Targeting lipid-protein interaction to treat Syk-mediated acute myeloid leukemia.

Membrane lipids control the cellular activity of kinases containing the Src homology 2 (SH2) domain through direct lipid-SH2 domain interactions. Here we report development of new nonlipidic small molecule inhibitors of the lipid-SH2 domain interaction that block the cellular activity of their host proteins. As a pilot study, we evaluated the efficacy of lipid-SH2 domain interaction inhibitors for spleen tyrosine kinase (Syk), which is implicated in hematopoietic malignancies, including acute myeloid leukemia (AML). An optimized inhibitor (WC36) specifically and potently suppressed oncogenic activities of Syk in AML cell lines and patient-derived AML cells. Unlike ATP-competitive Syk inhibitors, WC36 was refractory to de novo and acquired drug resistance due to its ability to block not only the Syk kinase activity, but also its noncatalytic scaffolding function that is linked to drug resistance. Collectively, our study shows that targeting lipid-protein interaction is a powerful approach to developing new small molecule drugs.

Structural racism is a mediator of disparities in acute myeloid leukemia outcomes.

Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic White (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult patients with AML from 6 urban cancer centers and revealed inferior survival among NHB (hazard ratio [HR] = 1.59; 95% confidence interval [CI]: 1.15, 2.22) and Hispanic (HR = 1.25; 95% CI: 0.88, 1.79) patients compared with NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across 6 composite variables: structural racism (census tract disadvantage, affluence, and segregation), tumor biology (European Leukemia Network risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization), and intensive care unit (ICU) admission during induction chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, and treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.

Use, variability, and justification of eligibility criteria for phase II and III clinical trials in acute leukemia.

Clinical trial eligibility criteria can unfairly exclude patients or unnecessarily expose them to known risks if criteria are not concordant with drug safety. There are few data evaluating the extent to which acute leukemia eligibility criteria are justified. We analyzed criteria and drug safety data for front-line phase II and/or III acute leukemia trials with start dates 1/1/2010-12/31/2019 registered on clinicaltrials.gov. Multivariable analyses assessed concordance between criteria use and safety data (presence of criteria with a safety signal, or absence of criteria without a signal), and differences between criteria and safety-based limits. Of 250 eligible trials, concordant use of ejection fraction criteria was seen in 34.8%, corrected QT level (QTc) in 22.4%, bilirubin in 68.4%, aspartate transaminase/alanine aminotransferase (AST/ALT) in 58.8%, renal function in 68.4%, human immunodeficiency virus (HIV) in 54.8%, and hepatitis B and C in 42.0% and 41.2%. HIV and hepatitis B and C criteria use was concordant with safety data (adjusted Odds Ratios 2.04 [95%CI: 1.13, 3.66], 2.64 [95%CI: 1.38, 5.04], 2.27 [95%CI: 1.20, 4.32]) but organ function criteria were not (all P>0.05); phase III trials were not more concordant. Bilirubin criteria limits were the same as safety-based limits in 16.0% of trials, AST/ALT in 18.1%, and renal function in 13.9%; in 75.7%, 51.4%, and 56.5% of trials, criteria were more restrictive, respectively, by median differences of 0.2, 0.5, and 0.5 times the upper limits of normal. We found limited drug safety justifications for acute leukemia eligibility criteria. These data define criteria use and limits that can be rationally modified to increase patient inclusion and welfare.

Impact of Postoperative Antibiotic Prophylaxis on Surgical Site Infections Rates After Mastectomy with Drains but Without Immediate Reconstruction: A Multicenter, Double-Blinded, Randomized Control Superiority Trial.

