Patricia Adams-Graves

Sickle cell pain

Sickle cell pain includes 3 types: acute recurrent painful crises, chronic pain syndromes, and neuropathic pain. The acute painful crisis is the hallmark of the disease and the most common cause of hospitalization and treatment in the emergency department. It evolves through 4 phases: prodromal, initial, established, and resolving. Each acute painful episode is associated with inflammation that worsens with recurrent episodes, often culminating in serious complications and organ damage, such as acute chest syndrome, multiorgan failure, and sudden death. Three pathophysiologic events operate in unison during the prodromal phase of the crisis: vaso-occlusion, inflammation, and nociception. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage. Our hypothesis is that managing these events with hydration, anti-inflammatory drugs, aggressive analgesia, and possibly vasodilators could abort the crisis and prevent or minimize further damage. Chronic pain syndromes are associated with or accompany avascular necrosis and leg ulcers. Neuropathic pain is not well studied in patients with sickle cell disease but has been modeled in the transgenic sickle mouse. Management of sickle cell pain should be based on its own pathophysiologic mechanisms rather than borrowing guidelines from other nonsickle pain syndromes.

Sickle cell pain: a critical reappraisal

Sickle cell pain includes 3 types: acute recurrent painful crises, chronic pain syndromes, and neuropathic pain. The acute painful crisis is the hallmark of the disease and the most common cause of hospitalization and treatment in the emergency department. It evolves through 4 phases: prodromal, initial, established, and resolving. Each acute painful episode is associated with inflammation that worsens with recurrent episodes, often culminating in serious complications and organ damage, such as acute chest syndrome, multiorgan failure, and sudden death. Three pathophysiologic events operate in unison during the prodromal phase of the crisis: vaso-occlusion, inflammation, and nociception. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage. Our hypothesis is that managing these events with hydration, anti-inflammatory drugs, aggressive analgesia, and possibly vasodilators could abort the crisis and prevent or minimize further damage. Chronic pain syndromes are associated with or accompany avascular necrosis and leg ulcers. Neuropathic pain is not well studied in patients with sickle cell disease but has been modeled in the transgenic sickle mouse. Management of sickle cell pain should be based on its own pathophysiologic mechanisms rather than borrowing guidelines from other nonsickle pain syndromes.

Hemodynamic Predictors of Mortality in Adults with Sickle Cell Disease

BACKGROUNDnPulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH.nnnOBJECTIVESnTo identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization.nnnMETHODSnNine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression.nnnMEASUREMENTS AND MAIN RESULTSnSpecific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05-2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09-3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP - pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23-3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14-2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09-1.89 per Wood unit increase; P = 0.009) as risk factors for mortality.nnnCONCLUSIONSnMortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.

A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers

Sickle cell leg ulcers are often debilitating, refractory to healing, and prone to recurrence. Healing of leg ulcers was incidentally observed during dose‐ranging trials of Arginine Butyrate in beta haemoglobinopathies. Here, a controlled Phase II trial was performed in sickle cell patients who had lower extremity ulcers refractory to standard care for at least 6u2003months. Patients were randomized to receive standard local care alone (Control Arm) or standard care with Arginine Butyrate administered 5u2003d/week (Treatment Arm), for 12u2003weeks. Ulcers were photographed weekly, traced, and ulcer areas were calculated by computerized planimetry and compared between the two study arms. Twenty‐seven study courses were evaluated. Control Arm subjects had 25 ulcers with a mean area of 25·7u2003cm2 initially and 23·2u2003cm2 after 12u2003weeks; 2/25 (8%) healed completely. Treatment Arm subjects had 37 ulcers with a mean area of 50·6u2003cm2 initially and 28·3u2003cm2 at 12u2003weeks; 11/37 of these (30%) healed completely. After 3u2003months, proportions of ulcers which healed were 6/25 (24%) and 29/37 (78%), in the Control and Treatment Arms respectively (Pu2003<u20030·001). These findings strongly suggest that Arginine Butyrate merits further evaluation for the treatment of refractory sickle cell leg ulcers in larger trials.

