/or trial options.

CD19-directed CART Therapy for T cell/Histiocyte Rich Large B-cell Lymphoma.

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare histologic variant of LBCL. Limited data regarding CD19-directed chimeric antigen receptor T-cell (CART) therapy in relapsed/refractory (R/R) THRLBCL suggest poor efficacy. We investigated CART outcomes for R/R THRLBCL through the CIBMTR registry. A total of 58 adult patients with R/R THRLBCL who received commercial CD19-CART between 2018-2022 were identified. Most patients (67%) had early relapse of disease (45% primary refractory) with a median of 3 (range: 1-7) prior therapies and were treated with Axicabtagene ciloleucel (69%). At median follow-up of 23 months post-CART, 2-year overall and progression-free survival were 42% (95% CI: 27-57) and 29% (95% CI: 17-43), respectively. In univariable analysis, poor performance status pre-CART was associated with higher mortality (HR 2.35, 95%CI 1.02-5.5). The 2-year cumulative incidences of relapse/progression and non-relapse mortality were 69% and 2%, respectively. Grade ≥3 CRS and ICANS occurred in 7% and 15% of patients, respectively. In this largest analysis of CD19-CART for R/R THRLBCL, approximately 30% of patients were alive and progression-free 2 years post-CART. Despite a high incidence of progression (69% at 2 years), these results suggest a subset of patients with R/R THRLBCL may have durable responses with CART.

Surrogates of endothelial injury predict survival after post-transplant cyclophosphamide.

BACKGROUND: Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. OBJECTIVE: We evaluate the prognostic ability of the HCT-CI and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy based GVHD prophylaxis. STUDY DESIGN: Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥ 2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. RESULTS: A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 years after alloHCT (34.5% vs. 12.3%, P = 0.003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 - 6.17, P = 0.005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 - 4.36, P = 0.034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 - 4.33, P = 0.005) and high risk (HR 5.77, 95% CI 2.31 - 14.39, P < 0.001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. CONCLUSION: Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

Outcomes of r/r B-cell NHL patients with limited (<5 Sites) pre-CART Disease Bridged With or Without Radiotherapy.

Unirradiated relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) patients who undergo anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized pre-CART disease. This study reports on the outcomes of r/r NHL patients with limited (<5 involved sites) disease bridged with or without radiotherapy (BRT). A multi-center retrospective review of 150 patients with r/r NHL who received CART with <5 disease sites prior to leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study endpoints included relapse free-survival (RFS), event-free survival (EFS) and overall survival (OS). Prior to CART infusion, 48 (32%) patients received BRT and 102 (68%) did not. The median follow-up was 21 months. Following CART infusion, BRT patients had higher objective response (92% vs 78%, p=0.046) and sustained complete response (54% vs 33%, p=0.015) rates. Local relapse in sites present prior to CART was lower in the BRT group (21% vs. 46%, p=0.003). BRT patients had improved 2-year RFS (53% vs 44%, p=0.023) and 2-year EFS (37% vs 34%, p=0.039) compared to no BRT patients. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared to 42% in those who did not (p=0.002). BRT prior to CART for patients with limited (<5 involved disease sites) r/r NHL improves response rate, local control, RFS, and EFS without causing significant toxicities.

Autologous transplant vs. CAR-T therapy in patients with DLBCL treated while in complete remission.

In patients with relapsed DLBCL in complete remission (CR), autologous hematopoietic cell transplantation (auto-HCT) and CAR-T therapy are both effective, but it is unknown which modality provides superior outcomes. We compared the efficacy of auto-HCT vs. CAR-T in patients with DLBCL in a CR. A retrospective observational study comparing auto-HCT (2015-2021) vs. CAR-T (2018-2021) using the Center for International Blood & Marrow Transplant Research registry. Median follow-up was 49.7 months for the auto-HCT and 24.7 months for the CAR-T cohort. Patients ages 18 and 75 with a diagnosis of DLBCL were included if they received auto-HCT (n = 281) or commercial CAR-T (n = 79) while in a CR. Patients undergoing auto-HCT with only one prior therapy line and CAR-T patients with a previous history of auto-HCT treatment were excluded. Endpoints included Progression-free survival (PFS), relapse rate, non-relapse mortality (NRM) and overall survival (OS). In univariate analysis, treatment with auto-HCT was associated with a higher rate of 2-year PFS (66.2% vs. 47.8%; p < 0.001), a lower 2-year cumulative incidence of relapse (27.8% vs. 48% ; p < 0.001), and a superior 2-year OS (78.9% vs. 65.6%; p = 0.037). In patients with early (within 12 months) treatment failure, auto-HCT was associated with a superior 2-year PFS (70.9% vs. 48.3% ; p < 0.001), lower 2-year cumulative incidence of relapse (22.8% vs. 45.9% ; p < 0.001) and trend for higher 2-year OS (82.4% vs. 66.1% ; p = 0.076). In the multivariable analysis, treatment with auto-HCT was associated with a superior PFS (hazard ratio 1.83; p = 0.0011) and lower incidence of relapse (hazard ratio 2.18; p < 0.0001) compared to CAR-T. In patients with relapsed LBCL who achieve a CR, treatment with auto-HCT is associated with improved clinical outcomes compared to CAR-T. These data support the consideration of auto-HCT in select patients with LBCL achieving a CR in the relapsed setting.