BACKGROUND: There is no consensus on the use of postoperative antibiotic prophylaxis (PAP) after mastectomy with indwelling drains. We explored the utility of continued PAP in reducing surgical site infection (SSI) rates after mastectomy without immediate reconstruction and with indwelling drains. PATIENTS AND METHODS: A multicenter, two-armed, randomized control superiority trial was conducted in Pakistan. We enrolled all consenting adult patients undergoing mastectomy without immediate reconstruction. All patients received a single preoperative dose of cephalexin within 60 min of incision, and postoperatively were randomized to receive either continued PAP using cephalexin (intervention) or a placebo (control) for the duration of indwelling, closed-suction drains. The primary outcome was the development of SSI within 30 days and 90 days postoperatively. Secondary outcomes included study-drug-associated adverse events. Intention-to-treat analysis was performed using multivariable Cox regression. RESULTS: A total of 369 patients, 180 (48.8%) in the intervention group and 189 (51.2%) in the control group, were included in the final analysis. Overall cumulative SSI rates were 3.5% at 30 days and 4.6% at 90 days postoperatively. PAP was not associated with SSI reduction at 30 (hazard ratio, HR 1.666 [95% confidence interval CI 0.515-5.385]) or 90 (1.575 [0.558-4.448]) days postoperatively, or with study-drug-associated adverse effects (0.529 [0.196-1.428]). CONCLUSIONS: Continuing antibiotic prophylaxis for the duration of indwelling drains after mastectomy without immediate reconstruction offers no additional benefit in terms of SSI reduction. There is a need to update existing guidelines to provide clearer recommendations regarding use of postoperative antibiotic prophylaxis after mastectomy in the setting of indwelling drains.

Impact of race on outcomes in intermediate-risk acute myeloid leukemia.

PURPOSE: Racial disparities in acute myeloid leukemia (AML) have been reported but the relative contribution of disease versus patient-specific factors including comorbidities and access to care is unclear. METHODS: We conducted a retrospective analysis of patient characteristics, treatment patterns and outcomes in a racially diverse patient cohort controlling for cytogenetic risk group. Patients were classified into four groups: non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic and Other. RESULTS: We evaluated 106 patients from 84 zipcodes incorporating demographics, clinicopathologic features, treatment patterns and outcomes. We identified significant differences in BMI and geographic poverty based on ethnoracial group, while prognostic mutations in NPM1 and FLT3 did not differ significantly. Utilization of intensive chemotherapy and transplant rate did not differ by ethnoracial group. However, there was a significantly higher use of alternate donor transplants in minority populations. There was a notably increased rate of clinical trial enrollment in NHW patients compared to other groups. In log-rank analysis, NHW patients had increased overall survival (OS) compared to NHB, Hispanic and Other patients (31.6 months vs. 16.7 months vs. 14.3 months, vs 18.1 months, p = 0.021). In bivariate analysis, overall survival was negatively influenced by advanced age and race. Obesity and zip code poverty levels approached statistical significance in predicting OS. In multivariate analysis, the only factors independently influencing OS were race and allogeneic stem cell transplant. CONCLUSION: These results suggest that race impacts survival in intermediate-risk AML, highlighting the need to dissect biologic and nonbiologic factors that contribute to this disparity.

A multi-institutional comparison of mitoxantrone, etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia.

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.

Clinical Decision Unit, an extension of emergency department: An experience and advantage in a tertiary care centre.

OBJECTIVE: To evaluate the clinical decision unit of a tertiary care health facility and to see the disease pattern. . METHODOLOGY: The cross-sectional retrospective study was conducted at the Department of Emergency Medicine, Aga Khan University Hospital, Karachi, from September to October 2011, and comprised data of patients admitted to the clinical decision unit from January to December 2010. The protocols were developed for 7 diseases: acute coronary syndrome, ureteric colic, abdominal pain, bronchial asthma, gastroenteritis with dehydration, headache, and minor head injury. Data-collection proforma recorded demographics, dates of admission, presenting complaints at triage, diagnosis at admission, final disposition and bounce back of the patients. Data was analysed using Microsoft Excel 2007. RESULTS: Of the 1515 patients whose data was analysed, 824(54%) were males. The overall age ranged from newborns to 93 years. Further, 904(60%) patients had presented to the triage counter as P3 category. Acute gastroenteritis was the most common complaint 240(15.84%). Of the total, 1311(87%) were sent home from the clinical decision unit; 39(2.8%) of them bounced back with the same complaint. Overall, 2(0.2%) adult patients expired. CONCLUSIONS: The unit evaluated had a productive initial year. Acute gastroenteritis was the most common protocol in use, but other protocols should also be developed to address local needs.

