Loss of ALK hotspot mutations in relapsed neuroblastoma.

ALK is the most commonly mutated oncogene in neuroblastoma with increased mutation frequency reported at relapse. Here we report the loss of an ALK mutation in two patients at relapse and a paired neuroblastoma cell line at relapse. ALK detection methods including Sanger sequencing, targeted next-generation sequencing and a new ALK Agena MassARRAY technique were used to detect common hotspot ALK variants in tumors at diagnosis and relapse from two high-risk neuroblastoma patients. Copy number analysis including single nucleotide polymorphism array and array comparative genomic hybridization confirmed adequate tumor cell content in DNA used for mutation testing. Case 1 presented with an ALK F1174L mutation at diagnosis with a variant allele frequency (VAF) ranging between 23.5% and 28.5%, but the mutation was undetectable at relapse. Case 2 presented with an ALK R1257Q mutation at diagnosis (VAF = 39%-47.4%) which decreased to <0.01% at relapse. Segmental chromosomal aberrations were maintained between diagnosis and relapse confirming sufficient tumor cell content for mutation detection. The diagnostic SKNBE1n cell line harbors an ALK F1174S mutation, which was lost in the relapsed SKNBE2c cell line. To our knowledge, these are the first reported cases of loss of ALK mutations at relapse in neuroblastoma in the absence of ALK inhibitor therapy, reflecting intra-tumoral spatial and temporal heterogeneity. As ALK inhibitors are increasingly used in the treatment of refractory/relapsed neuroblastoma, our study highlights the importance of confirming whether an ALK mutation detected at diagnosis is still present in clones leading to relapse.

Calcific tendinitis of the rotator cuff: management options.

Calcific tendinitis of the rotator cuff tendons is a common cause of shoulder pain in adults and typically presents as activity-related shoulder pain. It is thought to be an active, cell-mediated process, although the exact pathophysiology remains unclear. Nonsurgical management continues to be the mainstay of treatment; most patients improve with modalities such as oral anti-inflammatory medication, physical therapy, and corticosteroid injections. Several options are available for patients who fail nonsurgical treatment, including extracorporeal shock wave therapy, ultrasound-guided needle lavage, and surgical débridement. These modalities alleviate pain by eliminating the calcific deposit, and several recent studies have demonstrated success with the use of these treatment options. Surgical management options include arthroscopic procedures to remove calcific deposits and subacromial decompression; however, the role of subacromial decompression and repair of rotator cuff defects created by removing these deposits remains controversial.

The phototoxic and photoallergy potential of clindamycin phosphate 1.2%/ tretinoin 0.025% gel for facial acne: results of two single-center, evaluator-blinded, randomized, vehicle-controlled phase 1 studies in healthy volunteers.

BACKGROUND: A fixed-dose combination of clindamycin phosphate 1.2% and tretinoin 0.025% gel (VELTIN® (clindamycin phosphate and tretinoin) 1.2%/0.025% Gel [VELTIN]) (clindamycin/tretinoin gel) is currently available for the once-daily topical treatment of acne. OBJECTIVES: Two-phase I studies were conducted to evaluate the phototoxic and photoallergic potential of clindamycin/tretinoin gel. METHODS: Study 1 (phototoxic) (n=37) and Study 2 (photoallergic) (n=58) were single-center, evaluator-blinded, randomized, vehicle-controlled, phase 1 studies conducted in healthy volunteers. In Study 1, clindamycin/tretinoin gel patches, vehicle gel patches and blank patches (no gel) were applied concurrently for 24 hours to naïve sites. After patch removal, sites were irradiated with 16 joules/cm2 of ultraviolet A light (UVA) then 0.75 minimal erythema dose (MED) of UVA/ultraviolet B light (UVB), the same irradiation protocol followed by 15 joules/cm2 of visible light (VIS), or served as non-irradiated controls. Study 2 examined the effect of repeated drug exposure and involved an induction period (6 repeat phases at the same body sites during which clindamycin/tretinoin gel and vehicle gel patches were applied for 24 hours, removed and sites irradiated with UVB +/- VIS), followed by a rest period (10 to 17 days), then a challenge period that used the protocol described for Study 1. In both studies, inflammatory responses and other cutaneous effects were evaluated at 1, 24, 48, and 72 hours after patch removal. RESULTS: No subject experienced any adverse events in Study 1 (phototoxic). One subject in Study 2 (photoallergic) experienced AEs (diffuse erythema; mild application site irritation at one each of UV/VIS-irradiated clindamycin/tretinoin gel and vehicle gel patch sites) considered definitely related to study product that resulted in discontinuation from the study. Data from Study 1 and the challenge phase from Study 2 showed most subjects had no visible inflammatory reaction to clindamycin/tretinoin gel after irradiation. CONCLUSIONS: Clindamycin/tretinoin gel has a favorable safety profile following UV/visible irradiation and a low potential for phototoxicity and photoallergenicity.

