Considerations for use of Fluorouracil cream 0.5% for the treatment of actinic keratosis in elderly patients

Actinic keratosis (AK), the initial lesion in a disease continuum that may progress to squamous cell carcinoma, often begins with ultraviolet B light-induced photo damage and increases in prevalence with age. Topical 5-fluorouracil (5-FU) for the treatment of widespread multiple AK lesions has cure rates of more than 90 percent. The associated skin irritation, however, may lead patients to prematurely discontinue treatment. To improve treatment efficacy and tolerability, 5-FU cream 0.5%, a novel Microsponge^®-based formulation, was developed. In the elderly population, 5-FU cream 0.5% may be preferable because of its convenient (once daily) administration and its lower potential for irritation and systemic absorption, which may impact adherence to therapy and, thus, possibly increase cure rates.Actinic keratoses (AKs), also called solar keratoses, occur more commonly in individuals with fair skin who have had extensive exposure to the sun.^1,2 The prevalence of AK lesions in adults increases with age: less than 10 percent for 20- to 29-year-olds, approximately 80 percent for 60- to 69-year-olds, and greater than 80 percent for 70-year-olds and older.^3,4 In the first five decades of life, the prevalence of AK lesions in men is almost twice that in women; however, after age 50, prevalence rates are similar between men and women.^3,4 A study using data from the National Ambulatory Medical Care Survey from 1990 to 1999 found that 47 million visits to physicians involved an AK diagnosis, and more than 80 percent of patients with AK diagnoses were at least 50 years old.⁵ AK was the second most frequent diagnosis made by dermatologists.⁵ Because surveys and studies typically include only patients seen in clinics or by physicians, the actual number of patients with AK is probably higher.⁶ The incidence of AK is higher in individuals living close to the equator, but is increasing in men and women in general.⁷ 8