Near missed diagnosis of extensive aortic dissection in a young patient presenting with non-specific symptoms.

Acute aortic dissection is a frequently fatal condition that rarely involves young individuals. It has an estimated worldwide prevalence of 0.5-2.95 per 100,000 persons per year, with a mean incidence at around age 60. Of all the aortic dissections, less than 10% involve patients younger than 40 years of age. We present the case of a forty-yearold male who presented in the emergency department with non-specific complaints of nausea and lightheadedness. The patient being hemodynamically and clinically stable was discharged after supportive treatment. However after 5 hours the patient presented again in the emergency department with a neck pain, hypotension and sweating. CT angiography revealed a massive aortic dissection involving ascending, arch and descending aorta up to the bifurcation of iliac arteries. The patient was immediately taken for surgery for the replacement of ascending aorta and resuspension of aortic valve. The patient tolerated surgery well and was discharged after being clinically and haemodynamically stable.

The rocky road to personalized medicine in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a malignant disorder of the myeloid blood lineage characterized by impaired differentiation and increased proliferation of hematopoietic precursor cells. Recent technological advances have led to an improved understanding of AML biology but also uncovered the enormous cytogenetic and molecular heterogeneity of the disease. Despite this heterogeneity, AML is mostly managed by a 'one-size-fits-all' approach consisting of intensive, highly toxic induction and consolidation chemotherapy. These treatment protocols have remained largely unchanged for the past several decades and only lead to a cure in approximately 30-35% of cases. The advent of targeted therapies in chronic myeloid leukaemia and other malignancies has sparked hope to improve patient outcome in AML. However, the implementation of targeted agents in AML therapy has been unexpectedly cumbersome and remains a difficult task due to a variety of disease- and patient-specific factors. In this review, we describe current standard and investigational therapeutic strategies with a focus on targeted agents and highlight potential tools that might facilitate the development of targeted therapies for this fatal disease. The classes of agents described in this review include constitutively activated signalling pathway inhibitors, surface receptor targets, epigenetic modifiers, drugs targeting the interaction of the hematopoietic progenitor cell with the stroma and drugs that target the apoptotic machinery. The clinical context and outcome with these agents will be examined to gain insight about their optimal utilization.

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease.

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 109/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.

Neonatal Purpura Fulminans, a rare genetic disorder due to protein C deficiency: A case report.

Neonatal Purpura Fulminans is a rare and fatal disorder associated with perivascular haemorrhage and disseminated intravascular coagulation. Early clinical recognition, timely investigation and treatment is utmost important. A 6 days old baby boy was brought to emergency with blackish ulcers all over the body. Initially these were over the feet and scalp but later appeared on the abdomen. On examination, child was vitally stable, mildly icteric and had multiple erythematous large bullous blackish lesions on scalp, lower abdomen, perineum, back and soles. Neonatal reflexes and systemic examination was normal. Laboratory investigations showed normal CBC, PT/APTT and Protein S level while Protein C and Antithrombin III levels were low. Neonatal Purpura Fulminans is a life threatening condition and family screening is also mandatory for early recognition of disease in the siblings.

Implementation of the World Health Organization Trauma Care Checklist Program in 11 Centers Across Multiple Economic Strata: Effect on Care Process Measures.

BACKGROUND: Trauma contributes more than ten percent of the global burden of disease. Initial assessment and resuscitation of trauma patients often requires rapid diagnosis and management of multiple concurrent complex conditions, and errors are common. We investigated whether implementing a trauma care checklist would improve care for injured patients in low-, middle-, and high-income countries. METHODS: From 2010 to 2012, the impact of the World Health Organization (WHO) Trauma Care Checklist program was assessed in 11 hospitals using a stepped wedge pre- and post-intervention comparison with randomly assigned intervention start dates. Study sites represented nine countries with diverse economic and geographic contexts. Primary end points were adherence to process of care measures; secondary data on morbidity and mortality were also collected. Multilevel logistic regression models examined differences in measures pre- versus post-intervention, accounting for patient age, gender, injury severity, and center-specific variability. RESULTS: Data were collected on 1641 patients before and 1781 after program implementation. Patient age (mean 34 ± 18 vs. 34 ± 18), sex (21 vs. 22 % female), and the proportion of patients with injury severity scores (ISS) ≥ 25 (10 vs. 10 %) were similar before and after checklist implementation (p > 0.05). Improvement was found for 18 of 19 process measures, including greater odds of having abdominal examination (OR 3.26), chest auscultation (OR 2.68), and distal pulse examination (OR 2.33) (all p < 0.05). These changes were robust to several sensitivity analyses. CONCLUSIONS: Implementation of the WHO Trauma Care Checklist was associated with substantial improvements in patient care process measures among a cohort of patients in diverse settings.