A Transition Pilot Program for Adolescents With Sickle Cell Disease

INTRODUCTIONnTransition from pediatric to adult care is challenging for adolescents with chronic illnesses, including those with sickle cell disease (SCD). We describe a pilot program created to facilitate transition from pediatric to adult care by helping adolescents with SCD identify an adult medical home.nnnMETHODSnWe investigated the feasibility of this program by evaluation of overall participation, satisfaction, and acceptance. A secondary objective was to compare the proportion of adolescents who fulfilled a first appointment with an adult hematologist among participants and nonparticipants.nnnRESULTSnDuring the first 18 months of the program, 83 adolescents were invited and 34 (41%) agreed to participate; 25 (74%) completed their first visit within 3 months after leaving the pediatric program, compared with 16 of 49 (33%) of nonparticipants (p = .0002). Overall, 41 of 83 adolescents (49%) completed an appointment with an adult SCD program, regardless of program participation, in contrast with 11 of 75 adolescents (15%) who did so during the 18 months before the program was created (p < .0001).nnnDISCUSSIONnThis transition pilot program was feasible, and most adolescent participants with SCD established an adult medical home.

Leg Ulcers in Sickle Cell Disease: Current Patterns and Practices

Leg ulcers are a debilitating complication of patients with sickle cell disease, and their frequency in North America was reported to be 2.5% by the Cooperative Study of Sickle Cell Disease more than 20 years ago. We sought to determine if the frequency of leg ulcers in sickle cell patients in the United States had declined and to assess which treatments providers use most commonly. We sent an e-mail survey to health professionals belonging to the national Sickle Cell Adult Provider Network. Responses were obtained from 31 of them (26.0%). Most of them (96.0%) reported having some patients with leg ulcers. Providers reported a total of 185 patients with active leg ulcers and 224 in the previous 5 years, for a total of 409 patients. Hb SS (homozygous sickle cell anemia) was the most common genotype of affected individuals, followed by Hb SC (double heterozygote for Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T] and Hb C [β6(A3)Glu→Lys, GAG>AAG; HBB: c.19G>A]). Males showed a 2:1 predominance. Two-thirds of patients were treated with either hydroxyurea (HU) or transfusion therapy and most used compression stockings and topical therapies as directed by wound care services. We conclude that leg ulcers continue to be a debilitating complication of young adults with sickle cell disease, despite improved supportive care and the widespread use of disease modifying agents such HU and transfusion. While some providers offer office-based ulcer care, the majority prefer specialty consultation including podiatry, plastic surgery and dermatology. Despite their frequency, there is no clear consensus among providers as to the best treatment.

Prevalence and Progression of Chronic Kidney Disease in Adult Patients With Sickle Cell Disease

Aim We evaluated the prevalence and progression of chronic kidney disease (CKD) during the 5-year period in a cohort of patients with sickle cell disease (SCD) aged 18 years and older. Methods We studied 98 patients with SCD. Chronic kidney disease stages I through V were defined based on estimated glomerular filtration rate (eGFR), and albuminuria grades were defined based on spot urine protein-to-creatinine ratio according to the 2012 Kidney Disease Improving Global Outcomes recommendations. In patients with eGFR of greater than 60 mL/min per 1.73 m2, CKD was diagnosed if grade A2 or A3 albuminuria was present. Chronic kidney disease progression was defined as an increase in CKD stage with an additional eGFR reduction of more than 25% from baseline. Results At baseline, 28.6% of patients had CKD. After a mean follow-up of 5.0 (SD, 0.9) years, 17 patients developed new CKD and the overall CKD prevalence increased to 41.8%. In addition, 8 patients experienced CKD progression. The following baseline variables were associated with the development and progression of CKD in univariate analysis: older age (P = 0.003), higher systolic blood pressure (BP; P = 0.003), lower eGFR (P = 0.001), higher serum creatinine (P = 0.001), and A3 albuminuria (P = 0.008). In multivariate analysis, baseline A3 albuminuria (adjusted odds ratio, 5.0; 95% confidence interval, 1.1-24.3; P = 0.048) and each 1-mm Hg increase in systolic BP (adjusted odds ratio, 1.04; 95% confidence interval, 1.0-1.07; P = 0.039) predicted CKD development and progression. Conclusions Chronic kidney disease is common in patients with SCD and its prevalence increases with age. Several baseline modifiable and nonmodifiable factors were associated with the development and progression of CKD in patients with SCD. Strategies targeting BP control and proteinuria may be beneficial for individuals with SCD.