Table 1

Risk factors for actinic keratoses⁸

Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program

OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).CONCLUSIONS— We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.The increasing incidence of diabetes continues to have a tremendous impact on diabetes-related morbidity and mortality around the world. Although much emphasis has been placed on the contribution of a Western lifestyle characterized by increasing caloric intake and physical inactivity to the diabetes epidemic, the role genetics plays in the development of diabetes is generally poorly understood. Additional insight into the contribution of genetic variants to diabetes incidence, gene-lifestyle interactions, and pharmacological response to antidiabetes medications is required to slow this tragic epidemic.The recent implementation of genome-wide association scans (GWASs) as an investigative tool has resulted in a qualitative leap in identifying diabetes-related genes (1,2). These surveys, which are agnostic to candidate genes, can cover ∼80% of common human genome variants with current technology, thus providing unprecedented insight into the genetic architecture of type 2 diabetes. In 2007, the first published type 2 diabetes GWAS confirmed the important impact of TCF7L2 on diabetes incidence (odds ratio [OR] 1.65, P < 1.0 × 10⁻⁷) and identified several new type 2 diabetes loci, SLC30A8 (1.26, P = 5.0 × 10⁻⁷), HHEX (1.21, P = 9.1 × 10⁻⁶), LOC38771 (1.14, P = 2.9 × 10⁻⁴), and EXT (1.26, P = 1.2 × 10⁻⁴) (3). SLC30A8 encodes a zinc transporter protein that carries zinc from the cytoplasm into insulin secretory vesicles within the pancreatic β-cell, an important step in insulin synthesis and secretion (4). HHEX is essential for the development of the pancreas and liver and is a target of the Wnt signaling pathway (5).After the initial GWAS publication, four other high-density scans were published simultaneously by different groups, confirming many of the initial findings. In addition to replicating the prior associations of TCF7L2, HHEX, and SCL30A8, investigators from Iceland identified CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1) as another potential diabetes-related gene (OR 1.2, P = 1.8 × 10⁻⁴) (6). This gene is hypothesized to lead to β-cell degeneration by modulating CDK5/CDK5R1 activity. The Diabetes Genetics Initiative, the Wellcome Trust Case Control Consortium, and the Finland–U.S. Investigation of Type 2 Diabetes Genetics concomitantly published GWASs that were combined in a preliminary meta-analysis of >30,000 samples (7–9). Again, the above findings were confirmed, and novel diabetes loci in or near IGF2BP2 (1.14, P = 8.9 × 10⁻¹⁶) and CDKN2A/B (1.2, P = 7.8 × 10⁻¹⁵) were identified. The EXT2 and LOC387761 gene regions have not been replicated in these or additional studies (10,11). Taken together, these studies support the potential power of GWASs in unraveling the genetic basis of type 2 diabetes.Several studies have attempted to characterize the physiological mechanisms affected by these genetic variants. Pascoe et al. (12) performed 75-g oral glucose tolerance tests (OGTTs) and hyperinsulinemic-euglycemic clamps on 1,276 healthy European subjects and demonstrated that common variants in CDKAL1 and HHEX are associated with decreased pancreatic β-cell function. Grarup et al. (13) reported that variants of HHEX, CDKN2A/B, and IFG2BP2 are associated with type 2 diabetes, and single nucleotide polymorphisms (SNPs) within the HHEX and CDKN2A/B loci impaired glucose-induced insulin release in healthy subjects, emphasizing the central role of pancreatic β-cell dysfunction in disease pathogenesis. Staiger et al. (14) found that the major alleles of the SLC30A8 and the HHEX SNPs associate with reduced insulin secretion stimulated by orally administered glucose but not with insulin resistance; the other reported type 2 diabetes SNPs within the EXT2 and LOC387761 loci did not associate with insulin resistance or β-cell dysfunction. Finally, a quantitative trait analysis of GWAS-identified type 2 diabetes susceptibility loci was recently completed by Palmer et al. (15) in their analysis of the Insulin Resistance Atherosclerosis Family Study (IRAS-FS). This study of 1,268 Hispanic and 581 African American subjects revealed that the increase in diabetes risk associated with variants in GWAS-identified gene regions, including CDKAL1, IGF2BP2, SLC30A8, and LOC387761, is mediated in part via defects primarily in insulin secretion. In Hispanic Americans, the acute insulinogenic response to glucose challenge decreased in high-risk genotype subjects at CDKAL1 (P = 0.005), and the disposition index was reduced in subjects with the high-risk genotype at IGF2BP2 (P = 0.01). Paradoxically, in Hispanic Americans, the previously identified risk allele of LOC387761 was significantly associated with an increased acute insulin response (P = 0.005) and disposition index (P = 0.036). IGF2BP2 rs4402960 was the only GWAS-identified SNP that associated with type 2 diabetes as a categorical trait (P = 0.02). Even fewer studies have attempted to analyze the influence of these genetic variants on response to pharmacological or behavioral interventions (16,17).The current study attempts to replicate and extend recent GWAS findings in the Diabetes Prevention Program (DPP) cohort. As a multiethnic, interventional study of >3,000 people at high risk for diabetes who have been carefully characterized, the DPP provides the opportunity to study insulin dynamics according to genotype and potential drug-genotype interactions. Studying pre-diabetic subjects as opposed to patients with overt diabetes provides insight into the role of genetic variation in the early stages of disease progression. As a longitudinal interventional study, the DPP provides the opportunity to carefully study the impact of genetic variation on insulin secretion and resistance over time. Finally, having multiple treatment arms allows for the identification of potential interactions of genotype with the results of the interventions. Studying gene-treatment interactions helps elucidate mechanisms of disease, identify specific treatments that may ameliorate the genetic predisposition to disease, and focus on subgroups that respond particularly well (or poorly) to specific therapies.     