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely performed in adult patients with sickle cell disease (SCD). We utilized the chemotherapy-free, alemtuzumab/total body irradiation 300 cGy regimen with sirolimus as post-transplantation immunosuppression in 13 high-risk SCD adult patients between November 2011 and June 2014. Patients received matched related donor (MRD) granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, including 2 cases that were ABO incompatible. Quality-of-life (QoL) measurements were performed at different time points after HSCT. All 13 patients initially engrafted. A stable mixed donor/recipient chimerism was maintained in 12 patients (92%), whereas 1 patient not compliant with sirolimus experienced secondary graft failure. With a median follow-up of 22 months (range, 12 to 44 months) there was no mortality, no acute or chronic graft-versus-host disease (GVHD), and no grades 3 or 4 extramedullary toxicities. At 1 year after transplantation, patients with stable donor chimerism have normalized hemoglobin concentrations and improved cardiopulmonary and QoL parameters including bodily pain, general health, and vitality. In 4 patients, sirolimus was stopped without rejection or SCD-related complications. These results underscore the successful use of a chemotherapy-free regimen in MRD HSCT for high-risk adult SCD patients and demonstrates a high cure rate, absence of GVHD or mortality, and improvement in QoL including the applicability of this regimen in ABO mismatched cases (NCT number 01499888).

Impact of delay in admission on the outcome of critically ill patients presenting to the emergency department of a tertiary care hospital from low income country.

OBJECTIVE: To assess the impact of admission delay on the outcome of critical patients. METHODS: The retrospective chart review was done at Aga Khan University Hospital, Karachi, and comprised adult patients visiting the Emergency Department during 2010. Outcome measures assessed were total hospital length of stay, total cost of the visit and in-hospital mortality. Patients admitted within 6 hours of presentation at Emergency Department were defined as non-delayed. Data was analysed using SPSS 19. RESULTS: Of the 49,532 patients reporting at the Emergency Department during the study period, 17,968 (36.3%) were admitted. Of them 2356(13%) were admitted to special or intensive care units, 1595(67.7%) of this sub-group stayed in the Emergency Department for >6 hours before being shifted to intensive care. The study focussed on 325(0.65%) of the total patients; 164(50.5%) in the non-delayed group and 161(49.5%) in the delayed group. The admitting diagnosis of myocardial infarction (p=0.00) and acute coronary syndrome (p=0.01) was significantly more common in the non-delayed group compared to other diagnoses like cerebrovascular attacks (p=0.03) which was significantly more common in the delayed group. There was no significant difference in the hospital length of stay between the two groups (p>0.05). The Emergency Department cost was significantly increased in the delayed group (p<0.05), but there was no difference in the overall hospital cost between the groups (p>0.05). CONCLUSIONS: There was no significant difference in the delayed and non-delayed groups, but long Emergency Department stays are distressing for both physicians and patients.

Bomb blast injuries: an exploration of patient characteristics and outcome using Pakistan National Emergency Departments Surveillance (Pak-NEDS) data.