A Phase 3 Study of L-Glutamine Therapy for Sickle Cell Anemia and Sickle ß0-Thalassemia

H Risk Papillomavirus (hr-HPV) genotypes are causal agents for cervical cancer and some geographical variation has been reported. Available vaccines cater for up to nine hr-HPV genotypes, which may not necessarily be the most predominant strains in every region of the world. Data on HPV genotype in South African regions is limited and unavailable for KwaZuluNatal (KZN) province .Our study aimed to describe hr-HPV genotype distribution among young women in relation to cervical cancer vaccination. A total of 1223 sexually active young women were recruited from high schools, 658 (54%) were from Ugu and 565 (46%) from Ilembe districts and these were investigated for high risk Human Papillomavirus, using GP5/6+ primers and enzyme immunoassay. Of the 1223 vaginal lavages, 301 (25%) were positive for hr-HPV. Of these, 177 (27%) and 124 (22%) were from Ugu and Ilembe districts respectively (p = 0.046). HPV type distribution per district revealed an overall similar distribution, the most predominant types in descending order were HPV 16, 51, 18, 35, 33, 56, 45, 52 and 59. Our data describes high-risk HPV strains infecting young women in the KwaZulu-Natal province and demonstrated that the new nanovalent HPV vaccine does not protect against all predominant hrHPV types. HPV 51, 35 and 56 are most prevalent in KZN yet not covered by the nanovalent vaccine. Investigation of cervical cancer cases would be necessary to ascertain that these types are involved in a significant proportion of these cases.Background: The tumor suppressor phosphatase and tensin homolog (PTEN) is a pleiotropic enzyme, inhibiting phosphatidyl-inositol-3 kinase (PI3K) signaling in the cytosol and stabilizing the genome in the nucleus. Nucleo-cytosolic partitioning is dependent on the posttranslational modifications ubiquitinylation and sumoylation. This cellular compartmentalization of PTEN was investigated in lung neuro-endocrine tumors (lung NET). Methods: Tumor tissues from 192 lung NET patients (surgical specimens=183, autopsies=9) were investigated on tissue microarrays. PTEN was H-scored by two investigators in nucleus and cytosol using the monoclonal antibody 6H2.1. Results were correlated with immunoreactivity for USP7 (herpes virus-associated ubiquitin-specific protease 7) and SUMO2/3 (small ubiquitin-related modifier protein 2/3) as well as PTEN and p53FISH gene status. Clinico-pathologic data including overall survival, proliferation rate and diagnostic markers (synaptophysin, chromogranin A, Mib-1, TTF-1) were recorded. Results: The multicentre cohort included 58 typical carcinoids (TC), 42 atypical carcinoids (AC), 32 large cell neuro-endocrine carcinomas (LCNEC) and 60 small cell lung carcinomas (SCLC). Carcinoids were smaller in size and had higher synaptophysin and chromogranin-A, but lower TTF-1 expressions. Patients with carcinoids were predominantly female and 10 years younger than patients with LCNEC/SCLC. In comparison to the carcinoids, LCNEC/SCLC tumors presented a stronger loss of nuclear and cytosolic PTEN associated with a loss of PTEN and p53. Concomitantly, a loss of nuclear USP7 but increase of nuclear and cytosolic SUMO2/3 was found. Loss of nuclear and cytosolic PTEN, loss of nuclear USP7 and increase of cytosolic SUMO2/3 thus correlated with poor survival. Among carcinoids, loss of cytosolic PTEN was predominantly found in TTF1-negative larger tumors of male patients. Among SCLC, loss of both cytosolic and nuclear PTEN but not proliferation rate or tumor size delineated a subgroup with poorer survival (all p-values <0.05). Conclusions: Cellular ubiquitinylation and sumoylation likely influence the functional PTEN loss in high grade lung NET. Both nuclear and cytosolic PTEN immunoreactivity should be considered for correlation with clinico-pathologic parameters.Background: New treatments for patients with sickle cell disease (SCD) are needed. Oxidative stress may lead to disturbance of cell membranes, exposure of adhesion molecules and damage to the contents of the sickle red blood cells (s-RBC). Nicotinamide adenine dinucleotide (NAD) molecules modulate oxidation-reduction in s-RBCs. Our previous laboratory work demonstrated enhancement of NAD in s-RBC by supplementing a precursor of NAD, L-glutamine. In our Phase-2 clinical study in SCD, oral prescription grade L-glutamine (PGLG) signaled a decreasing trend for painful crises at 24 weeks and a significant decrease in hospitalization at 24 weeks. Methods: A randomized (2:1) Phase 3 placebo-controlled trial was conducted across the United States. Subjects were stratified by hydroxyurea usage. Eligibility criteria included patients ≥5 years of age with diagnoses of HbSS or HbS/β 0 -thalassemia with at least two episodes of sickle cell crises (SCC) during the 12 months prior to screening. PGLG at 0.6 g/kg/day (max 30 g), or placebo, was self-administered in two divided doses orally. The primary endpoint was number of SCC; secondary endpoints included rates of hospitalization and adverse events; additional analyses included cumulative hospital days, incidence of acute chest syndrome (ACS) and time to first crises. Results: A total of 230 patients were enrolled at 31 sites. Groups were well balanced for clinical characteristics. The median incidence of SCC (3 vs. 4 events; p=0.008) as well as hospitalizations (2 events vs. 3; p=0.005) was significantly lower in the treatment group compared to the placebo group. Median cumulative hospital days were lower by 41% in the treatment group (6.5 days) vs. the placebo group (11 days) (p=0.022); ACS was 11.9% in the treatment group and 26.9% in the placebo group (p=0.006). The median time to first crisis was 87 days in the treatment group vs. 54 days in placebo group (p=0.010). Analysis by hydroxurea use, age, and gender yielded consistent findings. Adverse events in the treatment arms were similar between groups. Conclusion: This Phase-3 study in SCD demonstrated that treatment with PGLG provided clinical benefit over placebo by reducing the frequency of painful crises and hospitalization. Additional benefit was observed when evaluating ACS, time to first crises and duration of hospital stay. PGLG was relatively easy to administer and did not require special monitoring.The oncofetal H19 long non-coding RNA (lnc RNA) is normally expressed in the embryo and down regulated at birth; however its expression is re-elicited in human tumors of almost every type. Accumulating data by us and others consolidate into a paradigm according to which H19 is in the center of a mammalian “selfish survival pathway” activated by the cancerous cell in order to cope with stress conditions. P53 nullification or dysfunction, hypoxia, serum starvation, chemotherapy and other stress inducers up-regulate H19 expression. H19 in turn supports tumor growth and enhances proliferation in response to hypoxia and p53 mutations. We have also recently proven that H19 RNA significantly contributes to epithelial to mesenchymal transition (EMT), a process which is known to emerge as a response to a multitude of stress conditions. Surprisingly, studies indicate that H19 is involved also in the further, apparently converse steps of mesenchymal to epithelial transition to support colonization and proliferation in the secondary tumor site. In view of the paradigm suggested above, H19’s unique expression in cancers and the active involvement of H19 in almost every deleterious aspect of cancer progression, H19 should serve as a state of the art target for highly selective cancer therapy. Indeed, we currently use a DNA-plasmid based drug that harnesses H19 regulatory elements to drive the expression of Diphtheria toxin – a translational regulated therapy designed to selectively kill cancer cells with no collateral damage to the healthy surrounding tissues. We will comprehensively review recent studies that align with our paradigm and demonstrate how understanding of H19 expression and biology is translated into promising results in bladder, pancreas and ovarian cancer clinical trials.