Dupuytren��s contracture following burn injury of the hand: A case report and review of literature

In burn patients, scar contractures adjacent to or across the joints lead to disabling deformities. In Dupuytren’s disease, the proliferative process involves the fascia of the palm and fingers, resulting in disabling flexion contractures of the fingers and the palm. A single insult involving the hand or even a more proximal injury may lead to Dupuytren’s disease.     

Fiberoptic intubation through an I-gel supraglottic airway in two patients with predicted difficult airway and intellectual disability

We describe successful fiberoptic-guided tracheal intubation through the novel supraglottic "I-gel" airway in two uncooperative adult patients with genetic syndromes, learning disability, and predicted difficult airway, scheduled for complex dental treatment under general anesthesia. The I-gel maintained the airway immediately after induction, allowing oxygenation and ventilation. Location of the laryngeal inlet was successful on the first attempt with a fiberscope, and the tracheal tube was inserted into the trachea over the endoscope without complication in both patients. This report suggests another option for management of predicted difficult airways.     

Long-term outcome following stent reconstruction of the aortic bifurcation and the role of geometric determinants

We assessed the long-term patency of kissing stent reconstruction of the aortoiliac bifurcation and identified variables that may influence it. We retrospectively reviewed our experience with stent-reconstruction procedures of the aortoiliac bifurcation from January 1998 through June 2005. The impact of demographic variables, vascular risk factors, disease location and characteristics, stent material and design, and stenting configuration on stent patency was assessed using univariate and multivariate analysis. In particular, we evaluated the effect of geometric mismatch between the protruding segment of the stents and the distal aortic lumen. Sixty-six patients underwent aortobi-iliac stent reconstruction. Indications were bifurcation or bilateral proximal iliac disease in 52 patients and unilateral ostial disease requiring contralateral protection in 14 patients. Limited disease (TASC A and B) was present in 40 limbs in 19 patients; extensive/diffuse disease (TASC C and D) was present in 78 limbs in 47 patients. Complete occlusions were present in 37 limbs in 28 patients (bilateral in nine patients). Self-expanding stents were used in 56 procedures and balloon-expandable stents in 10. Crossing configuration was used in 43 procedures, while abutting configuration was used in 23 procedures. Technical success was achieved in 62 patients (94%), with all four failures due to inability to cross a chronically occluded limb. Three of these patients underwent aortomono-iliac stenting with a crossover femoral-femoral bypass graft, with the remaining one opting for no further interventions. Median combined follow-up was 37 +/- 27 months (range 0-102). Hemodynamically significant restenosis developed in nine patients (14%). The management of restenosis was endovascular in eight patients and was successful in all (balloon dilation in four, restenting in three, thrombolysis and stenting in one) and operative in one patient who developed aortic occlusion and underwent aortobifemoral grafting. Survival table analysis showed primary and assisted patency rates at 4 years of 81% and 94%, respectively. The mortality rate during follow-up was 19 (cardiac cause in eight, pulmonary cause in three, and malignancy in five). Univariate analysis showed radial mismatch (aortic lumen dead space around the protruding segment of the stents), female gender, prior occlusion, and residual stenosis to be significant predictors of restenosis. Multivariate logistic regression analysis showed radial mismatch to be the only significant determinant of restenosis, although the statistical power of the model was limited by the small number of restenoses. Stent reconstruction of the aortoiliac bifurcation for occlusive disease is effective and durable, even with complex aortoiliac disease and long segment occlusions. Most restenoses are amenable to endovascular treatment, with excellent long-term assisted patency. Geometric variables related to individual aortic anatomy and disease pattern (patient-dependent) and stenting configuration (operator-dependent) may have an impact on long-term patency.     