BACKGROUND: Bomb blast injuries result in premature deaths and burdening of healthcare systems. The objective of this study was to explore the characteristics and outcome of patients presenting to the emergency departments in Pakistan with bomb blast injuries. METHODS: Active surveillance was conducted in seven major emergency departments of Pakistan from November 2010-March 2011. All the sites are tertiary care urban centers. All the patients who presented to the hospital's emergency department (ED) following a bomb blast injury as per self-report or the ambulance personnel were included in the study. Frequency of demographics, injury pattern, and outcomes were calculated. RESULTS: A total of 103 patients with bomb blast injuries presented to the selected emergency departments. The median age of patients was 30 years. Around three-fourth of the patients were males (n = 74, 74.7%). Most of the bomb blast patients were seen in Peshawar (n = 41, 39.8%) and Karachi city (n = 31, 30.1%) and the most common mode of arrival was non-ambulance transport (n = 71, 76.3%). Upper limb injuries (n = 12, 40%) were common in the under 18 age group and lower limb injuries (n = 31, 39.2%) in the 18 years and above group. There were a total of 8 (7.7%) deaths reported out of these 103 patients. CONCLUSION: Bomb blast injuries in Pakistan generally affect young males. Non-ambulance transport is the most common way to access emergency departments (ED). Overall ED mortality is high and capturing data during a disaster in an emergency department is challenging.

Vulnerable road users are at greater risk during Ramadan -- results from road traffic surveillance data.

OBJECTIVE: To assess how the frequency, nature and outcome of road traffic crashes differ during the fasting month of Ramadan. METHODS: The retrospective study was conducted in Karachi and comprised data from the Road Traffic Injury Surveillance Project which entailed information on all road traffic injury victims presenting to Emergency Departments in the city between September 2006 and September 2011. Data was analysed to find the frequency of road traffic crashes according to time of incident, road user group and survival. Ramadan and Non-Ramadan groups were compared with respect to time and frequency of incidents, road user group and mortality. SPSS 16 was used for statistical analysis. RESULTS: There were 163,022 subjects from whom 13,640(8.36%) came during Ramadan and 149,382 (91.6%) during the non-Ramadan months. Frequency of road traffic crashes did not change significantly during Ramadan, but was clustered around the breaking of Fast and the Taravih prayers. The most commonly affected road user group was motorbike riders followed by pedestrians. Overall survival of the RTI victims was 96.1% with a mortality rate of 4.1% which was higher than the figure of 3.5% in the non-Ramadan period. CONCLUSIONS: Vulnerable road users were more frequently involved in road traffic injuries during Ramadan. Moreover, the frequency of crashes increased around evening which requires more careful planning of traffic controls, especially for the vulnerable road users.

Nail as a foreign body in a neonate, an unusual presentation at an unusual age.

Children are prone to ingest substances due to their exploratory nature and tendency to put everything in the mouth. Commonly ingested foreign bodies are coins, batteries and buttons. Foreign body ingestion in neonates is a very rare presentation and always needs important consideration as it can be a part of child abuse and can lead to serious life threatening consequences.

Combination of linear accelerator-based intensity-modulated total marrow irradiation and myeloablative fludarabine/busulfan: a phase I study.

Here we examined the addition of intensity-modulated total marrow irradiation (TMI) delivered using a linear accelerator to a myeloablative chemotherapy conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT). In this phase I study, we enrolled 14 patients with high-risk hematologic malignancies who received escalating doses of TMI at 3 Gy (n = 3), 6 Gy (n = 3), 9 Gy (n = 6), and 12 Gy (n = 2) in combination with intravenous (i.v.) fludarabine 160 mg/m(2) and targeted busulfan (area under the curve, 4800 µM*minute). Peripheral blood mobilized stem cells were obtained from HLA-matched related (n = 9) or unrelated (n = 4) or 1 antigen-mismatched unrelated (n = 1) donors. All patients rapidly engrafted and recovered their immune cells. Overall, Bearman extrahematologic toxicity were limited to grades 1 or 2, with oral mucositis grade 1 in 64% and grade 2 in 36% of the patients. With a median follow-up of 1126 days (range, 362 to 1469) for living patients, the overall survival was 50% and relapse-free survival was 43%. Of 7 deaths, 3 were due to relapse and 4 to transplantation-related complications. We conclude that 9 Gy TMI can be combined with myeloablative chemotherapy in the design of new preparative regimens for HSCT. This study was registered at clinicaltrials.gov as NCT00988013.