Adherence to iron chelation therapy and associated healthcare resource utilization and costs in Medicaid patients with sickle cell disease and thalassemia

Abstract Background: Sub-optimal patient adherence to iron chelation therapy (ICT) may impact patient outcomes and increase cost of care. This study evaluated the economic burden of ICT non-adherence in patients with sickle cell disease (SCD) or thalassemia. Methods: Patients with SCD or thalassemia were identified from six state Medicaid programs (1997–2013). Adherence was estimated using the medication possession ratio (MPR) of ≥0.80. All-cause and disease-specific resource utilization per-patient-per-month (PPPM) was assessed and compared between adherent and non-adherent patients using adjusted incidence rate ratios (aIRR). All-cause and disease-specific healthcare costs were computed using mean cost PPPM. Regression models adjusting for baseline characteristics were used to compare adherent and non-adherent patients. Results: A total of 728 eligible patients treated with ICT in the SCD cohort, 461 (63%) adherent, and 218 in the thalassemia cohort, 137 (63%) adherent, were included in this study. In SCD patients, the adjusted rate of all-cause outpatient visits PPPM was higher in adherent patients vs non-adherent patients (aIRR [95% CI]: 1.05 [1.01–1.08], pu2009<u20090.0001). Conversely, adherent patients incurred fewer all-cause inpatients visits (0.87 [0.81–0.94], pu2009<u20090.001) and ER visits (0.86 [0.78–0.93], pu2009<u20090.001). Similar trends were observed in SCD-related resource utilization rates and in thalassemia patients. Total all-cause costs were similar between adherent and non-adherent patients, but inpatient costs (adjusted cost differenceu2009=u2009−

Recent treatment guidelines for managing adult patients with sickle cell disease: challenges in access to care, social issues, and adherence

1530 PPPM, pu2009=u20090.0360) were lower in adherent patients. Conclusion: Patients adherent to ICT had less acute care need and lower inpatient costs than non-adherent patients, although they had more outpatient visits. Improved adherence may be linked to better disease monitoring and has the potential to avoid important downstream costs associated with acute care visits and reduce the financial burden on health programs and managed care plans treating SCD and thalassemia patients.