Practice patterns for arthroscopy of osteoarthritis of the knee in the United States.

BACKGROUND: Knee arthroscopy is one of the most common orthopaedic procedures performed in the United States. The publication of a randomized controlled trial of arthroscopy versus sham surgery by Moseley et al in 2002 showed no efficacy and challenged the role of arthroscopy for the treatment of osteoarthritis. HYPOTHESIS: (1) Knee arthroscopy for osteoarthritis has decreased after the publication of the study by Moseley et al, (2) arthroscopy as a percentage of orthopaedic cases has decreased, and (3) the average age of patients undergoing arthroscopy has decreased. STUDY DESIGN: Descriptive epidemiology study. METHODS: The authors examined the American Board of Orthopaedic Surgery (ABOS) database that includes 6-month case logs for each examinee sitting for the Part II board examination for 1999 to 2009. Knee arthroscopy cases were identified by CPT (Current Procedural Terminology) code and knee osteoarthritis diagnosis was defined by ICD-9 (International Classification of Diseases, 9th Revision) code. Piecewise linear regression was used to evaluate knee arthroscopy before and after the publication of the Moseley et al article in 2002. RESULTS: The number of knee arthroscopy cases for patients with osteoarthritis had greatly decreased by 2009 after peaking in 2001 (1621 vs 966 total cases, 2.36 vs 1.40 cases per surgeon). Cases classified as chondroplasty also decreased from 10.0% to 5.8% of knee arthroscopies (P < .0001). In addition, the total number of knee arthroscopy cases per surgeon decreased from a high of 11.9 in 2003 to a low of 8.6 in 2009. As expected, knee arthroscopy as a percentage of total orthopaedic cases decreased from a high of 9.9% in 2003 to 6.6% in 2009 (P < .0001). CONCLUSION: Knee arthroscopy for patients with osteoarthritis among orthopaedic surgeons during their ABOS examination case collection period has decreased after the publication of a highly publicized article demonstrating a lack of efficacy of this procedure. Further study is needed to determine if this change occurred in the orthopaedic community at large or if practice patterns only changed for surgeons during their board collection periods. CLINICAL RELEVANCE: Randomized controlled trials can be effective in changing orthopaedic surgeon practice.

Randomized tolerability analysis of clindamycin phosphate 1.2%-tretinoin 0.025% gel used with benzoyl peroxide wash 4% for acne vulgaris.

The multiple etiologic factors involved in acne vulgaris make the use of several medications necessary to treat the condition. Use of a fixed combination of clindamycin phosphate 1.2% and tretinoin 0.025% in conjunction with a benzoyl peroxide (BPO) wash 4% targets several pathologic factors simultaneously and mitigates the potential for clindamycin-induced Propionibacterium acnes-resistant strains. New formulations may allow such regimens to be effectively used without overly reduced tolerability resulting from the irritation potential of tretinoin and BPO. This randomized, single-blind study investigated the local tolerability, irritation potential, and safety of an aqueous-based gel (clindamycin phosphate 7.2%-tretinoin 0.025% [CT gel]) when used in conjunction with a BPO wash 4% in participants with mild to moderate acne vulgaris. Participants applied the CT gel once daily in the evening for 4 weeks in conjunction with once-daily morning use of either BPO wash 4% or nonmedicated soap-free cleanser lotion (SFC). Local tolerability and irritation potential were assessed by participants and investigators using separate 6-point scales. The frequency and severity of dryness, scaling, erythema, burning/stinging, and itching increased during the first week of treatment in both treatment arms but decreased thereafter. Local tolerability reactions were slightly more frequent in the CT gel + BPO wash group versus the CT gel + SFC group at week 1 but were generally mild and improved within 1 to 2 weeks. In conclusion, therapy with CT gel + BPO wash appears safe and well-tolerated in participants with mild to moderate acne vulgaris.

The dislocating hip arthroplasty: prevention and treatment.

The dislocating hip is functionally impairing and leads to patient dissatisfaction. The etiology is multifactorial and may include component malpositioning, soft tissue laxity, and component or anatomical impingement. Initial treatment of dislocation usually consists of closed reduction followed by the use of an abduction pillow or brace or a knee immobilizer, although evidence to support these actions is limited. Operative intervention is generally reserved for patients with more than 2 dislocations and should aim to correct the cause of dislocation using a simple algorithm. Proper component positioning is key to prevention of further dislocation, but other tools include modular implants, jumbo heads, and increased offset. Finally, constrained acetabular components may be considered if a patient fails one of the above surgical options.