Chimeric antigen receptor T-cell infusion for large B-cell lymphoma in complete remission: a center for international blood and marrow transplant research analysis.

CD19 CAR T-cell (CAR-T) therapy is commonly administered to patients with relapsed or refractory large B-cell lymphomas (LBCL), but salvage or bridging therapy can sometimes lead to a complete response (CR) prior to infusion. Limited studies have assessed the outcomes of patients infused in CR. A total of 134 patients with LBCL in CR prior to CAR-T infusion were identified from the CIBMTR registry, with median prior lines of therapy of 3 (range 2-9). At two years post-infusion, the probability of progression-free survival was 43.5% (95% CI 34.4-52.8) and the probability of overall survival was 63.8% (95% CI 54.4-72.6). The cumulative incidence rates of non-relapse mortality and relapse/progression at two years were 9.2% (95% CI 4.5-15.4) and 47.3% (95% CI 38.2-56.6), respectively. The rate of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were 2.2% and 8.2%, respectively. In summary, CAR-T in heavily pretreated patients with LBCL who are in CR following two or more lines of prior therapy demonstrate that a subset of patients may remain free of progression at two years. Additionally, the toxicity profile was impressive with very low rates of grade 3 CRS and ICANS.

Clinical Practice Recommendations for Hematopoietic Cell Transplantation and Cellular Therapies in Follicular Lymphoma: A Collaborative Effort on Behalf of the American Society for Transplantation and Cellular Therapy and the European Society for Blood and Marrow Transplantation.

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL), accounting for nearly one-third of all NHL. The therapeutic landscape for patients with FL has significantly expanded over the past decade, but the disease continues to be considered incurable. Hematopoietic cell transplantation (HCT) is potentially curative in some cases. Recently, the emergence of chimeric antigen receptor T-cell therapy (CAR-T) for patients with relapsed/refractory (R/R) FL has yielded impressive response rates and long-term remissions, but definitive statement on the curative potential of CAR-T is currently not possible due to limited patient numbers and relatively short follow up. A consensus on the contemporary role, optimal timing, and sequencing of HCT (autologous or allogeneic) and cellular therapies in FL is needed. As a result, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines endorsed this effort to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 15 consensus statements/recommendations. These clinical practice recommendations will help guide clinicians managing patients with FL. Of note, the use of bispecific antibodies in R/R FL was not in the scope of this project.

Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study.

ABSTRACT: We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Pretentious genomic selection signatures in CYP19A1 gene associated with silent estrous behavior in water buffalo in Pakistan

Background: Poor reproductive efficiency of river buffalos hampers the production capabilities of animals. Buffalos are mainly considered poor breeders owing to the constrained expression of estrus behavior. Failure to display heat signs is an indication of improper functionality of signaling peptides to trigger on a series of behavioral changes, which can be detectable by breeders for timely insemination of females. This might cause an animal to be a repeat breeder. Genomic variations underlying synthesis of signaling peptides can be a useful marker to select superior animals with better reproductive efficiency. In this context, the current study was designed to analyze the CYP19A1 gene in Nili-Ravi buffalo. Results: A total of 97 animals were selected and were divided into two groups on the basis of their heat score. PCR amplification and sequencing of the amplicons were performed using the specific sets of primer, and then, sequences were analyzed for novel variants. A total of 11 polymorphic sites were identified illustrating phenotypic variation in the heat score. Most of the loci were found homologous. Single Nucleotide Polymorphisms (SNPs) were analyzed for association with silent estrus. A three-dimensional protein model was also generated to locate the position of exonic SNPs. Conclusion: This study illustrated that polymorphic sites in the CYP19A1 gene provided potential markers for selection of buffalos with better estrus behavior.

Surgery for tetralogy of fallot in adults: early outcomes

Abstract Objective: To study the in-hospital outcome of adult patients who had undergone surgical repair for Tetralogy of Fallot. Methods: A retrospective descriptive study was conducted at the Punjab Institute of Cardiology searching the hospital records. All those adult patients who had undergone repair for Tetralogy of Fallot from January 2012 to December 2014 were included in the study. All the patients were operated by the same surgical team. Patients who underwent primary repair as well as those with previous palliative procedures were included in the study. Thirty days outcome was studied by recording variables from the database. Data was analysed using Statistical Package for Social Sciences version 16. Results: A total of 80 patients was included in the study, in which there were 48 (60%) male patients and 32 (40%) female patients. Mean age was 21±0.21 years. Those with previous palliation were 15 (18.75%). The associated problems observed were: atrial septal defect 27 (33.75%), right aortic arch 30 (37.5%), patent ductus arteriosus 6 (7.5%) and double outlet right ventricle 3 (3.75%). In-hospital mortality recorded was 7 (8%). Postoperative complications encountered were low cardiac output syndrome 9 (11.25%), pleural effusion requiring tapping 3 (3.75%), reoperation for bleeding 3 (3.8%), pulmonary regurgitation (moderate to severe) 20 (25%) which occurred in the transannular patch group only and atrial arrhythmia 4 (5%). Conclusion: A large number of adult patients are still operated for tetralogy of Fallot in Pakistan. With increasing experience in the technique the mortality and morbidity is comparable to international literature.