Evaluation of abduction range of motion and avoidance of inferior scapular impingement in a reverse shoulder model

The purpose of this study was to determine the effects of prosthetic design and surgical technique of reverse shoulder implants on total abduction range of motion and impingement on the inferior scapular neck. Custom implants in three glenosphere diameters (30, 36, and 42 mm), with 3 different centers of rotation offsets (0, +5, and +10 mm), were placed into a Sawbones scapula (Pacific Research Laboratories, Vashon, WA) in 3 different positions: superior, center, and inferior glenoid. Humeral sockets were manufactured with a 130 degrees , 150 degrees , and 170 degrees neck-shaft angle. Four independent factors (glenosphere diameter, center of rotation offset, glenosphere position on the glenoid, and humeral neck-shaft angle) were compared with the 2 dependent factors of range of motion and inferior scapular impingement. Center of rotation offset had the largest effect on range of motion, followed by glenosphere position. Neck-shaft angle had the largest effect on inferior scapular impingement, followed by glenosphere position. This information may be useful to the surgeon when deciding on the appropriate reverse implant.     

Is the utility of prostate‐specific antigen velocity for prostate cancer detection affected by age?

OBJECTIVE

To determine whether prostate‐specific antigen velocity (PSAV) is useful for prostate cancer detection in men from different age groups, and whether the same PSAV thresholds can reasonably be applied to all men aged ≥40 years.

PATIENTS AND METHODS

From a large prostate cancer screening study, 13 615 men had data on age and a calculable PSAV. We used statistical analysis to examine the ability of PSAV to predict prostate cancer risk in each age decade.

RESULTS

For men of all ages, the median PSAV was 0.6–0.7 ng/mL/year in men with prostate cancer, and 0–0.1 ng/mL/year in men with no prostate cancer (P < 0.005 for all). On receiver operating characteristic (ROC) analysis, the area under the curve was 0.800, 0.697, 0.693, and 0.668 for predicting prostate cancer risk using PSAV for men aged 40–49, 50–59, 60–69 and ≥70 years, respectively. In the multivariate model controlling for race, family history, and the total PSA level, both PSA and PSAV were significant independent predictors of prostate cancer risk in men of all ages.

CONCLUSIONS

The PSAV is significantly higher in men of all ages with prostate cancer compared with men with no prostate cancer; although on ROC analysis it performed the best in young men. Interestingly, the median PSAV in men with prostate cancer was <0.75 ng/mL/year regardless of age, suggesting that this threshold may be too high. Overall, this data confirms that PSAV is a useful tool for prostate cancer detection for men aged ≥40 years.     

The relationship between greater tuberosity osteopenia and the chronicity of rotator cuff tears

This study investigated whether a relationship exists between greater tuberosity osteopenia and chronicity of rotator cuff tears. In a retrospective study, anteroposterior radiographs of 28 shoulders in 27 patients who had undergone surgical repair for rotator cuff tears were reviewed. Greater tuberosity osteopenia scores were created using National Institutes of Health digital image software. There was no significant difference in the mean age between patients with minimal to mild rotator cuff tear retraction (63.1 +/- 6.14 years) and patients with moderate to severe rotator cuff tear retraction (63.4 +/- 9.76 years; P = .77). Of the 13 patients with minimal to mild rotator cuff tear retraction, 10 (77%) were women and 3 (23%) were men. Of 14 patients (50%) with moderate to severe rotator cuff tear retraction, 7 were men and 7 were women. The mean greater tuberosity osteopenia score in the 15 patients with moderate to severe retraction (0.48 +/- 0.095) was significantly less than the greater tuberosity osteopenia score in the 13 patients with minimal to mild retraction (0.58 +/- 0.135; P < .05). Furthermore, the mean greater tuberosity osteopenia score in 6 patients with chronic retracted rotator cuff tears (0.48 +/- 0.125) was significantly less than in the 6 patients with acute minimally retracted tears (0.64 +/- 0.119, P < .05). There were significantly greater osteopenic changes in the greater tuberosity in patients with chronic retracted rotator cuff tears. The greater tuberosity osteopenia may affect anchor pullout strength and the healing biology that influences overall rotator cuff repair healing rates.